Probiotics and Health: A Review of The Evidence: E. Weichselbaum

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Probiotics and health: a review of the evidence

E. Weichselbaum
British Nutrition Foundation, London, UK
Summary
Probiotics are live microorganisms mainly bacteria which when administered in adequate amounts confer a health benet on the host. There is rising interest in this area, but reports in the media are often conicting. The aim of this review is to consider the current evidence on the effects of probiotics on health, focusing on gut-related health issues and the immune system, with the objective to provide a clearer picture of whether and how probiotics can be benecial for health. The outcomes of this review are based on more than 100 original studies, meta-analyses and systematic reviews. A variety of different strains have been used in studies on probiotics, and it is important to remember that the effectiveness of probiotics is strain-specic, which means that each single probiotic strain has to be tested to assess its potential health benets. Overall, despite the diversity of strains used in the studies included in this review, there is evidence that probiotics have the potential to be benecial for our health. Studies in patients with inammatory bowel disease show probiotic strains to be able to decrease the recurrence of ulcerative colitis and occurrence and recurrence of pouchitis, however, current evidence suggests that probiotics are ineffective in treating patients with Crohns disease. Patients with irritable bowel syndrome show a reduction in symptoms when treated with selected probiotic strains, but high placebo effects have been reported as well. The evidence of the efcacy of probiotics in patients suffering from constipation is limited, but the evidence seems promising for some strains to bring relief to patients suffering from constipation. There is good evidence that a number of probiotic strains are effective in preventing antibiotic-associated diarrhoea. The most commonly studied strains are Lactobacillus rhamnosus GG (LGG) and Saccharomyces boulardii, but other strains and mixtures of strains seem to be effective as well. There is also promising evidence of a preventive effect of probiotics in Clostridium difcile-associated diarrhoea, although some studies have been too small to obtain statistically signicant ndings. The effect of probiotics in acute diarrhoea, particularly in children, is well studied. Selected probiotic strains seem to be effective in reducing the duration of acute diarrhoea. LGG and S. boulardii are again the most commonly used strains and a number of studies have shown them to be effective, although one metaanalysis showed that the effect of LGG was only signicant in children in Western countries, not in children in developing countries, which may be due to different causes of diarrhoea in these regions. Studies investigating the preventive effect of probiotics in the context of common cold and u infections show that the studied strains failed to lower the incidence of episodes but that they have the potential to decrease the duration of episodes, which suggests that the immune system may be
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2009 The Author Journal compilation 2009 British Nutrition Foundation Nutrition Bulletin, 34, 340373
Probiotics and health
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more efcient in ghting off common cold and u infections after consuming these strains. The evidence so far does not suggest that probiotics are effective in preventing or treating allergies or in treating eczema. However, some probiotic strains seem to lower the risk of developing eczema if taken by pregnant women and their infants in early life.
Keywords: gut health, gut ora, live bacteria, probiotics
Introduction
The Food and Agriculture Organization of the United Nations and the World Health Organization have dened probiotics as live microorganisms which when administered in adequate amounts confer a health benet on the host (FAO/WHO 2002). To be recognised as a probiotic, it is necessary to know the genus and species of a specic probiotic strain. Strain identity is important in order to link a strain to a specic health effect and to enable accurate surveillance and epidemiological studies (FAO/WHO 2002). It has been suggested that dead bacteria, products derived from bacteria or end products of bacterial growth may also impart some health benets, but these are not considered to be probiotics because they are not alive when administered (Sanders et al. 2007). The term probiotics embraces a large range of microorganisms, mainly bacteria but also yeasts. Each species covers various strains with varied benets for health. Studies have shown that the effects of probiotics are strain-specic (Luyer et al. 2005; Canani et al. 2007; Kekkonen et al. 2008) and it may be misleading to talk about health properties of probiotics in general, as some strains may provide a certain health benet whereas others do not. Therefore, it is important to study each strain separately for its efcacy in providing specic health benets. However, strains may share common health outcomes, such as reduction of diarrhoea or improved symptomology in irritable bowel syndrome (IBS). Orally ingested probiotics must survive harsh conditions during their passage through the intestinal tract to be able to inuence the human gut microora. Ingested strains do not become established members of the normal
intestinal ora but generally persist only for the period of consumption and for a relatively short period thereafter (Corthsy et al. 2007). Probiotics are usually administered orally and are available in various forms, including food products (e.g. dairy food), capsules, sachets or tablets. The choice of the format of probiotics has much to do with personal preference, product availability or individual needs (Sanders et al. 2007). An advantage of food sources of probiotics, such as dairy products, is that they may additionally provide nutrients, such as calcium and protein. However, the shelf life of tablets, capsules and sachets is generally longer than that of dairy foods.
BOX 1: Abbreviations used in the text

L. B. S. E. St. P. C. H. LGG CFU IBD CD UC IBS AAD CDAD CDD ORT ssp N.S. n.a. WMD RCT RR Lactobacillus Bidobacterium Saccharomyces Escherichia Streptococcus Propionbacterium Clostridium Heloicobacter Lactobacillus rhamnosus GG Colony-forming units Inammatory bowel disease Crohns Disease Ulcerative Colitis Irritable bowel syndrome Antibiotic-associated diarrhoea Clostridium difcile-associated diarrhoea Clostridium difcile-associated disease Oral rehydration treatment Subspecies Not signicant Not available Weighed mean difference Randomised controlled trial Relative risk
Correspondence: Dr Elisabeth Weichselbaum, Nutrition Scientist, British Nutrition Foundation, High Holborn House, 52-54 High Holborn, London, WC1V 6RQ, UK. E-mail: e.weichselbaum@nutrition.org.uk
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E. Weichselbaum
There has been rising interest in the health benets of probiotics, which is reected in the large number of studies now published in this eld. The aim of this review is to consider the current evidence on the effects of probiotics on health, focusing on gut-related health issues and the immune system. This review covers a number of health outcomes, including antibiotic-associated diarrhoea (AAD) and Clostridium difcile-associated diarrhoea (CDAD), acute diarrhoea, inammatory bowel disease (IBD), IBS, constipation, immune function (common colds, u), allergies and eczema. The objective is to provide a clearer picture of whether and how probiotics can be benecial for our health.
Methodology
The literature was searched for meta-analyses, systematic reviews and intervention studies examining the effects of probiotics on the selected health outcomes in this review (AAD, CDAD, acute diarrhoea, IBS, IBD, constipation, immune system, allergies and eczema). The literature search was conducted using PubMed; only controlled clinical trials, meta-analyses and systematic reviews have been considered. If meta-analyses or systematic reviews on a health outcome were available, these were used as a basis for the review and their ndings updated with subsequent publications. If no meta-analysis or systematic review was available, original studies from the past 10 years (i.e. from 1999 onwards) were included. The search strategy used a combination of Medical Subject Heading (MeSH) terms and free text terms as follows: probiotic*, Lactobacillus[MeSH], Bidobacterium[MeSH], Bacillus subtilis, Bacillus mesentericus, Clostridium butyricum, Lactococcus lactis, Leuconostoc mesenteroides, Pediococcus pentosaceus, Propionibacterium freudenreichii, Saccharomyces boulardii, Saccharomyces cerevisiae var boulardii, Streptococcus faecalis, Streptococcus thermophilus, inammatory bowel disease[MeSH], inammatory bowel disease, ulcerative colitis, Crohns disease, pouchitis, surgically created structures[MeSH], irritable bowel syndrome[MeSH], irritable bowel syndrome, diarrhea[MeSH], diarrhea, diarrhoea, penicillins[MeSH], antibacterial agents[MeSH], Clostridium difcile[MeSH], Clostridium difcile, constipation[MeSH], constipation, inuenza human[MeSH], common colds[MeSH], common cold*, u, chest infection, respiratory infection, rhinitis, immune system[MeSH], allergy and immunology[MeSH], allergy, allergies, atopic disease, sensitivity, eczema, dermatitis atopic[MeSH].
Searches were limited to title/abstract, human studies, clinical trials, randomised controlled trials, controlled clinical trials and meta-analyses. The studies identied by the search strategy were ltered for relevant articles. Abstracts were scanned to determine whether a study was examining effects on one of the included health outcomes. Full papers of potentially relevant studies were retrieved and read in detail. Studies with poor quality were excluded, for example those that lacked important information, such as compliance, study period, method of randomisation, or those with incomplete reporting of results. Other exclusion criteria were: probiotic strains used not specied, use of probiotics in combination with prebiotics (synbiotics), results already presented in other publications included in this review, signicant difference in outcome measure at baseline, no live bacteria (i.e. killed probiotic strain, which technically is not a probiotic) or outcome measures not relevant. One study (Shen et al. 2005) was excluded due to a high drop-out rate (probably due to the high costs incurred by study participants who had to purchase the probiotic preparation themselves). Studies using synbiotics were excluded to avoid false reporting of effects of probiotics that may be attributable to the use of prebiotics. No restrictions on the type of study participants were imposed and the search strategy was not limited by language. Results from meta-analyses, systematic reviews and randomised, blinded, placebo-controlled trials are presented separately as these outcomes are considered more robust than trials that are not blinded/placebocontrolled. Only data from meta-analyses, systematic reviews and randomised, blinded, placebo-controlled studies are presented in the tables. Where sufcient data on the effect of specic strains on a certain health outcome are available, the results are presented separately. If important information was missing or unclear (e.g. bacterial strains used, results), authors were contacted for clarication.
Results
The literature search yielded 448 original studies and 30 meta-analyses and systematic reviews. These studies were screened, and 179 original studies and 27 metaanalyses and systematic reviews were selected for detailed screening. Following detailed screening, full papers of 128 original studies and 21 meta-analyses and systematic reviews were retrieved. Eighty-six original studies and 15 meta-analyses and systematic reviews were included in the review.
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Inammatory bowel disease (IBD)

The term inammatory bowel disease (IBD) is an umbrella term comprising different conditions of the gut, of which the two main types are ulcerative colitis (UC) and Crohns disease (CD). UC is limited to the colon and is characterised by diffuse mucosal inammation. UC can affect parts of the colon or the whole colon; it is divided into distal and more extensive disease. In the distal form of the disease inammation is conned to the rectum (proctitis) or rectum and sigmoid colon (proctosigmoiditis). The more extensive disease also affects parts of the colon beyond the two lower parts of the gut. CD is not limited to the colon but may affect any part of the gastrointestinal tract, most commonly the lower small intestine. It is characterised by patchy, transmural inammation. CD can be dened by location (terminal ileal, colonic, ileocolic, upper gastrointestinal) or by pattern of disease (inammatory, stulating or stricturing) (Carter et al. 2004). There is evidence that bacteria and bacterial components may play a role in aggravating IBD (Seksik et al. 2006). Up to 240 000 people are affected by IBD in the UK. Typically, young people are affected by UC and CD with a peak incidence at the age of 1040 years. The incidence of UC is estimated to be 1020 per 100 000 with a reported prevalence of 100200 per 100 000. Incidence and prevalence of CD are lower compared to UC; the incidence is estimated to be around 510 per 100 000 with a reported prevalence of 50100 per 100 000 (Carter et al. 2004).
Other studies In a small randomised controlled trial the effect of Saccharomyces boulardii in addition to standard treatment (mesalizine) was tested in patients with CD who were in remission at study entry. After 6 months of treatment, 6 of 16 patients receiving standard treatment relapsed, whereas only 1 of 16 patients also receiving S. boulardii relapsed (P = 0.04) (Guslandi et al. 2000). An unblinded study by Lorea Baroja et al. (2007) examined whether a yogurt supplement with two probiotic strains, L. rhamnosus GR-1 [1 103 colony-forming units (CFU)] and L. reuteri RC-14 (2 107 CFU) once daily may promote anti-inammatory immunological milieu in subjects with active chronic inammatory conditions (CD and UC). In this study, the examined strains showed an immunosuppressive capacity. More studies are needed to conrm these ndings. None of the studies reported safety concerns or side effects from the use of probiotics in CD patients.
Summary Crohns disease Most probiotic strains studied so far were not effective in maintaining or achieving remission in patients suffering from CD, both pre- and post-operatively. Only S. boulardii in combination with standard treatment in a small, unblinded study was effective in decreasing the relapse rate compared to standard treatment only. These ndings need to be conrmed by larger, randomised, blinded, placebo-controlled studies.
Ulcerative colitis (UC) Crohns disease (CD)

Randomised, blinded, placebo-controlled trials Randomised, blinded, placebo-controlled trials A limited number of randomised, blinded, placebocontrolled studies on probiotics and CD are available (see Table 1). Three randomised, double-blind, placebocontrolled studies examined the efcacy of probiotics in preventing recurrence of CD after surgery in patients older than 18 years. Two studies used Lactobacillus johnsonii LA1 (Marteau et al. 2006; Van Gossum et al. 2007) and one used the strain L. rhamnosus GG (LGG) (Prantera et al. 2002). In all three studies, there was no signicant difference in recurrence rate between the intervention and placebo group, although one study showed a slightly lower but non-signicant recurrence rate in those treated with LA1 (Marteau et al. 2006). A limited number of randomised, blinded, placebocontrolled studies on the effects of probiotics on UC were available (see Table 1). Two study groups studied the efcacy of Escherichia coli Nissle (EcN) in maintaining remission in patients with UC (Rembacken et al. 1999; Kruis et al. 2004). In both studies the probiotic was compared to the gold standard for treating UC in remission, mesalazine (often also referred to as 5-aminosalicylic acid). During 12 months of treatment there was no signicant difference in the relapse rate between patients treated with the gold standard treatment, mesalazine and patients treated with EcN. Thus, in these two studies EcN was as effective as the gold standard treatment of UC in maintaining remission. Rembacken et al. (1999) also examined the efcacy of
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Table 1 Effects of probiotics on inammatory bowel disease

