Dig Dis Sci (2016) 61:673–683
DOI 10.1007/s10620-015-3925-0
REVIEW
Pathophysiology and Therapeutic Strategies for Symptomatic
Uncomplicated Diverticular Disease of the Colon
Eleonora Scaioli1 • Antonio Colecchia1 • Giovanni Marasco1 • Ramona Schiumerini1
Davide Festi1
Received: 9 July 2015 / Accepted: 5 October 2015 / Published online: 12 October 2015
Ó Springer Science+Business Media New York 2015
Abstract Colonic diverticulosis imposes a significant
burden on industrialized societies. The current accepted
causes of diverticula formation include low fiber content in
the western diet with decreased intestinal content and size
of the lumen, leading to the transmission of muscular
contraction pressure to the wall of the colon, inducing the
formation of diverticula usually at the weakest point of the
wall where penetration of the blood vessels occurs.
Approximately 20 % of the patients with colonic diver-
ticulosis develop abdominal symptoms (i.e., abdominal
pain and discomfort, bloating, constipation, and diarrhea),
a condition which is defined as symptomatic uncompli-
cated diverticular disease (SUDD). The pathogenesis of
SUDD symptoms remains uncertain and even less is known
about how to adequately manage bowel symptoms.
Recently, low-grade inflammation, altered intestinal
microbiota, visceral hypersensitivity, and abnormal colonic
motility have been identified as factors leading to symptom
development, thus changing and improving the therapeutic
approach. In this review, a comprehensive search of the
& Eleonora Scaioli
elescaio@gmail.com
Antonio Colecchia
antonio.colecchia@aosp.bo.it
Giovanni Marasco
giovannimarasco89@gmail.com
Ramona Schiumerini
ramona_schiumerini@libero.it
Davide Festi
davide.festi@unibo.it
1 actually defined as symptomatic uncomplicated diverticular
Department of Medical and Surgical Science, Policlinico
S.Orsola, University of Bologna, Via Massarenti 9,
40138 Bologna, Italy
•
literature regarding on SUDD pathogenetic hypotheses and
pharmacological strategies was carried out. The patho-
genesis of SUDD, although not completely clarified, seems
to be related to an interaction between colonic microbiota
alterations, and immune, enteric nerve, and muscular sys-
tem dysfunction (Cuomo et al. in United Eur Gastroenterol
J 2:413–442, 2014). Greater understanding of the inflam-
matory pathways and gut microbiota composition in sub-
jects affected by SUDD has increased therapeutic options,
including the use of gut-directed antibiotics, mesalazine,
and probiotics (Bianchi et al. in Aliment Pharmacol Ther
33:902–910, 2011; Comparato et al. in Dig Dis Sci
52:2934–2941, 2007; Tursi et al. in Aliment Pharmacol
Ther 38:741–751, 2013); however, more research is nec-
essary to validate the safety, effectiveness, and cost-ef-
fectiveness of these interventions.
Keywords Diverticular disease
Gut microbiota
Low-
grade inflammation
Mesalazine
Probiotics
Introduction
Colonic diverticulosis is a structural alteration of the
colonic wall characterized by herniation of the mucosa and
submucosa due to defects in the muscle layer of the colon
wall. It is the fifth most relevant gastrointestinal disease of
the western world in terms of direct and indirect costs;
furthermore, recent data have shown that its prevalence is
increasing throughout the world [1, 2].
Approximately 20 % of subjects with colonic divertic-
ulosis develop abdominal symptoms, and this condition is
disease (SUDD); the simultaneous presence of clinical signs
of inflammation (fever, leukocytosis, etc.) characterizes the
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acute diverticulitis, which can be with or without compli-
cations (i.e., hemorrhage, perforation, etc.) [3, 4].
Symptomatic uncomplicated diverticular disease is a
syndrome characterized by recurrent abdominal symptoms,
such as abdominal pain and discomfort, bloating, altered
bowel function with constipation, or diarrhea attributed to
diverticula in the absence of macroscopic mucosal alter-
ations. Approximately 10–25 % of patients with SUDD
may develop acute diverticulitis. The latter is an acute
episode of severe prolonged ([24 h) lower abdominal pain,
change in bowel movements, fever, and leukocytosis with a
clinical spectrum ranging from mild self-limiting episodes
to complicated conditions such as abscess, perforation,
peritonitis, and sepsis [5].
The current accepted etiology of diverticular formation
includes a lack of fiber in the western diet [6, 7], with
decreased intestinal contents and, thus, a decrease in size of
the lumen, leading to the transmission of muscular con-
traction pressure to the wall of the colon rather than to the
feces. The result of the increased pressure on the wall is the
formation of diverticula at the weakest point of the wall
where penetration of the blood vessels occurs.
The pathogenesis of SUDD remains uncertain. Recently,
low-grade inflammation, altered intestinal microbiota,
visceral hypersensitivity, and abnormal colonic motility
have been identified as factors leading to symptom devel-
opment [8, 9], thus changing the therapeutic approach to
the disease.
The management of SUDD is aimed at improving symp-
toms, preventing their recurrence, and avoiding the develop-
ment of infection (i.e., diverticulitis) and complications.
A comprehensive search of the literature, using the
MEDLINE and PubMed databases, for new SUDD
pathogenetic hypotheses and pharmacological strategies
was carried out, and the evidence available was critically
reviewed.
Pathophysiology of Symptom Development
in Diverticular Disease
The pathogenesis of symptoms in SUDD is complex, and
many factors have been invoked, such as the presence and
maintenance of low-grade inflammation, alteration of the
intestinal microflora, and establishment of visceral hyper-
sensitivity as well as motor alterations. Thus, the devel-
opment of symptoms seems to be more likely due to the
synergic action of multiple factors [5].
Low-Grade Inflammation
In 2014, Tursi et al. [10] suggested that SUDD may be
considered a chronic inflammatory process of the bowel
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Dig Dis Sci (2016) 61:673–683
ranging from low-grade inflammation, localized within the
colonic mucosa, to full-blown acute diverticulitis as a
result of an extension of the inflammation to the colonic
wall due to micro-/macro-perforation of the wall in the
diverticulum [10].
Moreover, patients with SUDD have increased colonic
mast cells in all the layers of the colonic wall which may
contribute to pain development [11]. Symptomatic
uncomplicated diverticular disease manifests significant
microscopic inflammatory infiltrate with increased chronic
lymphocytic infiltration and neutrophilic infiltrate which
seem to be linked to the severity of disease [12–14]. In a
large series of 930 patients undergoing surgery for SUDD,
but not having overt diverticulitis, Horgan et al. [15] doc-
umented chronic inflammation in and around the divertic-
ula in 75 % of the resected specimens. An enhanced
expression of proinflammatory cytokines has also been
observed in SUDD and their overexpression decreases in
response to therapy [16–20]. Interestingly, low-grade
mucosal inflammation has also been observed in some
patients with irritable bowel syndrome (IBS) in which there
is an increased number of inflammatory cells in the colonic
and ileal mucosa. It is well known that the symptoms of
IBS and SUDD overlap considerably [19] (Fig. 1). Since
diverticulosis occurs more frequently after the age of 60
and IBS presents a peak between the age of 30 and 40, the
greater diagnostic challenge is represented by patients over
60 years of age. Several studies have tried to differentiate
these two entities from a clinical point of view, finding less
frequent but prolonged episodes of pain, especially in the
lower left quadrant in SUDD patients as compared to IBS
patients [5, 19–21]. Furthermore, SUDD affects males and
females equally as compared to a prevalent female
involvement of IBS [5, 21].
In conclusion, in SUDD, a pathogenic immune response
is activated, and inflammation is induced by the release of
proinflammatory cytokines, such as tumor necrosis factor a
[17]. These inflammatory and functional changes lead to
the development of abdominal symptoms, such as lower
abdominal pain/discomfort, bloating, tenesmus, and
diarrhea.
Visceral Hypersensitivity
An additional pathophysiological pathway involved in the
symptom development of SUDD is visceral hypersensi-
tivity, an abnormal motor function, and a reduced threshold
for the perception of visceral sensitivity. Visceral hyper-
sensitivity describes an excessive perception or an exces-
sive neuronal afferent response to physiological stimuli.