N analysed (n randomised) Study population Probiotic Control Study medication Duration of treatment Outcome Primary study outcome/endpoint
E. Weichselbaum
Author (year)
Study type
28 (34)
27 (36)
L. johnsonii LA1 (1010 CFU/ day), or placebo 12 weeks Endoscopic recurrence 6 months 12 months
43 (48) 18 (23) 19 (22)
Crohns disease (CD)/original studies Van Gossum et al. MC RDB PC II 1865 years; curative (2007) ileo-caecal resection for CD; Marteau et al. (2006) MC RDB PC II >18 years; recent surgical resection CD; Prantera et al. (2002) SC RDB PC II >18 years; scheduled for curative resection for CD 47 (50) L. johnsonii LA1 (4 109 CFU/ day), or placebo LGG (1.2 1010 CFU/day), or placebo Endoscopic recurrence at 6 months Endoscopic recurrence at 12 months+ reduction in the severity of recurrent lesions Relapse of UC
No sign. difference in recurrence or severe recurrence (P = 0.33) No sign. difference in recurrence (P = 0.15) No sign. difference in recurrence or severe recurrence (P = 0.297 and P = 0.313)
Ulcerative colitis (UC)/original studies Kruis et al. (2004) MC RDB C II 1870 years; UC in remission 110 (162) 112 (165) 12 months
SC RDB C II Active mild to moderate UC (no age range); 10 (10) 9 (10)
1880 years; UC in remission
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12 months 12 weeks
Rembacken et al. (1999) Kato et al. (2004)
Relapse of UC Clinical improvement (fall in CAI score 3 = response) at 12 weeks 9 months Relapse within 9 months 12 months Relapse after 12 months 12 months
MC RSB C II
E. coli Nissle 1917 (550 109 viable bacteria/ day), or mesalazine E. coli Nissle (5 1010 bacteria/day), or mesalazine B. breve Yakult, B. bidum Yakult, L. acidophilus (1010 CFU/day), or placebo, plus SASP or 5-ASA
Sign. equivalence (PP: P = 0.003, ITT: P = 0.013) Sign. equivalence (P = 0.006) 70% (prob.) vs. 33% responders (P = n.a.); sign. difference in average CAI score (P < 0.05)
Pouchitis/original studies Gionchetti et al. SC RDB PC II (2000) 1865 years; chronic relapsing pouchitis in remission Previous pouchitis (no age range given); in remission 20 (20) 20 (20) 16 (16) 20 (20) 20 (20)
Mimura et al. (2004)
SC RDB PC II
Gionchetti et al. (2003) 10 (11)
SC RDB PC II
20 (20)
VSL#3 (1.8 1012 viable lyophilised bacteria/day), or placebo VSL#3 (3.6 1012 viable lyophilised bacteria/day), or placebo VSL#3 (1.8 1012 bacteria/ day), or placebo 10 (11) LGG (24 1010 CFU/day), or placebo
Kuisma et al. (2003)
SC RDB PC II
1865 years; ileostomy closure after surgery for UC 2370 years; restorative surgery for UC;
3 months
Occurrence of pouchitis during rst year after closure Post-treatment PDAI
Sign. lower relapse in prob. group (15% vs. 100%, P < 0.001) Sign. higher remission rate in prob. group (85% vs. 6%, P < 0.0001) Sign. lower occ. of pouchitis in prob. group (10% vs. 40%, P < 0.05) No sign. difference (P = 0.97)
5-ASA, mesalazine; CAI, clinical activity index; CFU, colony-forming units; Ctrl, control; ITT, intention-to-treat analysis; LGG, L. rhamnosus GG; MC, multi centre; n.a., not available; PDAI, pouchitis disease activity index; PP, per protocol analysis; prob., probiotic; RDB PC II, randomised, double-blind placebo controlled trial (parallel design); SASP, salazosulphapyridine; SC, single centre; sign., signicant.
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EcN compared to mesalazine in treating patients with clinically active colitis. Within the rst 12 weeks of the study, 75% in the mesalazine group and 68% in the probiotics group achieved remission. In these patients the mean duration of remission was signicantly longer in the E. coli group (221 days) compared to the mesalazine group (206 days, P = 0.0174); however, the clinical signicance of this difference is equivocal. Another randomised, blinded, placebo-controlled study examined the efcacy of probiotics in treatment of active UC. The study drug was a combination of different probiotic strains (Bidobacterium breve strain Yakult, B. bidum strain Yakult and L. acidophilus) and was given over a period of 12 weeks. The response rate, dened as a decrease in the clinical activity index (CAI) score of at least three points (overall score maximum 21 = highest activity), was higher in the probiotic group (70%) compared to the placebo group (33%), although statistical signicance was not achieved, probably due to the small number of subjects (n = 19). The number of patients achieving remission did not seem to differ signicantly between the probiotics and placebo group (40% and 33%, respectively). The average CAI score in the probiotics group was signicantly lower at week 12 compared to the placebo group (3.7 0.4 and 5.7 0.7, respectively; P < 0.05) (Kato et al. 2004).
Venturi et al. (1999) studied the efcacy of VSL#31, a probiotic preparation containing eight different bacterial strains, on maintaining remission in UC patients allergic to mesalazine. After 12 months, 15 of 20 patients (75%) were still in remission. In one unblinded study the efcacy of probiotics in treating active UC was examined. Two different standard treatments (balsalazide 4.5 g daily) and mesalazine 2.4 g daily) of UC were compared with VSL#3 (9 1011 viable lyophilised bacteria daily) in combination with balsalazide (2.25 g daily). In this study, balsalazide plus VSL#3 was signicantly superior to mesalazine alone in obtaining remission (80% and 53%, respectively) within 8 weeks of treatment, but it did not seem to signicantly differ from balsalazide alone (70%, P value not given). Balsalazide plus VSL#3 was faster (4 days) in achieving remission than balsalazide alone (7.5 days) or mesalazine (13 days) (Tursi et al. 2004).
Summary Ulcerative colitis Although only a limited number of randomised, blinded, placebo-controlled trials investigating the efcacy of probiotics in UC are available, the results so far seem to be promising. EcN, but also other probiotic strains, seem to be as effective as standard treatments in maintaining remission, and may increase treatment success in standard treatment of active UC.
Other studies An unblinded study by Henker et al. (2008) supported the ndings of Rembacken et al. (1999) and Kruis et al. (2004) and showed that EcN (5 1010 viable bacteria daily) was as effective as mesalazine in maintaining remission in children and adolescents (1118 years) suffering from UC. Another unblinded study compared LGG (18 109 viable bacteria daily) with mesalazine, and mesalazine plus LGG. After 12 months of medication, there was no signicant difference in relapse rate between the study groups (Zocco et al. 2006). One small unblinded study showed that patients having daily fermented milk containing B. breve Yakult, B. bidum Yakult and L. acidophilus YIT 0168 (1010 CFU/day) in addition to standard treatment had a lower rate of exacerbation of UC compared to those on standard treatment only (27% and 90%, respectively). However, the study was small and exacerbation was measured on the basis of self-reported clinical symptoms (Ishikawa et al. 2002).
Pouchitis
Around 2530% of patients suffering from UC require surgery, where the colon is removed and replaced by an articial pouch, which is created from the lower part of the small intestines (Pardi & Sandborn 2006). It is estimated that up to 4060% of those who undergo ileal pouch surgery for UC suffer from pouchitis, which is an inammation of the ileal pouch and is the most common long-term complication in patients undergoing surgery for UC (Carter et al. 2004; Pardi & Sandborn 2006; Yu et al. 2007). The causes of pouchitis are not fully understood, but it is assumed that the microora in the pouch plays a role in the abnormal mucosal immune response (Pardi & Sandborn 2006; Yu et al. 2007).
VSL#3 contains 300 billion viable lypholised bacteria per gram of four strains of Lactobacilli (L. casei, L. plantarum, L. acidophilus, and L. delbrueckii ssp. bulgaricus), three strains of Bidobacteria (B. longum, B. breve, and B. infantis) and one strain of St. salivarius ssp. thermophilus.
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Randomised, blinded, placebo-controlled trials Only limited randomised, controlled trials on probiotics and pouchitis are available, but the evidence so far seems to be very promising (see Table 1). Two randomised, double-blind, placebo-controlled trials examined the efcacy of VSL#3 in the maintenance of remission in patients suffering from chronic relapsing pouchitis, and recurrent or refractory pouchitis (Gionchetti et al. 2000, Mimura et al. 2004). In both studies, signicantly fewer patients who were in remission at study entry after being treated with antibiotics relapsed during 12 months treatment with VSL#3 compared to those in the placebo group. In the study of Gionchetti et al. (2000), all patients receiving placebo (n = 20) relapsed within 4 months, whereas 85% (17/20) of those receiving the probiotic mix were still in remission after 9 months (P < 0.001). In the study of Mimura et al. (2004) 17 out of 20 (85%) patients in the probiotics group were still in remission after 12 months, whereas only one of 16 (6.3%) in the placebo group remained in remission (P < 0.0001). As a consequence, the quality of life signicantly deteriorated in the placebo group but showed a slight increase in the VSL#3 group. In another study, Gionchetti et al. (2003) examined the efcacy of VSL#3 compared with placebo in the prevention of onset of pouchitis during the rst year after restoration of the faecal stream. In this study, signicantly fewer patients developed pouchitis in the VSL#3 group (2/20, 10%) compared with the placebo group (8/20, 40%; P < 0.05). The median Pouchitis Disease Activity Index score (PDAI; 0 lowest activity, 18 highest activity) signicantly increased in the placebo group but did not signicantly increase in the VSL#3 group. One randomised, double-blind, placebo-controlled trial evaluated the clinical efcacy of L. rhamnosus GG (LGG) in treating pouchitis in patients undergoing surgery for UC. After 3 months, no differences were found in the mean pre- or post-treatment PDAI scores between LGG and placebo group. The authors concluded that, as primary therapy, LGG was not effective for the clinical improvement of pouchitis (Kuisma et al. 2003). Other studies One unblinded study showed that patients undergoing surgery for UC with no active disease or chronic pouchitis showed a slight but signicant reduction in PDAI score after 3 month of treatment with VSL#3, whereas those who did not receive treatment showed relatively stable PDAI scores (data not available; Pronio et al.
2008). In an uncontrolled study by Gionchetti et al. (2007), high doses of VSL#3 (36 1011 viable lyophilised bacteria per day) were successful in treating mild active pouchitis after 4 weeks of treatment, with complete remission in almost 70% of patients and signicantly improved PDAI scores after 4 weeks (median 4, range 211) and 6 months (median 3, range 24) compared to baseline (median 10, range 912; P < 0.001). In three uncontrolled studies the effect of treatment with a commercially available product (from Norway) containing L. acidophilus La-5 and B. lactis Bb-12 on inammation of the pelvic pouch was investigated. The probiotic product was not able to increase mucosal perfusion (Laake et al. 2003, 2004) reduced mucosal blood perfusion is suggested to be one of the possible explanations for the development of pouchitis (Armstrong et al. 1995; Sagar & Pemberton 1997) but decreased PDAI scores (Laake et al. 2004, 2005). Summary Pouchitis A probiotic product combining 8 bacterial strains (VSL#3) seems to be effective in maintaining remission in patients with chronic, reluctant or recurrent pouchitis and in delaying the onset of pouchitis in patients after surgery for UC. More studies are required to determine if single strains are effective in maintaining remission. VSL#3 and a combination of L. acidophilus La-5 and B. lactis Bb-12 had a positive effect on PDAI scores. One unblinded study with high doses of VSL#3 was successful in treating active mild pouchitis, whereas another study failed to show a treatment effect of LGG. Further studies are needed to determine whether probiotics can be used successfully in the treatment of active pouchitis. None of the studies reported any safety issues in using probiotics in patients who had surgery for UC.
Irritable bowel syndrome (IBS)

IBS is a chronic condition that is characterised by intermittent abdominal pain, altered bowel habits (diarrhoea and/or constipation) and other gastrointestinal symptoms including atulence and bloating in the absence of structural abnormalities in the intestine (Cremonini & Talley 2005). People with IBS commonly report incomplete evacuation/rectal hypersensitivity, as well as urgency, which is increased in diarrhoea-predominant IBS (NICE 2008). IBS clearly impacts on quality of life and it is estimated that around 325% of the general population suffer from the condition (Cremonini &
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Talley 2005). This relatively vague estimation could be explained by the fact that the assessment of IBS is in general based on self-reported symptoms. Physical measurements such as blood tests or colonoscopy are only used to exclude structural diseases, such as IBD or bowel cancer (NICE 2008). Among the most commonly used criteria based on self-reported symptoms are the Rome Criteria for IBS (Longstreth et al. 2006). The pathophysiology of IBS seems to be multifactorial (Cremonini & Talley 2005), with bacterial overgrowth in the small intestine in up to 78% of patients suffering from IBS (Pimentel et al. 2000; Lin 2004). Therefore, probiotics are thought to have the potential to alleviate symptoms of IBS, and their efcacy has been tested in several studies. As no curative treatment for IBS is available (Agrawal & Whorwell 2006), probiotics could be valuable in relieving IBS symptoms if found to be effective.
Meta-analyses and randomised, blinded, placebo-controlled trials

In a meta-analysis carried out by McFarland and Dublin (2008) the results of randomised, controlled, blinded trials in humans of all age groups were examined to determine the efcacy of probiotics for IBS. The strains used in the included studies were variable but two single strains were used in multiple studies (LGG in 3 and B. infantis in 2 studies). Compared to placebo, probiotics were found to signicantly reduce global IBS symptoms (abdominal discomfort, bloating and altered bowel habits), with a pooled relative risk (RR) of 0.77 [95% condence interval (CI), 0.620.94]. Weighting the studies by study quality showed similar results (RRpooled 0.65; 95% CI, 0.520.82), and even when one large study that appeared to heavily inuence the pooled RR was excluded, the protective effect remained signicant (RRpooled 0.82; 95% CI, 0.670.99). Compared to placebo, probiotics were also associated with a decreased risk of abdominal pain (RRpooled 0.78; 95% CI, 0.690.81). There was insufcient data to examine individual IBS symptoms or the efcacy of individual probiotic strains. The treatment periods varied between 2 and 24 weeks, most of the 20 studies having a treatment period of 4 to 8 weeks (85%) (McFarland & Dublin 2008). Another meta-analysis examining the effect of probiotic microorganisms on IBS conrmed the ndings by McFarland and Dublin (2008) and showed that the odds of clinical improvement were higher in patients taking probiotics compared to the control group [odds ratio (OR) 1.22; 95% CI,1.071.4] (Nikfar et al. 2008).
Four subsequent placebo-controlled, blinded and randomised studies have generated interesting results. Drouault-Holowacz et al. (2008) found an increase in patients with satisfactory relief of overall IBS symptoms and of abdominal discomfort/pain with time in those receiving a probiotic mix (B. longum LA 101, L. acidophilus LA 102, Lactococcus lactis LA 103, St. thermophilus LA 104), but also noted a similar effect in the placebo group (proportion of patients with satisfactory relief at week four was 42.6 and 42.3% in the probiotic and placebo group, respectively). The proportion of patients with satisfactory symptom relief at week four was not signicantly different in the two groups. Abdominal pain improved signicantly during the study in both treatment groups, independent of IBS category (constipation-predominant, diarrhoea-predominant or alternating). The difference between the rst week and the fourth week was signicantly higher in the probiotic treated patients (-41.9% 44.6 vs. -24.2% 51.1; P = 0.048). Overall, the number and consistency of stools were not signicantly different between the probiotic and placebo groups. In the group of subjects reporting constipation, the number of stools was signicantly higher in the probiotic treated group compared to the placebo group from the rst week of treatment (P = 0.043 at the end of rst week, P = 0.026 at end of second, and P = 0.049 at end of third week). The authors highlighted a large placebo effect (DrouaultHolowacz et al. 2008). Another study examining the effect of L. acidophilus strains SDC 2012 and 2013 on IBS symptoms found signicantly more responders in the probiotic group at week four compared to the placebo group (based on abdominal pain scores from 0 (good) to 10 (bad). There was a signicant improvement in the average score in the probiotic group (-1.5; 95% CI -2.0 to -0.9; P < 0.001), but not in the placebo group (-0.3; 95% CI, -0.9 to 0.2; P = 0.253). Further, signicant changes of the symptom scores from baseline for bowel habit satisfaction, straining at stool, and sense of incomplete evacuation were observed in the probiotics group, whilst only a sense of incomplete evacuation was improved from baseline in the placebo group (Sinn et al. 2008). A study by Kajander et al. (2008) found an effect on IBS symptoms of a mixture of probiotic strains (see Table 2) consumed as a milk drink. The decrease in IBS symptom score was signicantly more pronounced in the group receiving probiotics compared to the placebo group (P = 0.0083). At the end of the study, distension was also signicantly milder in the probiotic group (P = 0.023), and abdominal pain tended to be milder with probiotic use (P = 0.052) compared to the placebo.
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Table 2 Effects of probiotics on irritable bowel syndrome and constipation