This pathway is also shared by IBS [22]. In fact, patients
with IBS demonstrate an increased visceral perception in
response to rectosigmoid distension [23].
Dig Dis Sci (2016) 61:673–683
Fig. 1 Overlapping between
symptomatic uncomplicated
diverticular disease (SUDD)
and irritable bowel syndrome
(IBS)
Furthermore, a recent study has shown that patients with
diverticulitis were 4.6 times more likely to develop IBS-
like symptoms over the observation period as compared to
matched controls [24]. Among the causes of the visceral
hypersensitivity, there is increasing evidence of an inter-
action between the enteric nervous and the immune sys-
tems [25, 26]. Indeed, it has been hypothesized that the
inflammatory response related to diverticulitis could dam-
age the enteric nerves and induce visceral hypersensitivity
[19].
In an experimental model of colitis, local tissue injury
resulted in the release of proinflammatory mediators which
can sensitize enteric afferent nerve terminals resulting in a
heightened response to noxious stimuli [27, 28]. These
changes may affect the muscle layers as well as the mucosa
and may also occur at non-inflamed sites [29]. In patients
with acute diverticulitis, neuronal changes with increased
nerve staining within the muscularis propria have also been
demonstrated [30]. It has also been shown that intestinal
muscle dysfunction and increased activity of primary
afferent enteric neurons may persist after resolution of the
acute mucosal inflammation [26, 31]. Thus, the low-grade
inflammation observed in post-infectious IBS [32] as well
as in SUDD [15] may in part explain the heightened vis-
ceral sensation.
Moreover, colonic visceral pain perception in response
to luminal distension was evaluated in SUDD patients and
in asymptomatic diverticulosis patients as compared to
healthy controls [33]. Only the SUDD patients showed
increased pain perception, not only in the sigmoid colon
with diverticula but also in the unaffected rectum [33],
suggesting that a generalized visceral hyperalgesia may be
implicated in symptom generation in SUDD.
Intestinal Microbiota
It has recently been hypothesized that SUDD is associated
with colonic microbial imbalance and that chronic
675
inflammation occurs as a consequence of this imbalance
[34]. In particular, fecal stasis may lead to chronic dys-
biosis, promoting the formation of abnormal metabolites
leading to chronic inflammation [35]. Furthermore, trauma
caused by fecaliths on the thin diverticular walls may lead
to epithelial laceration causing bacterial translocation and a
related inflammatory response. Bacteria activate the
immune system through specific receptors known as Toll-
like receptors (TLRs) [36]. Bacterial lipopeptides and
lipopolysaccharides are recognized by TLR2 and TLR4
which are involved in the generation of innate and adaptive
immunity [36]. Cianci et al. [37] have recently shown that,
in SUDD patients, TLR2 and TLR4 expression on immune
cell subpopulations and on the colonic mucosa is altered as
compared to the controls, and these alterations are reversed
after antibiotic (Rifaximin) treatment.
Several aspects support a potential association between
the altered intestinal microbiota and SUDD. Indeed,
Rifaximin, a nonsystemic antibiotic, may be effective for
treating gastrointestinal symptoms in patients with SUDD,
decreasing the metabolic activity of the intestinal bacterial
flora [34]. In patients with diverticulosis, the cyclic
administration of Rifaximin plus dietary fiber supplemen-
tation with respect to dietary fiber supplementation alone is
more effective in reducing both symptoms and complica-
tion frequency [38]. Nevertheless, low dietary fiber intake,
a putative risk factor for SUDD, is associated with alter-
ation of the gut microbiota [34, 39]. A study comparing the
cultures of gut microbiota from a rural African population
eating a high-fiber diet with that of an English population
eating a low-fiber diet found much higher levels of Bac-
teroides and lower levels of Bifidobacteria in the popula-
tion eating the low-fiber diet [39]. Indeed, DNA sequencing
confirmed that fecal microbiota composition is consider-
ably affected by the consumption of supplemental fibers
[40, 41].
In conclusion, increasing evidence supports the hypoth-
esis that changes in intestinal microbiota composition may
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play a role in the development of SUDD due to the acti-
vation of the intestinal immune responses [34]. Similarly to
inflammatory bowel disease (IBD), reduced host immune
defences and dysfunction of the bowel barrier effect result in
increased mucosal adherence and translocation of bacteria.