N analysed (n randomised) Probiotic Control Study medication Duration of treatment Outcome Primary study outcome/ endpoint
E. Weichselbaum
Author (year)
Study type
Study population
Irritable bowel syndrome (IBS) Meta-analysis McFarland and Meta-analysis Dublin (2008) 1404 Improvement in global IBS symptoms Single strains (13 studies) and mixes of strains (eight studies) 52 (53) 4 weeks Satisfactory relief of IBS
All age groups; IBS; randomised, controlled, blinded trials
Pooled relative risk (severity): 0.77 (95% CI, 0.620.94), favours probiotics No sign. difference (P = n.a.)
Original studies Drouault-Holowacz et al. (2008) 48 (53)
MC RDB PC II
Adults with IBS (all forms); fullling Rome II criteria (no age range)
Sinn et al. (2008) 4 weeks
SC RDB PC II
1870 years; IBS, fullling Rome II criteria 43 43 5 months, 3 weeks follow-up
20
20
Improvement in abdominal discomfort/pain Weekly composite IBS symptom score
Kajander et al. (2008)
SC RDB PC II
2065 years; IBS, fullling Rome II criteria
Sign. more responders in prob. group (80% vs. 35%, P = 0.011) Sign. higher decrease in prob. group (14 vs. 3 points, P = 0.008)
Guyonnet et al. (2007) 135 (137) 132 (137)
MC RDB PC II
1865 years; IBS, fullling Rome II criteria; constipationpredominant type 18 Plac.: 9 43 41 MgO: 18 L. rhamnosus Lcr35 (8 108CFU/day), or traditional laxative MgO, or placebo LGG (2 109CFU/day), or placebo, plus lactulose L. casei Shirota (6.5 1010CFU/ day), or placebo
B. longum LA 101, L. acid. LA 102, Lactococcus, lactis LA 103, Streptococcus thermoph. LA 104 (1010CFU/day), or plac. L. acidophilus SDC 2012 and SDC 2013 2 109CFU/ml, 2 capsules, or placebo LGG, L. rhamnosus Lc705, P. freudenreichii ssp. shermanii JS and B. animalis ssp. lactis Bb12 (1.2 108 CFU/day each), or placebo B. animalis DN-173 010 (2.5 1010 CFU/day), or plac. 6 weeks Discomfort HRQoL dimension, week 3
No sign. difference (sign. change from baseline in both groups) 4 weeks Treatment success: 3 spontaneous defecations/ week +no faecal soiling in week 4 Sign. difference between all groups (treatment success: 77.8% (prob.), 72.2% (MgO), 11.1% (plac.), P = 0.01, prob. vs. MgO: P = 0.71) No sign. difference (P = 0.9)
Constipation/Original studies Bu et al. (2007) MC RDB PC II
Children <10 years; chronic constipation
SC RDB PC II
Children 216 years; constipation for 12 weeks 35 35
Banaszkiewicz and Szajewska (2005) Koebnick et al. (2003)
SC RDB PC II
1870 years; chronic idiopathic constipation
12 weeks, follow-up at 24 weeks 4 weeks, 1 week follow-up
Treatment success: 3 spontaneous defecations/ week + no faecal soiling Stool consistency & defecation Sign. difference, favours prob. frequency (P < 0.001 and P = 0.004)
L. rhamnosus GG (LGG) [3 (studies)], B. infantis 35624 (2), Saccharomyces boulardii (1), St. faecium 40371 (1), L. acidophilus (1), L. plantarum DSM9843 (2), L. plantarum 299v (1), L. reuteri 55730 (1), L. salivaricus UCC4331 (1). VSL#3 [2 (studies)], 29 soil strains and probiotics (1); LGG + L. rhamnosus LC705 + B. breve Bb99 + P. freudenreichii (1), B. subtilus + St. faecalis (1), Eschericia coli + St. faecalis (1), B. longum + L. acidophilus + Lactococcus lactis + St. thermophilus (1), L. paracasei + L. acidophilus + B. lactis (1). Score ranging from 0 (good) to 10 (bad), any reduction = response. abdominal pain + distension + atulence + rumbling; possible range: 0122. Measures impact of IBS on health-related quality of life (HRQoL), score 0 (worse) to 100 (best) CFU, colony-forming units; Ctrl, control; MC, multi centre; MgO, magnesium oxide n.a., not available; plac., placebo; prob., probiotic; RDB PC II, randomised, double-blind placebo controlled trial (parallel design); SC, single centre; sign., signicant; ssp., sub-species.
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No differences were found in the percentage of soft stools, hard stools or diarrhoea (Kajander et al. 2008). Another study examining the effect of B. animalis DN-173 010 showed no difference between the treatment and placebo group in improvement of the discomfort dimension of health related quality of life (HRQoL), which measures the impact of the whole range of IBS symptoms on HRQoL; both groups showed a signicant improvement at week 3 and week 6. The percentage of responders for the discomfort dimension was signicantly higher at week 3 in the probiotic compared to the placebo group. Also bloating and abdominal pain scores at weeks 3 and 6 signicantly improved in both groups; only the improvement in bloating score at week 3 was signicantly higher in the probiotic compared to the placebo group. The authors concluded that the high placebo response in the IBS patients may have been responsible for a lack of differences between the treatment and placebo groups (Guyonnet et al. 2007) (see Table 2).
Summary Irritable bowel syndrome

Current evidence shows promising results for the use of probiotics in the treatment of IBS. However, available studies use different bacterial strains and there is not enough evidence to make any rm conclusions about individual strains or dose. Furthermore, there seems to be a relatively high placebo response, which could be attributed to the fact that assessment of IBS mostly relies on subjective estimations of symptoms. Further studies, if possible with more objective end-points, are needed to determine whether the demonstrated benets of probiotics are attributable to a placebo effect or are genuine effects of the probiotic bacteria.
Constipation
Randomised, blinded, placebo-controlled trials
A study in children under 10 years of age with chronic constipation assessed the efcacy of L. casei rhamnosus Lcr35 as a treatment, by comparing its effects with a traditional laxative (magnesium oxide, MgO) and a placebo. After 4 weeks of treatment, those receiving either the MgO or the probiotic showed a higher defecation frequency (0.55 0.13 and 0.57 0.17 times/ day, respectively) compared to placebo (0.37 0.10 times/day; P = 0.03). Further, the MgO and probiotics groups also had less hard stools (23.5 7.9% and 22.4 14.7%, respectively) compared to the probiotics group (75.5 6.1%, P = 0.01). There was no signi-
cant difference between the two treatment groups. The percentage of patients with treatment success, dened as 3 spontaneous defecations per week with no episodes of faecal soiling in the fourth week, was higher in the MgO and probiotic groups (72.2% and 77.8%, respectively) compared to the placebo group (11.1%, P = 0.01). Again, there was no difference between the MgO and probiotic groups. Abdominal pain occurred less frequently in the probiotic group compared to the MgO and placebo groups (P = 0.03) (Bu et al. 2007). Another study carried out in children examining the effectiveness of LGG as an adjunct to lactulose in the treatment of constipation failed to nd an effect of this probiotic strain. The treatment success was similar in both the lactulose plus LGG and lactulose plus placebo group. There was also no signicant difference in secondary outcome measures, including the number of bowel movements per week, number of episodes of faecal soiling per week, stool consistency, and straining frequency per week (Banaszkiewicz & Szajewska 2005). A study in adults with chronic constipation showed that L. casei Shirota (LcS) was successful in improving gastrointestinal symptoms. In those receiving a probiotic drink once daily the occurrence of severe or moderately severe constipation decreased from 95% to 34% (P < 0.001), whereas no signicant change was reported for the control group receiving a drink that was identical to the probiotic drink but did not contain LcS. The effect became apparent from the second week (P = 0.001) and persisted to the end of the 4-week intervention. The occurrence of hard and lumpy stools in the treatment group was lower from the second week of intervention compared to baseline (P < 0.011). No changes were observed in the placebo group. During intervention, defecation frequency increased to six times per week in the treatment group compared to ve times per week in the control group (P = 0.001). The differences between the two groups were signicant from the second week onwards. Improvement in symptoms was reported by 94% of subjects in the treatment group and by 57% in the control group (P < 0.001). General selfreported well-being (assessment method not described) was signicantly improved in the treatment group compared with the placebo group (P = 0.008) (Koebnick et al. 2003) (see Table 2).
Other studies
One unblinded study examining the efcacy of bre-rich rye bread, LGG and a combination of both in treating self-reported constipation in women showed LGG in combination with bre-rich rye bread to be the most
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effective, followed by rye bread alone and then LGG alone. The difference between the two rye bread groups compared to the two non-rye bread groups in mean frequency of bowel movements and stool consistency was statistically signicant (both P < 0.001; Hongisto et al. 2006).
Summary Constipation
Studies examining the effects of probiotics on constipation are limited, and different strains have been used in those published to date. Although results are conicting, the evidence so far seems promising for selected strains (Lcr35, LcS). However, more studies will be needed to conrm these results.
Antibiotic-associated diarrhoea (AAD)

Diarrhoea is a common side effect of treatment with antibiotics, both long and short-term. The rates of AAD vary depending on type of antibiotic (McFarland 1998). About 1020% of all AAD cases are positive for toxigenic Clostridium difcile (Hgenauer et al. 1998). C. difcile-associated disease (CDD) can range from uncomplicated diarrhoea to sepsis and even death, and its incidence is increasing (Sunenshine & McDonald 2006).

A number of studies have been carried out to examine a potential preventive effect of probiotics on AAD (see Table 3). McFarland (2006) carried out a metaanalysis in which a total of 25 randomised controlled trials (RCTs) were included. The results of this analysis showed that S. boulardii and LGG were the most frequently studied strains (6 RCTs each) and were shown to be effective in reducing the occurrence of AAD in patients undergoing antibiotic treatment. The combined RR of developing AAD using S. boulardii compared to placebo/no treatment was 0.37 (95% CI 0.26, 0.52; P < 0.0001), and it was 0.31 (95% CI 0.13, 0.72; P = 0.006) for LGG. A further 6 studies examined other single strain probiotics; combining these studies did not show a signicant effect on AAD. However, as the effects of probiotics seem to be strain specic, more studies on each strain are needed to see if they are effective in reducing the risk of AAD. Mixtures of different probiotic strains were effective in reducing the risk of AAD; the combined RR of probiotic mixtures compared to placebo/no treatment was
0.51 (95% CI 0.38, 0.68; P < 0.0001) (McFarland 2006). Szajewska and Mrukowicz (2005) carried out a meta-analysis examining the effect of S. boulardii in the prevention of AAD, and found similar results as McFarland (2006). Data from 5 randomised controlled studies showed that S. boulardii reduced the risk of diarrhoea in patients treated with antibiotics from 17.2% to 6.7% (RR: 0.43; 95% CI 0.230.78). Three subsequent randomised, double-blind, placebocontrolled studies have conrmed the ndings of McFarland (2006). Hickson et al. (2007) found that L. casei DN-114 001 (2 1010 CFU/day) was signicantly more effective in reducing the occurrence of AAD compared to placebo. Beausoleil et al. (2007) found similar results for a probiotic mix containing L. acidophilus CL 1285 and L. casei (5 1010 CFU/day), and Wenus et al. (2008) for a probiotic mix containing LGG (2.5 1010 CFU/day), L. acidophilus La-5 (2.5 109 CFU/day) and B. lactis Bb-12 (2 1010 CFU/day). One additional randomised, double-blind, placebocontrolled trial showed that triple therapy for Heloicobacter pylori eradication (including two antibiotics) was better tolerated in combination with S. boulardii compared to placebo. Signicantly fewer patients of the S. boulardii group suffered from diarrhoea and epigastric discomfort compared to the placebo group (P = 0.02 and P = 0.01, respectively) (Cindoruk et al. 2007). A meta-analysis of probiotics in preventing AAD in children was published by Szajewska et al. (2006). Data from 6 RCTs were included in this meta-analysis, and a total RR analysis was made using these data. The RR of AAD when using probiotics compared to placebo/no treatment in combination with antibiotics was 0.44 (CI 95% 0.25, 0.77) (Szajewska et al. 2006). Only one randomised, blinded, controlled study has since been published investigating the effect of probiotics on AAD in children. Ruszczynski et al. (2008) examined the efcacy of a combination of three different L. rhamnosus strains (E/N, Oxy and Pen) in preventing any diarrhoea and AAD specically. Signicantly fewer patients in the probiotics group compared to the placebo group developed any diarrhoea (including diarrhoea caused by rotavirus, adenovirus and salmonella) in the course of antibiotic treatment. Although fewer children in the probiotic group developed AAD compared to the placebo group, these ndings were not statistically signicant (P = 0.08).
C. difcile
The number of studies examining the efcacy of probiotics in preventing CDAD/CDD is rather limited (see
Table 3 Effects of probiotics on antibiotic-associated diarrhoea and Clostridium difcile-associated disease