Colonic Motility
Altered colonic motility may also be associated with
SUDD. In the study by Bassotti et al. [42], patients with
SUDD displayed increased duration of rhythmic, low fre-
quency, contractile activity of the colon, particularly in the
segments having diverticula. The authors herein concluded
that patients with SUDD have abnormal motor and
propulsive activities in the colonic segment exhibiting
diverticulosis. Moreover, patients with SUDD have a sig-
nificantly reduced density of interstitial cells of Cajal (the
intestinal ‘‘pacemaker cells’’) as compared to normal con-
trols [43]. A reduction in interstitial Cajal cell function may
decrease the colonic electrical ‘‘slow wave.’’ The term
‘‘slow wave’’ is used to describe the spontaneous rhythmic
electrical activity present within the circular and longitu-
dinal smooth muscle layers of the gut wall, which deter-
mines the frequency and propagation of smooth muscle
contractile activity [44]. A lack of such function in DD
presumably leads to abdominal symptoms, such as pain and
constipation.
Milner et al. [45] suggested that shifts in the concen-
trations of mucosal vasoactive intestinal peptide and other
chemical mediators may also play a role in the symptom
pathogenesis.
In conclusion, the pathogenesis of SUDD, although not
completely clarified, seems to be related to an interaction
between colonic microbiota alterations, and enteric nerve
and muscular immune system dysfunction.
Therapeutic Strategies for Symptomatic
Uncomplicated Diverticular Disease
While it is well known that there is no rationale for drug
treatment in diverticulosis, little is known about the best
way to manage symptoms in SUDD and to prevent diver-
ticulitis recurrence [5].
Recent evidence regarding the role of intestinal micro-
biota and low-grade inflammation in DD pathophysiology
has suggested that modulating the microbiota or adminis-
tering anti-inflammatory agents could be effective strate-
gies in treating SUDD.
Data deriving from studies on SUDD treatment and on
the prevention of acute diverticulitis are reported in
Tables 1 and 2, respectively.
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Dig Dis Sci (2016) 61:673–683
Fiber Supplementation
The therapeutic effect of fiber supplements has been
evaluated in several studies, although the majority of them
are poor quality studies and are affected by major biases, as
documented by a recent systematic review [46]. Indeed, the
review identified only three old randomized clinical trials
(RCTs) and one case–control study: One RCT [47] docu-
mented a significant reduction in pain and an improvement
in overall clinical symptoms, another RCT [48] was unable
to document a positive effect of fiber supplementation on
symptoms, only a reduction in constipation, and the third
RCT [49] showed a significant positive effect on symptoms
with the administration of methylcellulose. Furthermore,
the case–control study [50] evaluated the effect of a high-
fiber diet on the development of disease complications and
the need for surgery, showing a positive effect of fiber
supplementation in reducing disease complications, the
need for surgery, and the occurrence of abdominal
symptoms.
Crowe et al. [51] more recently evaluated the dietary
habits of 47,033 men and women in England and Scotland,
and found that individuals who were on a vegetarian diet
had a lower risk of admission to the hospital due to
symptomatic uncomplicated and complicated diverticular
disease. An inverse association with fiber intake was also
observed [52]. Regarding diet, the classic advice is to avoid
eating seeds, popcorn, or nuts based on the assumption that
such substances could enter, block, or irritate a diverticu-
lum, resulting in diverticulitis. However, no recent evi-
dence exists to support this theory, and on the contrary, a
protective effect has been suggested [53].
In conclusion, although high-quality evidence for a
high-fiber diet in the treatment of SUDD is lacking, several
guidelines and position papers [51, 54–57] still recommend
the use of high-fiber diets in the treatment of SUDD in
order to reduce the recurrence of diverticulitis.
Antibiotics
Since the natural history of SUDD is characterized by a
possible evolution to acute diverticulitis, several studies
have tried to evaluate the role of antibiotics in the treatment
of SUDD symptoms and in prevention of acute diverticulitis.
Antimicrobial drugs have been shown to reduce hydro-
gen (H2) production and gas-related symptoms and to
increase mean stool weight in subjects taking fiber, most
likely due to reduced fiber degradation [58].