N analysed (n randomised) Probiotic Control Study medication Duration of treatment Primary study outcome/ endpoint Outcome
Author (year)
Study type
Study population
Antibiotic-associated diarrhoea (AAD)/Meta-analysis McFarland Meta-analysis All age groups (incl. infants (2006) and children (36%); treatment with antibiotics 1453 1357 S. boulardii [6 (randomised controlled trials)], LGG (6), other single strain and multi strain probiotics Relative risk of AAD (combined)
Sign. difference favouring prob. for S. boulardii (RR: 0.37, P < 0.0001), LGG (RR: 0.31, P = 0.006), and multi-strains (RR: 0.51, P < 0.0001); no sign. difference for single strains (RR:0.46, P = 0.06) Sign. lower incidence in prob. group (16% vs. 36%, P = 0.05)
AAD Adults/Original studies Beausoleil et al. SC RDB PC II (2007) 44 45 Antibiotic treatment +21 days follow-up Antibiotic treatment +1 week; 3 weeks follow-up 14 days 57 (69) 56 (66)
Hospitalised patients, 18 years; antibiotic treatment
Incidence of AAD
2009 The Author Journal compilation 2009 British Nutrition Foundation Nutrition Bulletin, 34, 340373 Incidence of AAD 34 (46) 29 (41) L. acidophilus CL1285 and L. casei (Bio-K + CL1285, 50 109 CFU/day), or plac. L. casei DN-114 001 2 1010 CFU/day), or placebo LGG (2.5 1010 CFU/day); L. acid. La-5 (2.5 109 CFU/ day); B. lactis Bb-12; (2.5 1010 CFU/day), or placebo S. boulardii: 2 daily (CFU/g not available) or placebo, plus H. pylori eradication treatment 2 weeks; 6 weeks follow-up Incidence of AAD Sign. lower incidence in prob. group (12% vs. 34%, P = 0.007) Sign. lower incidence in prob. group (6% vs. 28%, P = 0.035) 62 62 Occurrence of diarrh., nausea, epigastric discomfort, taste disturbance, urticaria, abdominal gas Sign. lower occurrence of diarrhoea in prob. group (15% vs. 31%, P = 0.02), and epigastric discomfort (15% vs. 44%, P = 0.01); no other sign. differences
Hickson et al. (2007)
MC RDB PC II
Inpatients; >50 years; antibiotic treatment
Wenus et al. (2008)
SC RDB PC II
Hospitalised patients, >18 years; antibiotics for 7 days;
AAD in Heloicobater pylori eradication/Original studies Cindoruk et al. RDB PC II 1876 years; H. pylori (2007) infection; 14 days of triple therapy
AAD Infants and children Meta-analysis Szajewska et al. Meta-analysis (2006) 376 390
Children (no age range); antibiotics treatment (out- or inpatient)
LGG [2 (studies)]; L. acid./B. infantis (1); L. acid./L. bulgaricus (1); B. lactis/ Streptococus thermophilus. (1); S. boulardii (1)
Incidence of AAD
Sign. difference in favour of prob.for B. lactis and St. thermophilus (RR 0.52, P = 0.044); lower RR for all other strains, but not signicant
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352
Table 3 Continued
N analysed (n randomised) Probiotic Control Study medication Duration of treatment Outcome Primary study outcome/ endpoint
E. Weichselbaum
Author (year)
Study type
Study population
Original studies Ruszczynski et al. (2008) 120 120 L. rhamnosus E/N + Oxy + Pen (4 109 CFU/day), or placebo Antibiotic treatment (330 days) Frequencies of any diarrhoea and AAD
MC RDB PC II
3 months to 14 years; at hospital for common infections; antibiotic treatment 28 days (antibiotic treatment: 10 days) Frequency of recurrence of CDAD
Sign. lower frequency of any diarrhoea in prob. group (7.5% vs. 16.7%, P = 0.03); no sign. difference in AAD
C. difcile/Original studies Surawicz et al. MC RDB PC II (2000) G1: 18 G2: 45 G2: 38 G1: 14
18100 years; occurrence of active diarrhoea; positive C. difcile assay; 1 recent, prior episode of CDD within 1 year
Sign. difference in CDAD recurrence between prob. and control group with high-dose vancomycin (17% vs. 50%, P = 0.05); no other sign. differences (P = n.a.)
Plummer et al. (2004) 12 (17) 9 (12) 38 days; 37 days follow-up
SC RDB PC II
G3: 27 69 20 days
G3: 26 69
Wullt et al. (2003)
MC RDB PC II
S. boulardii (1 g/day; CFU/g n.a.) or placebo G1: +high-dose vancomycin (2 g/day) G2: +low-dose vancomycin (500 mg/day) G3: +metronidazole (1 g/day) L. acidophilus and B. bicum (2 1010 CFU/day), or placebo L. plantarum 299v (5 1010 CFU/day), or placebo, plus metronidazole 2 400 mg (10 days)
Occurrence of diarrhoea No sign. differences (P = n.a.) and CDAD; stool positive for C. dif./toxins Clinical recurrence of No sign. difference (P = 0.370) CDAD until day 70
Hickson et al. (2007) 57 67
MC RDB PC II
Patients on antibiotic treatment (no age range); treatment 20 days; In- and outpatients >18 years; positive C. difcile toxin assay; ongoing diarrhoea; 1 prior CDAD within past 2 months See above S.a. S.a. See above See above
CDAD occurrence
McFarland et al. (1994)
MC RDB PC II
Adults (no age range); active CDD;
S. boulardii (3 1010 CFU/day), or placebo, plus antibiotic treatment
4 weeks or until recurrence of CDD
Recurrence of CDD
Sign. lower CDAD occurrence in prob. group (0 vs. 17%, P = 0.001) No sign. difference in recurrence in patients with initial CDD at baseline (P = 0.86); sign. lower recurrence in prob. group in patients with recurrent CDD at baseline (35% vs. 65%, P = 0.04)
B. clausii [1 (study)]; B. longum (1); C. butyricum (1); Escherichia faecium SF68 (2); L. acidophilus (1). L. acidophilus and L. bulgaricus (2); L. acidophilus and B. lactis (1); L. acidophilus and B. longum (1); B. lactis and Streptococcus thermophilus (1); L. sporogenes and fructo-oligosaccharide (1); L. acidophilus and B. infantis (1). Any diarrhoea includes AAD plus diarrhoea caused by rotavirus, adenovirus and salmonella. CDAD, C. dicile-associated diarrhoea; CDD, C. difcile-associated disease; CFU, colony-forming units; Ctrl, control; LGG, L. rhamnosus GG; MC, multi centre; n.a., not available; RDB PC II, randomised, double-blind placebo controlled trial (parallel design); plac., placebo; prob., probiotic; RR, relative risk; SC, single centre; sign., signicant.
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Table 3). Although some studies show a tendency for probiotics to decrease the risk of CDAD, in many of the studies the number of patients recruited is not sufcient to reach statistical signicance, but there are some studies that show signicant effects of probiotics on CDAD. Surawicz et al. (2000) showed that signicantly fewer patients had recurrent CDAD after being treated for CDAD with high-dose antibiotics in combination with S. boulardii. However, S. boulardii did not have a signicant effect in patients treated with lower doses of antibiotics. Hickson et al. (2007) showed that a probiotic yogurt containing L. casei DN-114 001, S. thermophilus and L. bulgaricus in hospitalised patients was able to signicantly decrease the risk of developing CDAD. None of the patients who had developed AAD in the probiotic group but 9/17 (52.9%) in the placebo group were C. difcile toxin positive. McFarland et al. (1994) found a signicant difference between S. boulardii and placebo, both in combination with antibiotics, in patients with recurrent CDD, but not acute CDD. Plummer et al. (2004) studied the effect of a mix of L. acidophilus and B. bidum on occurrence of diarrhoea and CDAD. The frequency of diarrhoea between patients receiving probiotics during antibiotic treatment for infections did not differ from that in the placebo group. However, although more patients in the probiotic group had C. difcile in the stool, fewer patients in the probiotic group developed CDAD compared with the placebo group. The authors concluded that toxin neutralisation rather than prevention of colonisation could be responsible for a preventive effect of probiotics on CDAD. Further studies are needed to conrm this conclusion.
rhoea caused by C. difcile (P < 0.0001). One study of S. boulardii in patients receiving chemotherapy showed that those treated with antibiotics in combination with the probiotic had signicantly fewer occurrences of AAD compared with the placebo group (P < 0.05). However, information on blinding or dose of probiotic was not available (Can et al. 2006). Two studies examined the effect of probiotics on H. pylori eradication in combination with triple therapy2. In one study, Bacillus subtilis and Str. faecium were given in combination with triple therapy. Patients receiving probiotics in combination with H. pylori eradication therapy were compared to patients receiving triple therapy only. Intention-to-treat analysis showed that H. pylori eradication was achieved in signicantly more patients receiving triple-plus-probiotic therapy. However, there was a signicantly higher drop-out rate in the control group, and per-protocol analysis did not nd a signicant difference in H. pylori eradication between the two groups (Park et al. 2007). Another small unblinded study using C. butyricum M588 in combination with triple therapy found a tendency towards better success in H. pylori eradication with this probiotic strain, but the study was too small to reach statistical signicance (Imase et al. 2008).
Summary Antibiotic-associated diarrhoea

S. boulardii and LGG are the most studied strains for preventing AAD, and both seem to be effective in lowering the risk of AAD. More recent studies used mixtures of probiotics, which also proved successful in lowering the risk of developing diarrhoea in the course of antibiotic treatment. Probiotic strains in these mixtures include L. rhamnosus, L. casei, L. acidophilus, L. bulgaricus and Bidobacterium Bb-12. Research on the use of probiotics in the prevention of AAD in children and infants looks promising. For some strains, more studies are needed to conrm their efcacy in preventing AAD. The use of probiotics to reduce the occurrence of CDAD has also been supported by other studies. However, many studies on CDAD have been too small to draw rm conclusions and more large scale studies will be needed to conrm current ndings.
Other studies
One study compared the effects of a probiotic yogurt containing St. thermophilus, L. acidophilus and B. animalis ssp. lactus with commercial yogurt or no yogurt. The patients in the yogurt groups were blinded to which yogurt they received. The rates of diarrhoea were not statistically different in the three arms (P = 0.20). In the probiotic group, fewer patients developed AAD compared to the commercial yogurt group; however, a separate analysis to compare these two yogurt groups only was not performed (Conway et al. 2007). An unblinded study by Stockenhuber et al. (2008) found that signicantly fewer patients developed AAD when consuming a probiotic drink containing L. casei Shirota (5%) compared to no probiotic drink (18.6%) in addition to antibiotic treatment in hospital patients (P < 0.001). In the same study, no one in the probiotic group and 21/338 (6%) of the control group had diar-
Acute diarrhoea
Acute diarrhoea can have several causes, including bacterial or viral infections, and is a common cause of
2 Standard therapy for Heloicobacter pylori eradication consisting of two antibiotics and a proton pump inhibitor.
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E. Weichselbaum
childhood morbidity and hospital admission, particularly in the rst 2 years of life (Guarino & Albano 2001). In developing countries acute diarrhoea is the leading cause of morbidity and mortality in children, and an important cause of malnutrition (WHO 2004). There are numerous studies examining the effects of probiotics on acute diarrhoea. A meta-analysis of 18 studies by Huang et al. (2002) showed that probiotics can signicantly reduce the duration of diarrhoea. The weighted mean difference (WMD) in diarrhoea duration was -0.8 days (95% CI -1.1 to -0.6, random effects) in patients taking probiotics compared with those not taking probiotics (see Table 4). A sufcient number of studies have been carried out to evaluate the effects of two specic strains (S. boulardii and LGG) on acute diarrhoea.
more severe conditions than the subjects included in this study (Canani et al. 2007) (see Table 4). Other studies An unblinded study in one hundred Myanmar children with acute watery diarrhoea aged 3 months to 10 years (most being 2 years or younger) showed that S. boulardii in combination with ORT signicantly reduced the duration of diarrhoea by 1.6 days (P < 0.05) compared to children receiving ORT only. The defecation frequency was less than 3 times on day 2 in signicantly more children in the S. boulardii group compared to the control group (54% and 30%, respectively; P = 0.019) (Htwe et al. 2008). In another unblinded study carried out in Pakistan in 100 children aged 2 months to 12 years suffering from acute watery diarrhoea, similar results were found. The mean duration of diarrhoea was 3.5 days in the S. boulardii group compared to 4.8 days in the control group receiving ORT only (P = 0.001) (Billoo et al. 2006).
Saccharomyces boulardii
Meta-analyses and randomised, blinded, placebo-controlled trials A meta-analysis by Szajewska et al. (2007a) showed a signicant reduction in the duration of acute diarrhoea in children aged 2 months to 12 years when receiving S. boulardii in combination with oral rehydration therapy (ORT). Based on four randomised controlled trials, the WMD was -1.1 days (95%CI, -1.3 to -0.83), which means that the duration of diarrhoea in children who received the probiotic preparation was on average about a day shorter compared to those receiving ORT only. In a double-blind, randomised, placebo-controlled trial, the effect of Lactobacillus strains and S. boulardii on persistent diarrhoea (diarrhoea for at least 14 consecutive days) was examined. The study showed that S. boulardii was effective in treating persistent diarrhoea. Within 5 days of treatment, only 17% of the S. boulardii group, but 90% of the placebo group still suffered from diarrhoea. In the placebo group most children continued to experience diarrhoea for up to 12 days. The average duration of diarrhoea differed signicantly between the treatment groups (S. boulardii 3.8 1.5 days, Lactobacillus 3.7 1.3 days) and the placebo group (8.5 4.2 days, P < 0.005) (Gaon et al. 2003). However, a further study in children aged 336 months with mild to moderate acute diarrhoea did not nd a signicant effect of S. boulardii on the duration or stool outputs of diarrhoea. The authors suggest that a reason for this unexpected treatment failure of S. boulardii could be that most other studies have been carried out in children admitted to hospitals, who would have
Lactobacillus rhamnosus GG (LGG)

Meta-analyses and randomised, blinded, placebo-controlled trials A meta-analysis by Szajewska et al. (2007b) concluded that L. casei ssp. rhamnosus GG (this is an old name for LGG) was successful in decreasing the duration of acute diarrhoea in children aged 1 to 36 months (WMD -1.1 days, 5% CI -1.9 to -0.3). Further analysis based on the setting of the various studies showed that the outcome was signicant for studies carried out in European countries (WMD -1.27 days, 95% CI -2.3 to -0.2), but not signicant for studies conducted in non-European countries (WMD -0.76 days, 95% CI -1.7 to 0.2), where infectious agents other than rotavirus are more often involved in the development of diarrhoea. Further sub-analyses showed that LGG was more efcient in reducing diarrhoea caused by rotavirus compared to other causes (Szajewska et al. 2007b). Four subsequent randomised, blinded, controlled studies showed conicting results. In the above mentioned study by Canani et al. (2007), carried out in Italian children with acute diarrhoea, LGG taken with oral rehydration therapy (ORT) was more effective in reducing the duration of diarrhoea than ORT only (-32 hour, 95% CI -47 to -23). In a study in Indian children suffering from persistent diarrhoea, LGG signicantly reduced the mean duration of diarrhoea and the stool frequency from day 4 onwards, but was not
Table 4 Effects of probiotics on acute diarrhoea