Furthermore, antibiotics may modulate the altered
intestinal microbiota (dysbiosis) responsible for low-grade
mucosal inflammation [59].
All the above findings represent a rationale for antibiotic
use in SUDD. The reduction in gas production and the
Dig Dis Sci (2016) 61:673–683 677

Table 1 Summary of studies regarding treatment for symptomatic uncomplicated diverticular disease
Study Year Treatment Treatment No. of Symptom reduction Side
period patients effects
(n)

Brodribb [47] 1977 6.7 g dietary fiber versus placebo 12 weeks 9 Yes, with fiber NA
9
Hodgson [49] 1977 Methylcellulose 500 mg bid versus 12 weeks 11 Yes, with fiber and placebo NA
placebo 16
Ornstein [91] 1981 7 g/day bran 16 weeks 94 No significant benefit with fiber NA
9 g/day ispaghula
2 g/day placebo
Smits [92] 1990 15 ml bid lactulose 12 weeks 22 Yes, with fiber and lactulose 9
30 g/day high-fiber diet 21 12
Papi [62] 1992 Rifaximin 400 mg bid 12 months 107 Yes, with Rifaximin NA
1 weeks/month ? glucomannan 110
2 g/day versus glucomannan 2 g/day
Papi [65] 1995 Rifaximin 400 mg bid 12 months 84 Yes, with Rifaximin 0
1 weeks/month ? glucomannan 84 0
2 g/day versus placebo bid
1 weeks/month ? glucomannan
2 g/day
Di Mario [93] 2005 Rifaximin 200 mg bid 10 day/month 12 weeks 39 Yes, in all group except NA
versus Rifaximin 400 mg bid 43 Rifaximin 200 mg
10 day/month versus mesalazine
40
400 mg bid 10 day/month versus
mesalazine 800 mg bid 10 day/month 48
Latella [64] 2003 Rifaximin 400 mg bid 12 months 595 Yes, with Rifaximin 10
1 weeks/month ? glucomannan 373 5
4 g/day versus glucomannan 4 g/day
Colecchia [59] 2007 Rifaximin 400 mg bid 24 months 184 Yes, with Rifaximin 4
1 weeks/month ? fiber 20 g/day versus 123 3
fiber 20 g/day
Stallinger [69] 2014 Rifaximin 400 mg bid 1 weeks/month 3 months 963 Yes 24
Comparato [77] 2007 Rifaximin 200 mg bid 10 day/month 12 months 66 Yes, in all group except 2
versus Rifaximin 400 mg bid 69 Rifaximin 200 mg. 3
10 day/month versus mesalazine
66 1
400 mg bid 10 day/month versus
mesalazine 800 mg bid 10 day/month 67 2
Comparato [94] 2007 Rifaximin 200 mg or 400 mg bid 6 months 27 Yes, in all groups NA
10 day/month versus mesalazine 31
400 mg or 800 mg bid 10 day/month
D’Inca [66] 2007 Rifaximin 600 mg bid ? bran 10 g bid 2 weeks 64 Yes, with Rifaximin 0
versus placebo ? bran 10 g bid
Tursi [95] 2002 Rifaximin 400 mg bid 12 months 109 Yes with 9
1 weeks/month ? mesalazine 800 mg 109 mesalazine ? Rifaximin
bid 1 weeks/month versus Rifaximin
400 mg bid 1 weeks/month
Kruis [76] 2013 Mesalazine 1000 mg tid versus placebo 6 weeks 56 Yes, with mesalazine 3
61 2
Dughera [90] 2004 Polybacterial lysate suspension bid 3 months 43 Yes, with polybacterial lysate 0
2 weeks/month versus no treatment 48 suspension
Lamiki [86] 2010 SCM-III symbiotic mixture, 10 ml three 6 months 45 Yes 0
times a day (Lactobacillus a. and
Bifidobacterium)

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678 Dig Dis Sci (2016) 61:673–683

Table 1 continued
Study Year Treatment Treatment No. of Symptom reduction Side
period patients effects
(n)

Annibale [85] 2011 High-fiber diet alone versus 1 sachet of 6 months 16 Yes, with 1
probiotic (Lactobacillus paracasei F19) 18 Lactobacillus paracasei F19 ?