N analysed (n randomised) Probiotic Control Study medication Duration of treatment Outcome Primary study outcome/endpoint
Author (year)
Study type
Study population
Acute diarrhoea All strains/Meta-analysis Huang et al. Meta-analysis Children with acute diarrhoea (no (2002) age range); duration of diarrh. <1 week 1917 Duration of diarrhoea Single strains and mixes of strains
Sign. shorter duration of diarrh. in prob. groups (WMD -0.8 (95% CI 1.1 to 0.6), P < 0.001)
Acute (and persistent) diarrhoea S. boulardii Meta-analysis Szajewska et al. Meta-analysis Children 2 months to 12 years of (2007a) age; acute diarrhoea 473 (489) S. boulardii (5 RCTs) 56 days Duration of diarrhoea
Sign. shorter duration of diarrhoea in prob. groups (WMD 1.1 days (95% CI:1.3 to 0.83), P < 0.00001)
Original studies Canani et al. (2007) G2: 100 5 days G3: 91 G4: 100 G5: 97 G6: 91 G2: 30 G3: 30 G1: 29 G1: 92
Duration of diarrhoea G1: ORT; G2: +LGG (1.2 1010 CFU/day); G3: +S. boul. (1010); G4: +Bacillus clausii O/C84, N/R84, T84, SIN84 (2 109); G5: +Prob. mix, G6: +Enterococcus faecium SF68 (1.5 108); G2: S. boul. (3.5 1011CFU/day); G3: L. acidophilus CRL 730 and L. casei CRL 431 (3.5 10121014 CFU); G1: placebo; All +ORT 5 days Duration of diarrhoea Sign. lower duration in G2 and G5 vs. G1 (both P < 0.001, G2: 32 hours [(95% CI) -47 to 23], G5: -37 hours (47 to 25); no other sign. differences (G3: P = 0.38; G4: P = 0.76, G6: P = 0.61) Sign. lower duration in G2 and G3 vs. G1 (3.8 1.5 days and 3.7 1.3 days vs. 8.5 4.2 days, P < 0.005) 494 494 LGG (8 RCTs) n.a. Duration of diarrhoea Sign. shorter duration of diarrh. in prob. groups (WMD 1.1 days ([95% CI] 1.9 to 0.3) 7 days max; follow-up 4 weeks Duration of diarrhoea (and vomiting) 117 118 LGG (1.2 108 bact./day) plus ORT, or ORT only; 323 (330) 323 (332) LGG (1.2 108 bact./day) plus ORT, or ORT only; 7 days max; follow-up 4 weeks Duration of diarrhoea (and vomiting) Sign. shorter duration of diarrh. in prob. group (5.3 2.1 days vs. 9.2 2.8 days, P < 0.05); no sign. difference in duration of vomiting (P = n.a.) No sign. differences in duration of diarrh. and vomiting (P = n.a.)
MC RSB C II
Children 12 years; outpatients; diarrhoea lasting less than 48 hours before recruitment
Gaon et al. (2003)
SC RDB PC II
Children 624 months; outpatients; frequent loose stools (>3 per day) 14 days
Acute (and persistent) diarrhoea LGG Meta-analysis Szajewska et al. Meta-analysis Children 136 months; acute (2007b) diarrhoea; most trials exclusively in inpatients Original studies Basu et al. SC RDB CII Children (no age range); (2007a) diarrhoea 14 days
Basu et al. (2007b)
SC RDB CII
Children (no age range); acute watery diarrhoea
L. rhamnosus GG (LGG) [10 (study arms)], L. acidophilus (2), L. rhamnosus (2), L. reuteri (3), Enterococcus SF68 (1), S. boulardii (1), Bidobacterium subtilis (1). S. thermophilus + L. acidophilus + L. bulgaricus (1), L. rhamnosus + L. delbruckii + L. bulgaricus (1), L. bulgaricus + S. thermophilus + L. acidophilus + B. bidum (1), L. acidophilus + B. infantis (1), L. rhamnosus + L. reuteri (2). L. deslbrueckii ssp bulgaricus LMG-P17550 + L. acidophilus LMG-P 17549 + St. thermophilus LMG-P 17503 + B. bidum LMG-P 17500 (2 109, 2 109, 2 109, 109 CFU/day, respectively). CFU, colony-forming units; CI, condence interval; Ctrl, control; MC, multi centre; n.a., not available; ORT, oral rehydration treatment; plac., placebo; prob., probiotic; RDB PC II, randomised, double-blind placebo controlled trial (parallel design); RCT, randomised control trial;. SC, single centre; sign., signicant; WMD, weighed mean difference.
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able to reduce the duration of vomiting (Basu et al. 2007a). Another study by the same group of researchers in Indian children with acute watery diarrhoea failed to show an effect of LGG on the duration of diarrhoea and vomiting (Basu et al. 2007b) (see Table 4).
Lactobacillus strains other than LGG (details of these studies are not shown in the tables)
Meta-analyses, randomised, blinded, placebo-controlled trials A meta-analysis of randomised, blinded, controlled studies examining the effect of Lactobacillus strains (L. reuteri, L. acidophilus, L. bulgaricus and LGG) showed that these probiotic strains signicantly reduced diarrhoea duration in children by 0.7 days (95% CI, 0.31.2 days) compared to control subjects (Van Niel et al. 2002). A subsequent study examining the effect of the probiotic strain L. casei DN-114001 in Indian children with acute diarrhoea, recruited either from an Indian hospital (n = 75) or from a slum in the area (n = 75), showed that the probiotic was effective in decreasing the duration of diarrhoea. In this study, children were provided either with fermented milk containing L. casei DN-114001 (2 1010 bacteria/day, and the same amounts of L. bulgaricus and Str. thermophilus), Indian Dahi (yogurt containing Lactococcus lactis, Lactococcus lactis cremoris and Leuconostac mesenteroids cremoris), or ultra-heated milk. There was a signicant difference in the duration of acute diarrhoea between the three treatment groups, with the probiotic preparation being the most effective in both a hospital and a community setting (1.5 and 1.9 days duration, respectively), followed by Indian Dahi (1.8 and 2.2 days, respectively). The duration of diarrhoea in the ultraheated milk group was 2.1 and 2.4 days, respectively (Agarwal & Bhasin 2002). In another study in Bangladeshi male children aged 424 months, the probiotic strain L. paracasei ST11 could not signicantly reduce the duration of diarrhoea compared to placebo; neither could it signicantly increase the number of children that had been successfully treated after 5 days. Similar results were found in the sub-group of rotavirus-infected children. However, signicantly more children in the non-rotavirus group ceased to have diarrhoea within the 5 days of treatment (Sarker et al. 2005). In two studies carried out in Denmark, a combination of L. rhamnosus 19070-2 and L. reuteri DSM 12246 was given to 636month-old children suffering from acute diarrhoea for 5 days and compared to a placebo preparation, one of the
studies being carried out in children hospitalised (Rosenfeldt et al. 2002a) and the other in nonhospitalised children attending day-care centres (Rosenfeldt et al. 2002b). In the hospitalised group, the reduction in diarrhoea duration nearly reached signicance (P = 0.07) in the whole group, and was signicant in those who started treatment within 60 hours of the rst loose stool (early intervention). In the nonhospitalised group, the reduction was signicant in both the whole group and the early intervention group. In another study in Polish children with acute diarrhoea aged 2 months to 6 years (both in- and outpatients), a combination of three L. rhamnosus strains (573L/1, 573L/2, 573L/3) was tested in the treatment of diarrhoea and compared to placebo. Overall, no difference in the duration of diarrhoea was found between the study groups. However, in the rotaviruspositive children there was a signicant reduction in diarrhoea duration if the intervention was started early (within 72 hours); early intervention did not signicantly reduce diarrhoea duration in the whole study group (Szymanski et al. 2006). In the above mentioned study by Gaon et al. (2003; see S. boulardii and Table 4), a combination of L. acidophilus CRL 730 and L. casei CRL 431 signicantly reduced the duration of diarrhoea, as well as number of stools on day 5 of treatment in children with persistent diarrhoea (more than 14 days) compared with placebo; there was no signicant difference in efcacy between these Lactobacillus strains and S. boulardii.
Other strains (ndings of these studies are not shown in the tables)
Randomised, blinded, placebo-controlled trials A study examining the effect of different amounts of B. lactis Bb12 and St. thermophilus TH4 (108 CFU/g and 5 107 CFU/g, and 109 CFU/g and 5 108 CFU/g, respectively; total amount given per day not known) in children with severe acute diarrhoea (average age 13.1 0.5 months) failed to show a difference between either of the treatments and placebo in the duration of diarrhoea or number of stools per day (Mao et al. 2008). One study examined the effect of B. lactis Bb12 (BbF) on the prevention of acute diarrhoea in infants in child care centres throughout France. All infants were younger than 8 months at the beginning of the study. They received either fermented infant formula supplemented with viable BbF (at least 108 bidobacteria per day, plus St. thermophilus and L. helveticus) or a commercial, conventional, non-fermented formula. Fewer
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infants (28.3%) receiving BbF than those receiving the control formula (38.6%) experienced acute diarrhoeal disease during the study. The duration was shorter in the BbF group (5.1 3.3 days) than in the control group (7 5.5 days). However, both results were not signicant (Chouraqui et al. 2004). The reason for this is likely to be that the sample size was inadequate to demonstrate a statistically signicant difference. In the above-mentioned study by Canani et al. (2007; see S. boulardii, LGG and Table 4), Bacillus clausii and Enterococcus faecium SF 68 showed no effect on duration of diarrhoea in children with acute diarrhoea. A mix of L. delbrueckii ssp. bulgaricus, L. acidophilus, St. thermophilus and B. bidum signicantly reduced the duration of diarrhoea. Only one randomised, doubleblind, placebo-controlled study examined the effect of E. coli Nissle 1917 (EcN) on acute diarrhoea in infants and toddlers (outpatients). In an intention-to-treat analysis, the median time to respond to treatment was signicantly lower in the EcN group compared to placebo (2.5 days compared to 4.8 days). Further, within 10 days diarrhoea had stopped in 94.5% of the EcN group and in 67.2% of the placebo group. However, the drop-out rate in the placebo group was clearly higher compared to the EcN group (n = 13 and n = 1, respectively) (Henker et al. 2007). A study examining the efcacy of VSL#3 in treating acute diarrhoea in Indian children with acute diarrhoea caused by rotavirus infection showed that this multi-strain probiotic signicantly reduced stool frequency on days 2, 3 and 4. Signicantly more children in the probiotic group recovered after 4 days of treatment (89.4%) compared with the placebo group (39.6%) (Prakash Dubey et al. 2008). Travellers diarrhoea There are very few studies available on the efcacy of probiotics in preventing travellers diarrhoea. McFarland (2007) combined the available data in a metaanalysis. Although only seven studies with 12 probiotic treatments were available, the number of study participants was large (n = 4709) and the studies were not signicantly heterogeneous, which means their comparability was good. Of the 12 randomised, controlled treatments, six (50%) trials reported signicant prevention of travellers diarrhoea for the probiotic in their trial, one study found a trend for efcacy (P = 0.07), and ve other treatments did not show a signicant difference between probiotic and control groups. The RR of the 12 pooled treatments was 0.85 (95% CI 0.79 to 0.91, P < 0.001). S. boulardii was used in four treatments, and it signicantly reduced travellers diarrhoea.
Data on the probiotic LGG was conicting. In one study the risk of developing travellers diarrhoea was signicantly lower in the treatment group compared with the placebo group. In another study, there was no signicant difference. However, analysing the two destination cities in Turkey separately, tourists in the probiotic group going to one city for only one week had a signicantly reduced risk of developing travellers diarrhoea compared to the placebo group; this difference could not be observed after 2 weeks stay in the same city or 1 or 2 weeks stay in the other city. Also the efcacy of S. boulardii was more pronounced with some destinations. L. acidophilus was not able to decrease the risk of travellers diarrhoea (McFarland 2007). Summary Acute diarrhoea Probiotics appear to be effective in reducing the duration of diarrhoea (Huang et al. 2002). However, although the effects are considered to be strain specic, different strains have been used in the published studies. A number of studies have shown that S. boulardii is effective in reducing the duration of acute and persistent diarrhoea (although one study did not nd any effect). A metaanalysis of the efcacy of LGG on acute diarrhoea showed that this strain is effective in reducing duration of diarrhoea. However, a sub-analysis showed that the effect of LGG is only signicant in children of Western countries, where rotavirus is the main cause of acute diarrhoea, compared with children in developing countries. Subsequent studies seem to support these ndings, although one study has shown that LGG is effective in Indian children with persistent diarrhoea. The results of studies on other strains are conicting. Some studies have shown that some strains signicantly reduce diarrhoea duration, whereas others have not found any difference between probiotic and placebo. Interestingly, the effectiveness of probiotics seems to depend on duration of diarrhoea before starting treatment (being most effective if treatment is initiated early), and also seems to depend on the cause of the acute diarrhoea. However, more studies are needed to conrms these ndings. The majority of studies have been carried out in children who already suffer from diarrhoea, and there is a lack of studies examining a preventive effect of probiotics. One study using B. lactis B12 suggested that this probiotic strain may have the potential to reduce the incidence of diarrhoea; however, owing to the small number of subjects, statistical signicance was not reached. Most studies examining the effect of probiotics on acute or persistent diarrhoea have been carried out in
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children, as they are the most commonly affected population group. More studies in other population groups, such as adults or the elderly, are needed to enable rm conclusions to be reached for other age groups. Studies on the potential of probiotics to prevent travellers diarrhoea are conicting, although a metaanalysis combining all available data did nd a small but signicant risk reduction (RR 0.85). The efcacy seems to depend not only on the specic strain (S. boulardii seems to be effective), but also on travel destination (different causes of diarrhoea in different regions) and travel duration.
Immune system
The human immune system is highly complex with various biological processes involved. Its major function is to combat infectious microorganisms, including bacteria, viruses and parasites (Macpherson 1999). There are a number of studies examining the effects of probiotics on different components of the human immune system, such as lymphocytes or immunoglobulins. As considering each single immune parameter would go beyond the scope of this review, this section concentrates on studies investigating the effect of probiotic use with common cold infections as the main outcome measure. The common cold is a frequently used term for a mild upper respiratory illness. The hallmark symptoms include nasal congestion and discharge, sneezing, sore throat and cough. The common cold is usually a selflimiting illness conned to the upper respiratory tract, but in some patients can spread to adjacent organs. Despite great advances in medicine and the benign nature of the illness, the economic burden on society in terms of medical costs and absence from work is enormous (Heikkinen & Jarvinen 2003).
Randomised, blinded, placebo-controlled trials