bid ? high-fiber diet versus 2 sachets of high-fiber diet
16
probiotic bid ? high-fiber diet for
14 day/month
Lahner [87] 2012 1 symbiotic sachet of Flortec (Ó) 6 months 24 Yes, with Flortec(Ó) 0
(Lactobacillus paracasei B21060) 21
qd ? high-fiber diet versus high-fiber
diet alone
Tursi [74] 2013 Group M (active mesalazine 1.6 g/day 12 months 51 Yes, with mesalazine and 0
plus Lactobacillus casei subsp. DG 55 Lactobacillus casei
placebo), Group L (active Lactobacillus
54
casei subsp. DG 24 billion/day plus
mesalazine placebo), Group LM (active 50
Lactobacillus casei subsp. DG 24
billion/day plus active mesalazine),
Group P (Lactobacillus casei subsp. DG
placebo plus mesalazine placebo) for
10 day/month

increase in the fecal mass both reduce intraluminal pres-
sure, thus improving symptoms and decreasing the
enlargement and the stretching of diverticula as well as the
generation of new diverticula. Moreover, the disruption of
dysbiosis may reduce the low-grade inflammation which
causes symptom development [37, 59, 60].
Among the several available antimicrobial drugs, Rifax-
imin displays characteristics of a useful antibiotic [61]. It is a
nonsystemic agent with a broad spectrum of antibacterial
action, covering gram-positive, gram-negative, aerobic, and
anaerobic organisms. Since it is virtually non-absorbed, its
bioavailability within the GI tract is rather high, with
intraluminal and fecal drug concentrations which largely
exceed the minimum inhibitory concentration values
observed in vitro against a wide range of pathogenic
organisms [62]. Rifaximin acts by binding to the b-subunit
of bacterial DNA-dependent RNA polymerase resulting in
the inhibition of bacterial RNA synthesis [63].
The use of Rifaximin to reduce the clinical symptoms of
SUDD (in addition to fiber treatment) has been studied in three
open [59, 62, 64] and two double-blinded [65, 66] RCTs which
have been analyzed in detail in a systematic review [67] and
two meta-analyses [38, 68]. The meta-analysis by Bianchi
et al. [38] included four prospective RCTs (only one was
double-blinded and placebo-controlled) including 1660
patients and found that the pooled rate difference for symptom
relief was 29.0 % in favor of the cyclic administration of
Rifaximin [Rifaximin versus control; 95 % confidence level
(CI) 24.5–33.6 %; p \ 0.0001] with a number needed to treat
(NNT) of 3. The results of these RCTs have recently also been
confirmed in a non-interventional study carried out in a private
practice outpatient setting [69].
Two systematic reviews which have evaluated the effi-
cacy of Rifaximin and other antibiotics in modifying the
clinical course of SUDD, i.e., in preventing acute diverti-
culitis, have shown conflicting results [70, 71], mainly due
to the presence of bias resulting from uncontrolled studies
and the absence of a cost-efficacy analysis regarding long-
life treatment.
However, a recent open-label pilot study found that the
cyclic administration of Rifaximin (800 mg/day for
10 days every month) is effective in preventing acute
diverticulitis [72].
The reasons for these conflicting results regarding the
role of Rifaximin in preventing diverticulitis recurrence are
still not clear. The ineffectiveness of Rifaximin may have
been caused by the short-lasting effect of the reduction in
fecal bacterial counts during oral treatment with Rifaximin.
The colon microbiota has been shown to recover within
1–2 weeks after the end of treatment [61]. Repeated oral
administration of Rifaximin may control the colonic bac-
terial population for only 15–20 days, with high colonic
bacterial concentration for the last 10 days of the month
and therefore with a high risk of diverticulitis recurrence.
In conclusion, the use of Rifaximin, in association with
high fiber intake, seems to be safe and useful for the
treatment of SUDD symptoms. However, the use of
Rifaximin and other antibiotics in the prevention of
diverticulitis recurrence and treatment of acute divertic-
ulitis has, until now, shown inconclusive results.