The number of randomised, blinded, placebocontrolled studies examining the effects of probiotics on common cold infections and the efcacy of probiotics in preventing episodes is limited, but some studies have shown interesting results (see Table 5). A research group in Germany simultaneously conducted two separate studies on probiotics and common cold infections in healthy adults. One study compared probiotics in combination with vitamins and minerals, with a control preparation containing vitamins and minerals only. The probiotic strains in the treatment tablets were L. gasseri PA 16/8, B. longum SP 07/3 and B. bidum
MF 20/5 (5 107 CFU/tablet). The study was carried out during two different periods: January to May 2001 (3 months, n = 242) and from December 2001 to June 2002 (5.5 months, n = 237). The total number of common cold episodes during the study periods was similar in both groups (70.2% in the probiotic and 66.8% in the control group). The total symptom score3 of common cold episodes was lower in the probiotic group compared to the control group and nearly reached statistical signicance (79.3 7.4 vs. 102.5 12.2, respectively; P = 0.56). When analysing single cold symptoms, signicantly lower symptom scores were found in those taking probiotics for bronchial symptoms, and a trend of lower symptom scores was found for nasal and pharyngeal symptoms. There was no difference in symptom score for headache, myalgia, conjunctivitis, fatigue or loss of appetite. The duration of common cold episodes was signicantly lower in the probiotic compared to the control group (7.0 0.5 vs. 8.9 1.0 days, respectively; P = 0.045). The duration of fever episodes was also signicantly lower in the probiotic compared to the control group (0.24 0.1 vs. 1.0 0.3 days, respectively; P = 0.017) (De Vrese et al. 2005). In the second study, the research group studied the effect of a higher dose of the same strains (5 108 CFU/ tablet) in combination with vitamins and minerals with a placebo containing neither probiotics nor vitamins or minerals. In the treatment group, 53% developed a common cold infection during the study periods JanuaryMay 2001 (3 months) and December 2001 June 2001 (5.5 months), and in the control group 60% had a common cold infection; however, the difference did not reach statistical signicance (P = 0.07). The average duration in the probiotic group was 6.8 0.4 days compared to 7.5 0.6 days in the placebo group; this difference was not signicant (P = 0.19). Although the total symptom score was lower in the treatment group (74.6 6.7) compared to the placebo group (92.5 8.7), the difference was again not signicant (P = 0.12). However, symptom scores of headache, myalgia, conjunctivitis, loss of appetite, days of fever and inuenza symptoms were signicantly lower in the probiotic group (Winkler et al. 2005). A study in marathon runners showed no effect of LGG (4 1010 CFU/day) on incidence or duration of upper respiratory tract infection episodes (Kekkonen et al. 2007). A study in male cadets showed that those consuming fermented milk containing L. casei
3
Daily symptom scores with a maximum daily score of 45 were added up over the illness period to produce a total symptom score.
Table 5 Effects of probiotics on common cold and u infections

N analyses (n randomised) Probiotic Control Study medication Duration of treatment Primary study outcome/endpoint Outcome
Author (year)
Study type
Study population
Common cold and u infections Adults and elderly/Original studies De Vrese et al. RDB PC II Healthy adults (no age 225 (237) (2005) range) 229 (242) 3 months (Jan-May) or 5.5 months (Dec-June) Total symptoms score (overall severity of common cold) Total symptoms score (overall severity of common cold) N of healthy days and n of upper resp. tract inf. (URTI)
No sign. difference (P = 0.056)
Winkler et al. (2005)
RDB PC II
Healthy adults, 1870 years
230 (239)
232 (238)
3 months (Jan.May) or 5.5 months (Dec.June) 3 months training period, 4 weeks follow-up
No sign. difference (P = 0.12)
Kekkonen et al. (2007)
RDB PC II
70
71
L. gasseri PA 16/8, B. longum SP 07/3, B. bidum MF 20/5 (5 107 CFU/day) + vitamins/ minerals; or v./m. only L. gasseri PA 16/8, B. longum SP 07/3, B. bidum MF 20/5 (5 108 CFU/day) + vitamins/ minerals; or placebo LGG (ATCC 53103) (4 1010 CFU/day), or placebo
No sign. difference in healthy days or URTI episodes (P = 0.82 and P = 0.32) No sign. difference in occurrence or duration (P = 0.46 and P = 0.67)
24 3 weeks with lower dose, 1 months with higher dose 23 L. casei DN-114 001 (N of bacteria not given), or placebo Occurrence and mean duration of respiratory tract infections 60 B. lactis BB-12 (G1) or L. reuteri ATCC 55730 (G2) (107 CFU/g humanised cows milk formula powder, total n of microorganisms unknown), or placebo 12 weeks Episodes of and number of days with fever (>38C), episodes and number of days with respiratory illness G2: 68 252 (282) 261 (289) 7 months Days with respiratory symptoms Sign. fewer days with fever in G2 vs. G1 and control [G2:0.17 (95% CI 0.040.30) vs. G1:0.86 (0.331.39) and control: 0.83 (0.501.16), P < 0.001], and sign. fewer episodes of fever in G1 and G2 vs. control [G1: 0.27 (0.170.37) and G2: 0.11 (0.040.18) vs. control: 0.41 (0.280.54), P < 0.001]; no sign. differences in episodes and duration of respiratory illness (P = 0.457 and P = 0.169) No sign. differences (P = 0.28 and P = 0.67)
Tiollier et al. (2007)
RDB PC II
People planning to participate in Helsinki City Marathon (no age range) Male cadets doing 3 weeks commando training + 5 days combat course (no age range)
Common cold and u infections Children/Original studies Weizman et al. MC RDB PC II Healthy term infants G1: 73 (2005) 414 months; attending child care centre;
Hatakka et al. (2001)
MC RDB PC II
Healthy children 16 years; attending day care centres 135 (155) 134 (154)
Hatakka et al. (2007)
RDB PC II
Otitis-prone children 10 months to 6 years of age
LGG (ATCC 53103) (510 105 CFU/ml of milk drink, aim of 200 ml/day), or placebo LGG (ATCC 53103), L. rhamnosus LC 705, B. breve 99, Propionbacterium freudenreichii shermanii JS (89 109 CFU/day each), or placebo
6 months
Occurrence and duration of acute otitis media episodes
No sign. differences (P = n.a.)
Daily symptom scores, max. of 45/day added up over illness period. Fermented probiotic drink, 100 ml/day during 3 weeks preceding training, 300 ml/day during training. CFU, colony-forming units; Ctrl, control; LGG, L. rhamnosus GG; MC, multi centre; n.a., not available; plac., placebo; prob., probiotic; RDB PC II, randomised, double-blind placebo controlled trial (parallel design); SC, single centre; sign., signicant.
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DN-114 001 3 weeks before and during one month of intensive training had fewer episodes of respiratory tract infections compared to those consuming the placebo drink (46% vs. 57%), but this difference was not signicant (P = 0.46). Also the mean duration of symptoms was lower in the probiotics group (5.5 1.6 days vs. 6.1 1.7 days), and so was the mean number of symptoms (0.7 0.2 vs. 1.3 0.3), but this again was not statistically signicant. However, the study population was small (47 cadets) and no minimum sample size was calculated beforehand, which could have contributed to the lack of statistical signicance (Tiollier et al. 2007). Although studies using synbiotics are not included in this review, it is worth mentioning that a large, three-stage study has been conducted comparing different synbiotics with placebo. In this study, all synbiotics used contained strains of L. plantarum, L. rhamnosus and B. lactis, and signicantly reduced the number of acute respiratory infections, as well as their duration and severity in otherwise healthy adults (Pregliasco et al. 2008). Three randomised controlled studies examined the effect of probiotics on common cold infections in young children. In a study in children visiting childcare centres, Weizman et al. (2005) compared the effects of two different probiotic strains on cold infections with placebo over a period of 12 weeks. One study group received humanised cows milk formula containing B. lactis Bb12 and another group the same formula containing L. reuteri ATCC 55730, both at a concentration of 1 107 CFU/g formula powder. The control group received formula without live bacteria. The results showed that incidence and duration of respiratory illness was not signicantly different between the groups. However, L. reuteri was successful in decreasing the duration of fever (0.17 days) compared to BB-12 or placebo (0.86 days and 0.83 days, respectively; P < 0.001). Both the L. reuteri group and the Bb12 group had signicantly fewer episodes of fever compared to the control group (0.11 and 0.27, respectively, vs. 0.41; P < 0.001). In another study carried out in childcare centres, the effect of consuming milk containing LGG (510 105 DFU/ml) over an extended period of time (7 months) on common cold infections was compared with placebo. In this study, the number of children with respiratory infections was signicantly lower in the treatment group compared to the control group (39% vs. 47%, P = 0.05). However, the signicant difference was lost following adjustment for age differences between the two groups (P = 0.13). Symptom scores and duration of respiratory symptoms were similar in both groups (Hatakka et al. 2001). Another
study examining the effect of the same probiotic strain on recurrence of otitis in otitis-prone children showed that LGG failed to reduce the recurrence or duration of acute otitis media episodes (Hatakka et al. 2007) (see Table 5).
Other studies
An unblinded study examining the effects of fermented milk containing L. casei DN-114 001 (2 1010 CFU/ day) on winter infections in free-living elderly subjects showed that the number of subjects suffering from respiratory infections, inuenza syndrome or gastrointestinal syndrome did not differ between the groups during the study period of 3 weeks. However, the duration of all these pathologies combined was signicantly shorter in the probiotic group compared to the control group (7.0 3.2 vs. 8.7 3.7 days, P = 0.024) (Turchet et al. 2003). A large study in preschool children examined the efcacy of three different probiotic preparations L. casei rhamnosus (6 108 CFU/day), L. rhamnosus T cell-1 (3.5 1010 CFU), and a mix of 12 bacterial strains4 (8.2 1010 CFU/day) compared to no treatment in preventing paediatric infectious diseases. The authors of the study claimed that those receiving a single strain probiotic during the long-term intervention (7 months) experienced a signicant improvement in recovery from any bacterial infectious disease. However, data to support this conclusion was not presented in the published article. During the 7 months of intervention, the incidence of respiratory infections was signicantly lower in the L. casei rhamnosus group compared to the control group (-0.309; 95% CI, -0.418 to -0.200, P < 0.0001) (Lin et al. 2009).
Summary Immune system

A limited number of probiotic strains have been studied to date in terms of their effects on common cold episodes. Some have suggested promising results, but many studies failed to reach statistical signicance; some of the studies were possibly underpowered. Even though most of these studies found that probiotics failed to lower the incidence of common cold episodes, results showed that there is potential for probiotics to reduce the duration and severity of symptoms. This means that the immune system may be more efcient at warding off infections when probiotic preparations are consumed
4
B. bidum, B. infantis, B. longum, L. casei, L. salivarius, L. brevis, L. plantarum, L. acidophilus, L. helveticus, L. rhamnosus, St. thermophilus, E. faecium.
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compared to placebo. More large-scale studies will be needed to conrm these ndings.
Allergy
Allergy is an abnormal response of the immune system to contact with a foreign substance (an allergen) (British Nutrition Foundation 2002). The act or process of inducing an acquired sensitivity (sometimes referred to as hypersensitivity) is called sensitisation and is the step that precedes allergy, which is an abnormal immune response to a second exposure to an allergen. Sensitisation is diagnosed by a positive skin prick test (SPT) or the detection of food-specic immunoglobulin E (IgE) levels. In susceptible (sensitised) individuals, allergies are usually associated with a high IgE response to substances such as insect venom, food proteins and grass pollen. Susceptibility has a strong genetic component (Macpherson 1999; British Nutrition Foundation 2002; Dreskin 2006; Dvila et al. 2009). A number of studies suggest that the gut ora also has an impact on the risk of developing allergies (Bjorksten et al. 1999, 2001; Shreiner et al. 2008; Smehilov et al. 2008; Sandin et al. 2009). Some studies have reported that the gut ora of children suffering from allergies differs from that of healthy children, with lower counts of bidobacteria in allergic children, but also differences in other bacterial species (Bjorksten et al. 1999, 2001; Smehilov et al. 2008). Based on these ndings, it has been suggested that probiotics may be able to lower the risk of developing allergies.
Systematic review and randomised, blinded, placebo-controlled trials

Children A recent Cochrane systematic review has been published on the use of probiotics for the prevention of allergic disease and food hypersensitivity in infants (Osborn & Sinn 2009). This review concluded that there is little evidence of an effect in the majority of studies. The reviewers identied only one study that examined the effect of probiotics on allergic disease in this age group, which found no signicant difference between the probiotic and non-probiotic group. The reviewers performed a meta-analysis of two studies and found no signicant difference in food hypersensitivity manifesting as gastrointestinal symptoms in infancy between those taking the probiotics and the control groups. A limited number of studies (n = 3) examined the effect of probiotics on asthma incidence and prevalence in child-
hood and found no effect. Two studies found no effect of probiotics on allergic rhinitis in children and infants and one study found no effect on food allergy in infants. A meta-analysis of three studies performed by the reviewers found no signicant difference in cows milk protein hypersensitivity in infants and one study reported no signicant difference in childhood prevalence (Osborn & Sinn 2009). One subsequent double-blind, randomised, placebocontrolled trial in 119 infants with cows milk allergy showed that a combination of probiotics (L. casei CRL431 and B. lactis Bb-12) had no effect on the acquisition of tolerance to cows milk. After 6 months of treatment, 56% of the probiotic group and 54% of the placebo group had become tolerant to cows milk (P = 0.92). After a subsequent 12 months of treatment of those who were still allergic 6 months after the initial intervention, 48% of the probiotics group and 60% of the placebo group became tolerant to cows milk (P = 0.58) (Hol et al. 2008). Another double-blind, placebo-controlled trial examined the impact of probiotic supplementation during pregnancy on infant sensitisation. The pregnant mothers received either LGG and B. lactis Bb-12, or placebo from the rst trimester of pregnancy to the end of exclusive breastfeeding. Atopic sensitisation of the infants was assessed by SPT at the ages of 6 and 12 months. At baseline, maternal allergic disease was found in 81% of the probiotic group and 78% of the placebo group, and 65% and 50%, respectively, showed positive reactions to SPT. Overall, at the age of 12 months, 30% of the infants showed one or more positive reactions to the SPT, with egg white and cows milk being the most common allergens responsible for a positive reaction. There was no difference between infant sensitisation in the probiotic vs. the placebo group at the age of 12 months (29% vs. 31%, respectively; P = 0.825). However, probiotic supplementation had a signicant protective effect against sensitisation in a sub-group of infants with a high hereditary risk due to maternal sensitisation: 26% of the infants in the probiotic group vs. 50% in the placebo group (P = 0.023) tested SPTpositive when the mother was SPT-positive. When the mother had allergic disease, 29% of the infants in the probiotic group and 36% in the placebo group tested SPT-positive at the age of 12 months (P = 0.462). Data from the age of 6 months was not presented in the published article (Huurre et al. 2008) (see Table 6). Even though studies using synbiotics are not included in this review, it is worth mentioning that one study examining the effect of probiotics in combination with prebiotics showed that the probiotic/prebiotic
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Table 6 Effects of probiotics on allergies and eczema

N analysed (n randomised) Probiotic Control Study medication Duration of treatment Primary study outcome/endpoint Outcome
E. Weichselbaum
Author (year) Study type
Study population
Allergies/original studies Hol et al. SC RDB PC II (2008) 55 (59) 56 (60) 12 months 72 68 L. casei CRL431 and B. lactis Bb-12 (107 CFU/g formula), or plac. LGG and B. lactis Bb-12 (1010 CFU/day)
Infants <6 months; cows milk allergy
Huurre et al. (2008)
SC RDB PC II
Pregnant women; no chronic or metabolic disease
Xiao et al. (2006a)
SC RDB PC II
2361 years, clinical history of JC pollinosis >2 years, presence of serum JC pollen-specic IgE
20
20
Xiao et al. (2007)
SC RDB PC XO 2556 years of age; clinical history of JC pollinosis >2 years; presence of serum JC pollen-specic IgE
21 (24)
Helin et al. (2002)
SC RDB PC II
1436 years; allergic to birch pollen;
15 (18)
16 (18)
% with tolerance towards No sign. difference at 6 or cows milk at 6&12 12 months (P = 0.92 months and P = 0.58) Third trimester of Prevalence of atopic Sign. lower prevalence in pregnancy during sensitisation in infants infants from mothers exclusive breastfeeding at 12 months tested SPT-positive (26% and 50%, P = 0.023) no sign. difference in all infants, and infants from mothers with allergic disease (P = 0.825 and P = 0.462) 14 weeks (starting 4 Scores of subjective Sign. difference in eye B. longum BB536 weeks before pollen symptoms symptom scores in ( 4 107 CFU/day), or placebo season) prob. group (prob.: OR 0.31 ([95% CI,] 0.100.97), P = 0.044); no other sign. Differences 4 weeks treatment, 2 Symptoms during Sign. lower ocular B. longum BB536 weeks wash-out, 4 controlled JC pollen symptom score during (1011 CFU), or placebo weeks treatment exposure and delayed exposure in prob. symptoms group (10.58 ([95% CI,] 5.7619.46) vs. 11.80 (6.5521.25), P = 0.033); no other sign. differences Symptom change from No sign. differences in L. rhamnosus ATCC 53103 5.5 months baseline (before pollen symptom change from ( 2 1010 CFU/ capsule), or placebo season) baseline for any single symptoms (nose, eye, lung, any) during or after pollen season
Eczema Systematic review/Meta-analyses Boyle et al. System. review (2008) (Cochr.) 313 (781) Short-term changes symptoms of eczema Single strains and mixed strains 390 (399) 288 (306) Single strains and mixed strains
Michail et al. (2008)
Meta-analysis
Patients of any age suffering from eczema (all included studies in children) Children of any age suffering from eczema
Lee et al. (2008)
Meta-analysis
Babies
2 years of age
786
795
Single strains and mixed strains
No sign. differences in symptom changes (P = 0.36) Change in total SCORAD Sign. higher decrease of score SCORAD score in prob. group (-3.01 (95%CI, -5.36 to -0.66), P < 0.01) Relative risk-ratio of Sign. lower risk of eczema eczema at 2 years in prob. group (RR: 0.69 (95% CI, 0.570.83) Mother: 35 weeks gestation + 6 months breastfeeding infant: from day 26 until 2 years Eczema prevalence in infant from birth to 2 years of age
Original studies Wickens et al. MC RDB PC II (2008) G1: 144 (157) 150 (159) G1: L. rhamnosus HN001 (6 109 CFU/day)
Pregnant women; they or the father of baby had history of treated asthma, eczema or hay fever G2: 152 (158) 50 (54) 44 (51)
Kopp et al. (2008)
MC RDB PC II
Pregnant women with family history of atopic disease
G2: B. animalis ssp lactis HN019 (9 109 CFU/ day), or placebo LGG (1010 CFU/day), or placebo
Mother: 46 weeks prior Manifestation of atopic birth + 3 months dermatitis during the breastf.; Infants: at 3 rst 2 years of life months for 3 months
Sign. lower prevalence in G1 compared to control (Hazard ratio 0.51 (95%CI, 0.300.85), P = 0.01); no sign. difference between G2 and control (P = 0.64) No signicant difference (P = 0.93)
Weekly symptom score from 0 to 28, based on daily symptom scores from 0 to 4 (0 = no symptoms or no sneezing/nose blowing, 4 = extremely severe symptoms or more than 21 counts of sneezing/nose blowing). Measured on 10-cm visual analogue scale plus counts of sneezing/nose blowing (scores 04). L. fermentum VR1-003PCC [1 (study)], L. rhamnosus Lcr35 (1), LGG (1). L. rhamnosus + B. lactis (1), L. rhamnosus 19070-2 + L. reuteri DSM 122460 (1). LGG [6 (studies)], L. fermentum VR1-003PCC (1), L. rhamnosus Lcr35 (1). L. rhamnosus 19070-2 + L. reuteri DSM 122460 (1), LGG + L. rhamnosus LC705 + B. breve Bbi99 + Propionbacterium freudenreichii ssp shermani JS (1), L. rhamnosus + B. lactis (1). L. acidophilus LA VRI-A1 (1 [study]), L. reuteri ATCC 55730 (1), LGG (ATCC 53103) (3). LGG (ATCC 53103) + L. rhamnosus LC705(DSM 7061) + B. breve Bb99 (DSM 13692) + P. freudenreichii ssp. shermanii JS (DSM 7076) + galacto-oligosaccharides (1).

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CFU, colony-forming units; Ctrl, control; JC, Japanese cedar; LGG, L. rhamnosus GG; MC, multi centre; plac., placebo; prob., probiotic; RDB PC II, randomised, double-blind placebo controlled trial (parallel design); SC, single centre; SCORAD, SCORing Atopic Dermatitis (0103, highest severity); sign., signicant; SPT, skin prick test; XO, crossover design.
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E. Weichselbaum
combination compared with placebo had no effect on sensitisation at 6 months, 2 years or 5 years in all infants overall, but that there was a signicant effect of the probiotic/prebiotic combination in caesarean-delivered children. These children had signicantly fewer IgEassociated allergic diseases, particularly eczema, and less IgE sensitisation, whereas there were no signicant differences between treatment groups in vaginally delivered children (Kukkonen et al. 2007; Kuitunen et al. 2009). Adults Most studies investigating probiotics and allergy in adults have looked at allergic rhinitis, and most of the studies have been carried out among Japanese adults allergic to Japanese cedar pollen (JCP). A study by Xiao et al. (2006a) examined the effect of B. longum strain Bb536 on symptoms related to Japanese cedar pollinosis in patients with clinical history of Japanese cedar pollinosis. The treatment was started 4 weeks before the pollen season and continued over a period of 14 weeks in total. The results showed that those receiving probiotics were 68% less likely to report allergic symptoms involving the eyes than those in the placebo group (P < 0.05). Other subjective symptoms (except for sneezing) appeared to be relieved by Bb536, but the differences were not statistically signicant. A year later Xiao et al. (2006b) carried out another study with the same study design, but this time a higher B. longum BB536 dose (5 1010 CFU twice a day) was used. The drop-out rate in this study was high, particularly in the placebo group (9 out of 22 in the placebo and 2 out of 22 in the probiotics group), owing to heavy pollen dispersion that year and a higher rate of participants using prescribed medication to treat allergy symptoms, which was an exclusion criterion. Altogether, along with pollen prevalence, subjective symptom scores increased markedly from the middle of February and peaked from the middle of March to the middle of April. Those who received probiotics, however, showed a signicantly lower progression curve of subjective scores for runny nose and nasal blockage compared to the control group and had signicantly lower symptom scores overall for these two conditions throughout the study (P = 0.017 and P = 0.012, respectively). No other signicant differences between the groups were found (specic data on symptom scores were not available in the article) (Xiao et al. 2006b). In another study by Xiao et al. (2007) the efcacy of this probiotic strain at a dose of 5 1010 CFU twice a day was tested in a cross-over study outside the pollen season in an environmental exposure unit in
patients with clinical history of Japanese cedar pollinosis and presence of serum JCP-specic IgE and relatively severe symptoms during the last cedar pollen season. Here again, signicantly lower symptom scores were found specically for symptoms involving the eyes (ocular symptoms) during exposure in the probiotics group compared to placebo (4.4 and 6.9, respectively; P = 0.033). There was no difference in nasal symptoms during or after exposure. A study examining the effect of L. casei Shirota (LcS) on symptoms of Japanese cedar pollinosis failed to show any differences between the probiotic and placebo groups. The study was carried out in 120 subjects having specic IgE for JCP, who consumed a fermented milk containing LcS at a dose of 4 1010 CFU or placebo daily for over 4 months (data on specic allergy symptoms not available in the article) (Tamura et al. 2007). One study examined the effect of a probiotic strain on birch-pollen allergy. In this study 36 young adults and teenagers allergic to birch pollen received either capsules containing L. rhamnosus ATCC 53103 (>5 109 CFU/ capsule) or placebo (two capsules twice per day) over a period of 5.5 months. The results showed that during and after the pollen season there was no difference in symptom scores recorded by patients in the two groups. The total use of allergy and asthma medication increased more in the L. rhamnosus group, but the difference did not reach statistical signicance (P = 0.06) (Helin et al. 2002). This reected the fairly small study group (only 18 in the intervention group) (see Table 6). Other studies Two unblinded studies examined the efcacy of L. acidophilus L-92 in relieving allergic symptoms caused by JCP (specic data on symptom scores were not available in the article). One study was carried out in 52 patients with perennial allergic rhinitis and high concentrations of IgE to house dust or house dust mite. They received 100 ml of fermented milk containing 3 1010 live bacteria or placebo. The results showed that nasal symptoms and medication scores decreased signicantly in the treatment group at weeks 6 and 8 of ingestion (P < 0.01), and they were signicantly different from the placebo group (P < 0.05), whereas ocular scores showed no signicant difference between these two groups (Ishida et al. 2005a). Another study by Ishida et al. (2005b) in adults who were allergic to JCP with typical symptoms and who were positive for IgE against JCP used a higher dose of L. acidophilus L-92 (1 1011 live
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bacteria per day) and was carried out in two different seasons (2002, 6 weeks of intervention and 2003, 10 weeks of intervention). This study failed to show any signicant differences between the probiotic and placebo groups in any of the symptoms, including sneezing, runny nose, stuffy nose, itchy eyes, watery eyes or nasal symptom medication score (Ishida et al. 2005b). Summary Allergy Probiotics do not seem to be effective in lowering the risk of allergic sensitisation and allergic disease in early life, although one study found a preventive effect in infants whose mothers tested SPT-positive. One study using probiotics in combination with prebiotics suggests that probiotics might be effective in preventing allergic diseases and sensitisation in caesarean born children, but more studies will be needed to conrm this. Although there is some suggestion that probiotics could reduce the symptoms of allergic rhinitis in adults, the evidence so far does not support the hypothesis that probiotics are effective in preventing or treating allergic reactions. The high drop-out rate in the placebo group but not in the probiotics group in the study by Ishida et al. (2005a) is interesting, considering that study participants were excluded once the symptoms were so severe that medication had to be prescribed. Only a limited number of strains have been tested, and most studies have investigated probiotic use in relation to Japanese cedar pollinosis in the Japanese population; studies using other strains and investigating their effect in relation to different allergens in different populations would be interesting.
A commonly used tool to measure the severity of eczema is the Scoring of Atopic Dermatitis (SCORAD) Index, which is a validated clinical tool for assessing the severity of atopic dermatitis as objectively as possible and includes questions on symptoms associated with this condition. The score can range from 0 to 103 (greatest severity). This measurement tool is generally used by physicians, but a feasibility study suggested that a patient-orientated SCORAD can also be used by patients themselves to assess the severity of eczema, producing results that are comparable to those of medical practitioners (Vourch-Jourdain et al. 2009).