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Table 2 Summary of studies evaluating the prevention of acute diverticulitis in symptomatic uncomplicated diverticular disease
Study Year Maintenance treatment Treatment No. of Acute diverticulitis
period patients in the follow up no.
(%)

Papi [62] 1992 Rifaximin 400 mg bid 1 weeks/month ? glucomannan 2 g/day 12 months 107 1 (0.9)
versus glucomannan 2 g/day 110 3 (2.7)
Papi [65] 1995 Rifaximin 400 mg bid 1 weeks/month ? glucomannan 2 g/day 12 months 84 2 (2.4)
versus placebo bid 1 weeks/month ? glucomannan 2 g/day 84 2 (2.4)
Latella [64] 2003 Rifaximin 400 mg bid 1 weeks/month ? glucomannan 4 g/day 12 months 595 6 (1.0)
versus glucomannan 4 g/day 373 11 (2.9)
Colecchia [59] 2007 Rifaximin 400 mg bid 1 weeks/month ? fiber 20 g/day versus fiber 24 months 184 2 (1.1)
20 g/day 123 4 (3.3)
Lanas [72] 2014 3.5 g of high-fiber supplementation bid ? Rifaximin 400 mg bid 12 months 77 8 (10.4)
versus 3.5 g of high-fiber supplementation bid 88 17 (19.3)
Comparato [77] 2007 Rifaximin 200 mg bid 10 day/month versus Rifaximin 400 mg bid 12 months 66 2 (3.0)
10 day/month versus mesalazine 400 mg bid 10 day/month versus 69 1 (1.5)
mesalazine 800 mg bid 10 day/month
66 1 (1.5)
67 0 (0.0)
Tursi [95] 2002 Rifaximin 400 mg bid 1 weeks/month ? mesalazine 800 mg bid 12 months 109 3 (2.7)
1 weeks/month versus Rifaximin 400 mg bid 1 weeks/month 109 16 (18.0)
Parente [80] 2013 Mesalazine 800 mg bid for 10 day/month versus placebo 24 months 45 6 (13)
47 13 (28)
Raskin [81] 2014 Mesalamine 1.2 versus 2.4 g versus 4.8 g versus placebo qd 104 weeks 291 108 (37)
290 113 (39)
299 117 (39)
289 98 (34)
Dughera [90] 2004 Polybacterial lysate suspension bid 2 weeks/month versus no 3 months 43 2 (4.6)
treatment 48 5 (12.5)
Tursi [89] 2007 Balsalazide 2.25 g qd for 10 day/month ? VSL#3450 billions/day for 12 months 15 3 (21)
15 day/month versus VSL#3 alone 450 billions/day for 15 5 (38)
15 day/month
Stollman [79] 2013 Placebo versus mesalazine versus mesalazine ? Bifidobacterium 12 months 41 13 (31)
infantis 35624 (Align) 40 11 (28.1)
46 17 (37)

Mesalazine although only in the per protocol population with a statis-

Controlling inflammation using mesalazine is another
treatment option for SUDD, both to induce symptom
remission and to prevent acute diverticulitis. Mesalazine
acts directly on the gastrointestinal epithelium, through
N-Ac-5ASA, the active metabolite of 5-ASA. Mesalazine
inhibits some key factors of the inflammatory cascade,
inhibits the production of interleukin-1 and free radicals,
and has intrinsic antioxidant activity [73]. The effect of
mesalazine on SUDD has been demonstrated by several
open-label studies [74–76]; two recent double-blinded,
placebo-controlled studies confirmed these preliminary
results [74, 76]; in particular, the Kruis study [76] carried
out at 17 centers in Germany showed a consistent trend of
mesalazine in reducing symptoms with respect to placebo,
tically significant difference. The second study [74]
showed that mesalazine and Lactobacillus casei DG
treatments, particularly when given in combination, are
more effective than a placebo in maintaining remission of
SUDD.
A prospective randomized open study compared differ-
ent doses of Rifaximin and mesalazine for 10 days per
month showing that a high dose of mesalazine was sig-
nificantly more effective than Rifaximin in relieving
symptoms [77].