A meta-analysis by Michail et al. (2008) and a Cochrane systematic review (Boyle et al. 2008) both examined the efcacy of probiotics in the treatment of eczema in children. The primary outcome measures were, in both studies, based on SCORAD. In the Cochrane systematic review, participant-rated, parent-rated or principal carer-rated symptoms of eczema were the primary outcome measure. The studies identied (n = 12) showed no signicant improvement following probiotic treatment. The severity of eczema as measured by a trained investigator or a medical practitioner, however, showed a mean difference in SCORAD change of -2.47 points (95% CI -4.72 to -0.21, P = 0.03; results based on 5 out of 12 studies that had data on this outcome) between the placebo and probiotics groups (Boyle et al. 2008). This outcome is not in accordance with the ndings of the feasibility study of Vourch-Jourdain et al. (2009), which suggested that similar results can be produced when SCORAD is used by patients or medical practitioners. The meta-analysis by Michail et al. (2008) used the change in SCORAD score before and after treatment as the primary outcome measure (separate data were not provided for changes in symptoms via self-assessment or assessment by trained investigator/medical practitioner). Results of 10 studies included in the meta-analysis showed greater improvement in the SCORAD score following probiotic treatment compared to placebo, with a mean difference in change from baseline between the probiotic and placebo groups of -3.01 points (95% CI, -5.36 to -0.66, P = 0.01) favouring probiotics. This means that, on average, probiotic treatment reduced the SCORAD score by 3 points more than placebo administration. However, the authors of this meta-analysis pointed out that, despite this signicant difference, a
Eczema/dermatitis
Although the lay term eczema usually refers to atopic or endogenous eczema, there are many other causes (Macpherson 1999). In this review eczema and dermatitis are used interchangeably. Eczema and dermatitis are very general terms meaning inammation of the skin from any cause, including allergies or infections. These terms do not describe a specic disease, but a facet of any one of a considerable range of disorders in which the skin is inamed. Atopic dermatitis has a familial tendency and is commonly associated with having hay fever and asthma (Youngson 2000). Susceptibility to dermatitis is genetically determined in some cases, in others environmental irritants and allergens are implicated (Macpherson 1999). Studies in children with atopic disease have demonstrated the use of probiotics to have a benecial effect on different symptoms associated with this condition (Prescott et al. 2005; Flinterman et al. 2007).
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E. Weichselbaum
3-point difference in the reduction in SCORAD scores has doubtful clinical signicance. A third meta-analysis by Lee et al. (2008) calculated the efcacy of probiotics in preventing paediatric atopic dermatitis based on six studies and showed that probiotics signicantly reduced the incidence of this condition. Treatment of paediatric atopic dermatitis was also examined in this meta-analysis and the results, based on four studies, conrmed the ndings by Michail et al. (2008) (i.e. no signicant improvement). Results from double-blind randomised controlled studies showed that probiotics were effective in lowering the risk of atopic dermatitis in the rst two years of life. The RR ratio based on xed effects analysis was signicantly lower with probiotic treatment compared to placebo (0.69; 95% CI, 0.57 to 0.83). Two subsequent studies have examined the efcacy of probiotics in preventing eczema. Wickens et al. (2008) studied the preventive effects of two different strains (L. rhamnosus HN001 and B. animalis subsp. lactis HN019) consumed daily by pregnant mothers from the 35th week of gestation onwards and after birth by their babies over a period of two years. The results showed that the Lactobacillus strain was successful in reducing the risk of eczema in infants in the rst two of life years (hazard ratio 0.51; 95% CI, 0.300.85, P = 0.01), whereas B. animalis failed to show any effect (hazard ratio 0.90; 95% CI, 0.581.41, P = 0.64). In another study, Kopp et al. (2008) failed to show an effect of LGG in preventing eczema in the rst two years of life. In this study the probiotic was taken by the pregnant mothers 4 to 6 weeks before delivery and during the rst 3 months of breastfeeding, and then provided to the infants directly for 3 months. The rates of atopic dermatitis were nearly identical in the LGG and placebo groups (28% and 27.3%, respectively; P = 0.93) (see Table 6).
risk of eczema in the LGG group compared with the placebo group at 4 years of age (RR 0.57, 95% CI 0.330.97) and at 7 years of age (OR 0.58; 95% CI, 0.35 to 0.94; P = 0.027).
Summary Eczema/dermatitis
The evidence from studies published to date does not suggest that probiotics can be used to treat eczema. Even though improvements in eczema have been observed, these may be too small to be clinically relevant. However, based on the small number of studies, probiotics seem to have the potential to lower the risk of developing eczema if taken by pregnant women and their infants in early life. One study suggests that the preventive effect of consuming a probiotic strain in the rst 6 months of life remained evident at the age of 7 years. Although further studies are needed to conrm these ndings and to clarify the strains and dose needed, a preventive effect of probiotics could be particularly valuable for chidren with a family history of eczema.
Discussion
The number of products containing probiotics has increased substantially over the past decades (Sanders et al. 2007). At the same time, there seems to be a relatively vague perception of the health benets of probiotics among consumers. This reects the wealth of conicting reports on probiotics in the media. Such articles are often based on a single intervention, in vivo or in vitro study, rather than a meta-analysis or review of several studies. This review aimed to give a clearer picture of the effects of probiotics on our health by summarising the results of the most informative published studies that have been carried out in this eld, focusing on higher quality studies. One of the major challenges in reviewing the evidence on probiotics is the large number of bacterial and yeast strains that have been studied for their potential probiotic properties and benets for health. Numerous in vivo and in vitro studies are available where probiotic strains have been tested for their ability to survive the gastrointestinal tract and to potentially colonise the gut. However, for the purposes of this paper, only intervention studies carried out in humans were included. Discussing survival in the gastrointestinal tract and colonisation of the gut of probiotic strains was not an objective of this review, which set out to examine the effect of probiotic strains on various health outcomes. As effects of probiotics have been shown to be strain specic (Luyer et al. 2005; Canani et al. 2007;
Other studies
A Finnish research group reported in a letter to the editor of the Lancet (Kalliomki et al. 2003) and a letter to the editor of the Journal of Allergy and Clinical Immunology (Kalliomki et al. 2007) follow-up results of a study included in the meta-analysis of Lee et al. (2008). Four and seven years after the start of their original study (Kalliomki et al. 2001), which found LGG taken for 6 months after delivery to reduce the risk of eczema in children in the rst two years of life, 67% (n = 107) and 73% (n = 116) of the children included in the original study, respectively, were examined again. The follow-up results also showed a signicant reduced
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Kekkonen et al. 2008), it is difcult to make rm conclusions on the health benets of probiotics in general. It is important to report health benets for single strains or for a mix of strains separately. However, most metaanalyses and systematic reviews have analysed the effects of probiotics merging data from studies using different strains (Huang et al. 2002; Mc Farland 2006; McFarland & Dublin 2008; Michail et al. 2008), and thus the results of these have to be interpreted with caution. On the other hand, many of the strains have been examined in an insufcient number of studies to carry out separate meta-analyses or systematic reviews. The results of meta-analyses and reviews merging results of studies using different strains can give an overview of the health potential of probiotics in general, but it is hard to draw conclusions from such studies about which strains are effective and which are not. Two of the most studied probiotic strains are LGG and S. boulardii. There is good evidence that LGG is effective in decreasing the risk of developing AAD and in decreasing the duration of acute diarrhoea in children. There is also some evidence that LGG may be effective in the treatment of UC, but a study in patients with CD failed to nd any benecial effect of this strain (Prantera et al. 2002). For S. boulardii, there is also good evidence that it is effective in decreasing the risk of AAD and in treating acute diarrhoea in children. One study examined the effect of S. boulardii in treating persistent diarrhoea and showed that it was effective (Gaon et al. 2003). A study using S. boulardii in treating CD patients showed that standard treatment (mesalizine) was more effective in combination with this probiotic (Guslandi et al. 2000). The fact that there is more evidence for these strains than for others does not mean that other strains are not effective, because they are not yet as well studied. This review has shown that there are promising results for a number of strains, but it is necessary to examine them in more detail before being able to draw any rm conclusions. Another difculty in comparing available studies on the effects of probiotics on health is that not only have various strains been used, but also the number of bacteria used in studies varies. As already mentioned, studies on survival and ability to inuence the gut ora are usually carried out before strains are tested for health benets in intervention studies and the number of microorganisms used will be affected by the outcomes of such studies. Survival rates have been estimated at 2040% for selected strains, the main obstacles to survival being gastric acidity and the action of bile salts (Bezkorovainy 2001). Therefore, for different strains
different numbers of microorganisms will be needed to achieve a potential health benet. A study by Whorwell et al. (2006) examining the effect of B. infantis 35624 showed that the dose of probiotics can have an important impact on its effectiveness. The researchers studied this probiotic strain using three different numbers of bacteria, given in the form of an encapsulated formulation. The results showed that a dose of 1 108 CFU/ml was signicantly superior to placebo in reducing several IBS symptoms, including abdominal pain, bloating, bowel dysfunction, incomplete evacuation, straining and the passage of gas at the end of 4 weeks of intervention. In contrast, a dose of 1 106 was not superior to placebo, and neither was a dose of 1 1010. The authors of the study were surprised about these ndings, as in a previous study the same strain in a dosage of 1 1010 given as a milk-based formula had been demonstrated to be effective in reducing IBS symptoms (OMahony et al. 2005). Therefore, the authors assumed that there must be another reason for the ineffectiveness of this higher dose and they conducted dissolution experiments with the capsules used in their study. These experiments clearly showed that the highest dose formulation coagulated into a rm gluelike mass that was resistant to acid and prolonged, intense agitation. The authors concluded that such a coagulum would inuence the growth characteristics of a bacterial strain and suggested that, when developing a product, not only does the strain have to be tested for efcacy, but also the nal version of the product, as minor changes can signicantly impact on the effectiveness of a probiotic strain (Whorwell et al. 2006). The duration of treatment with probiotics in studies included in this review varied greatly depending on the study outcome. Intervention studies examining the effect of probiotics on acute diarrhoea lasted on average only a few days, as acute diarrhoea generally ceases within 12 weeks. Duration of treatment with probiotics in patients taking antibiotics ranged from 3 days to 4 weeks. Studies in patients with IBD generally lasted up to a year, as recurrence of inammation of the gut mucosa usually happens within this time period. General recommendations on how long probiotics should be taken are therefore difcult to make as based on treatment duration in intervention studies. The studies in patients with acute diarrhoea included in this review suggest that probiotics can be effective within only a few days of treatment. Effects of probiotics in patients with IBS or constipation were observed from the rst and second week onwards (Koebnick et al. 2003; Drouault-Holowacz et al. 2008). Research suggests that for probiotics to be effective, it is usually
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necessary to take them on a regular basis, as ingested strains do not become permanently established members of the normal intestinal ora but generally persist only during the period of consumption and for a relatively short period thereafter (Corthsy et al. 2007). This would suggest that probiotics act during the period they are consumed and a short time afterwards. However, one study examining a potential effect of the consumption of LGG in preventing eczema in high risk infants showed that those receiving this probiotic during their rst 6 months of life had a signicantly reduced risk of eczema even at 7 years follow-up (Kalliomki et al. 2007). The mechanisms for this remain unclear. A possible explanation could be that by giving the probiotics very early in life, an abnormal immune response, which might have led to eczema, was prevented and this may have reduced the prevalence of eczema in later childhood. Also, other studies suggest that early lifetime exposure with different microbes can alter the composition of gut ora in the rst weeks of life and impact on health in later life (Bjorksten et al. 2001; Kero et al. 2002). Although these ndings will have to be conrmed in further studies, they indicate that there may be potential for probiotics to not only have benecial effects during and shortly after their consumption, but also beyond, if they are consumed during critical windows of development, for example. Many of the studies included in this review were carried out in subjects with a certain disease or health problem, such as IBD, acute diarrhoea or constipation, rather than healthy people. However, IBS for example is not associated with any structural changes to the gut mucosa but has been suggested to be the result of an imbalance in the gut bacteria. It is a condition that is characterised by intermittent abdominal pain, altered bowel habits (diarrhoea and/or constipation) and other gastrointestinal symptoms including atulence and bloating (Cremonini & Talley 2005). The evidence so far shows promising results for the use of probiotics in these patients, which indicates that temporarily inuencing the gut ora through ingestion of probiotic bacteria can ease IBS symptoms. Many healthy people suffer from bloating or milder forms of constipation but it may not be severe enough to be classied as IBS. It is plausible that probiotics could also alleviate less severe abdominal symptoms in healthy people. Studies on common cold and u infections have also been carried out in otherwise healthy people. The incidence of common cold and u infections does not seem to be decreased by those strains studied so far, but there is some evidence that probiotic strains could shorten the
length of a common cold or u infection, which indicates that the immune system may work more efciently when taking probiotics. The most widely studied condition in relation to probiotics is acute diarrhoea. However, as diarrhoea mainly occurs in children, most studies have been carried out in this population group. The most commonly used strains in studies on acute diarrhoea are LGG and S. boulardii, and the large number of studies enable conclusions on the effects of these single strains on acute diarrhoea to be reached. Both strains have been found to be effective in decreasing the duration of acute diarrhoea in children. Another condition where rm conclusions about the effectiveness of a probiotic are possible is pouchitis. Most studies used VSL#3, a mix of 8 bacterial strains, and showed that this was effective in maintaining remission in patients with pouchitis and delaying its onset after surgery.
Conclusions
In conclusion, despite the diversity of strains used in the studies included in this review, there is evidence that probiotics have the potential to be benecial for our health. Studies in patients with IBD show probiotic strains to be effective in decreasing the recurrence of UC and occurrence and recurrence of pouchitis, whereas current evidence suggests that probiotics are ineffective in treating patients with CD. Patients with IBS show a reduction in symptoms when being treated with selected probiotic strains; however, high placebo effects have been reported as well. The evidence of the efcacy of probiotics in patients suffering from constipation is limited. Although results are conicting, evidence seems promising for some strains to bring relief to patients suffering from constipation. There is good evidence that a number of probiotic strains are effective in preventing AAD. The most commonly studied strains are LGG and S. boulardii, but other strains and mixtures of strains seem to be effective as well. There is also promising evidence of a preventive effect of probiotics in C. difcile associated diarrhoea, although some studies have been too small to obtain statistically signicant ndings. The effect of probiotics in acute diarrhoea is well studied, most studies being carried out in children as they are most affected by this condition. Selected probiotic strains seem to be effective in reducing the duration of acute diarrhoea. LGG and S. boulardii are again the most commonly used strains and a number of studies have shown them to be effective in reducing the duration of acute diarrhoea. However, one meta-analysis showed that the effect of LGG was only
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signicant in children from Western countries, but not in children from developing countries, which may be due to different causes of diarrhoea in these regions. Studies investigating the preventive effect of probiotics in the context of common cold and u infections found that the studied strains failed to lower the incidence of episodes but that they have a potential to decrease the duration of episodes, which suggests that the immune system may be more efcient in ghting off common cold and u infections after taking probiotics. The evidence so far does not suggest that probiotics are effective in preventing or treating allergies or in treating eczema. However, some probiotic strains seem to lower the risk of developing eczema if taken by pregnant women and their infants in early life.
Acknowledgements
The Foundation wishes to thank Professor Glenn Gibson and Professor Fergus Shanahan for their comments on a draft of this paper.
Conict of interest
The Foundation is grateful for nancial support from Danone UK to assist with the preparation of this review. The views expressed, however, are those of the author alone and Danone UK have not been involved in writing or shaping the contents of this paper.
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Probiotics and Health: A Review of The Evidence: E. Weichselbaum

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Probiotics and health: a review of the evidence

Probiotics and health

BOX 1: Abbreviations used in the text

Probiotics and health

Inammatory bowel disease (IBD)

Ulcerative colitis (UC) Crohns disease (CD)

Table 1 Effects of probiotics on inammatory bowel disease

43 (48) 18 (23) 19 (22)

SC RDB C II Active mild to moderate UC (no age range); 10 (10) 9 (10)

1880 years; UC in remission

Rembacken et al. (1999) Kato et al. (2004)

Mimura et al. (2004)

Gionchetti et al. (2003) 10 (11)

Kuisma et al. (2003)

Occurrence of pouchitis during rst year after closure Post-treatment PDAI

Probiotics and health

Irritable bowel syndrome (IBS)

Probiotics and health

Meta-analyses and randomised, blinded, placebo-controlled trials

Table 2 Effects of probiotics on irritable bowel syndrome and constipation

All age groups; IBS; randomised, controlled, blinded trials

Original studies Drouault-Holowacz et al. (2008) 48 (53)

Sinn et al. (2008) 4 weeks

1870 years; IBS, fullling Rome II criteria 43 43 5 months, 3 weeks follow-up

Improvement in abdominal discomfort/pain Weekly composite IBS symptom score

Kajander et al. (2008)

2065 years; IBS, fullling Rome II criteria

Guyonnet et al. (2007) 135 (137) 132 (137)

Constipation/Original studies Bu et al. (2007) MC RDB PC II

Children <10 years; chronic constipation

Children 216 years; constipation for 12 weeks 35 35

Banaszkiewicz and Szajewska (2005) Koebnick et al. (2003)

1870 years; chronic idiopathic constipation

12 weeks, follow-up at 24 weeks 4 weeks, 1 week follow-up

Probiotics and health

Summary Irritable bowel syndrome

Antibiotic-associated diarrhoea (AAD)

Meta-analyses and randomised, blinded, placebo-controlled trials

Table 3 Effects of probiotics on antibiotic-associated diarrhoea and Clostridium difcile-associated disease

Hospitalised patients, 18 years; antibiotic treatment

Hickson et al. (2007)

Inpatients; >50 years; antibiotic treatment

Wenus et al. (2008)

Hospitalised patients, >18 years; antibiotics for 7 days;

Probiotics and health

Children (no age range); antibiotics treatment (out- or inpatient)

Plummer et al. (2004) 12 (17) 9 (12) 38 days; 37 days follow-up

Wullt et al. (2003)

Hickson et al. (2007) 57 67

McFarland et al. (1994)

Adults (no age range); active CDD;

S. boulardii (3 1010 CFU/day), or placebo, plus antibiotic treatment

4 weeks or until recurrence of CDD

Probiotics and health

Summary Antibiotic-associated diarrhoea

Lactobacillus rhamnosus GG (LGG)

Table 4 Effects of probiotics on acute diarrhoea

Gaon et al. (2003)

Basu et al. (2007b)

Children (no age range); acute watery diarrhoea

Probiotics and health