A systematic review of six randomized controlled trials
involving 818 patients with either uncomplicated acute
diverticulitis or SUDD found that mesalazine was signifi-
cantly better in relieving symptoms than a placebo and that
the daily dosing was superior to cyclical dosing [78].

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Thus, the use of mesalazine in controlling symptoms in
SUDD is accepted, but controversial results have been
reported regarding its role in preventing diverticulitis
recurrence. These conflicting results may be due to
heterogeneity in the study populations, in the type of
mesalazine used, and in the endpoints of the different trials.
The use of mesalazine in preventing diverticulitis
recurrence has been evaluated by several double-blinded,
placebo-controlled studies [63, 79, 80]. The majority of
them did not find mesalazine to be significantly superior to
a placebo in preventing diverticulitis recurrence. On the
other hand, mesalazine was found to be significantly better
than a placebo in reducing abdominal symptoms following
acute diverticulitis [79, 80]. Furthermore, a more recent
study which involved two randomized, double-blinded,
placebo-controlled, multicenter trials found that mesalazine
did not reduce time to recurrence and the need for surgery
[81].
In conclusion, while mesalazine seems to be somewhat
effective in the treatment of SUDD, the data available
indicate that it is not effective in preventing acute diver-
ticulitis. A possible explanation is that, since only a
mucosal inflammation is present in SUDD whereas there is
a full thickening inflammation in diverticulitis, mesalazine
may be able to penetrate through the mucosa but not to the
entire bowel wall, thus being more effective in treating
symptoms of SUDD rather than diverticulitis.
Probiotics
Probiotics are living microorganisms capable of affecting
several physiological functions, including pathogen
adherence inhibition, enhancement of IgA secretion in
Peyer’s patches, and immune system activity [82]. More-
over, they may interfere with the pathogen metabolism by
means of a mechanism of metabolic competition [82]. The
rationale for the use of probiotics in SUDD is the attempt to
restore normal gut microbiota in subjects with documented
bacterial overgrowth.
Although several studies have evaluated the clinical
efficacy of probiotics, no definitive results have yet been
achieved, mainly due to the heterogeneity of the studies
[83]. The majority of the studies have used probiotics in
combination with topical antibiotics [84] or anti-inflam-
matory drugs, mainly 5-aminosalicylates (5ASA) [74].
Only two studies have tested a single probiotic (Lacto-
bacillus paracasei) [85] and a symbiotic mixture (con-
taining Lactobacillus acidophilus and Bifidobacterium spp.
420) [86] in patients with SUDD, documenting that the
active drug was effective in reducing clinical symptoms.
More recently a 6-month multicenter randomized,
controlled, parallel-group intervention with a preceding
4-week washout period was carried out [87]. The SUDD
123
Dig Dis Sci (2016) 61:673–683
patients were randomized to treatment A (L. paracasei
B21060 strain once daily plus high-fiber diet for
6 months) or treatment B (high-fiber diet alone for
6 months). The proportion of patients with long-lasting
abdominal pain ([24 h) decreased from 60 to 20 % and
5 % after 3 and 6 months, respectively, in group A
(p \ 0.001) and from 33.3 to 9.5 % at both 3 and
6 months in group B (p = 0.03). The mean visual ana-
logue scale (VAS) values of both short-lasting (\24 h)
abdominal pain and abdominal bloating decreased in both
groups, whereas the VAS values of prolonged ([24 h)
abdominal pain decreased in group A, but did not change
in group B.
Other authors evaluated the effect of probiotics in the
prevention of acute diverticulitis in SUDD patients. Fric
et al. [88] administered Escherichia coli strain Nissle to
patients with SUDD after the third relapse of the disease
and showed that the interval until the following relapse was
significantly longer after probiotic treatment [88]. Tursi
et al. [89] also evaluated the role of probiotics in pre-
venting the recurrence of diverticulitis. The combination of
balsalazide/VSL#3 was more effective than VSL#3 alone
in preventing the relapse of uncomplicated diverticulitis.
Dughera et al. [90] found an oral immunostimulant highly
purified polymicrobial lysate (containing 80 9 109 E. coli
strains 01,02,055 and 0111, and 1 9 109 Proteus vulgaris)
to be effective in preventing diverticulitis recurrence after 1
and 3 months of therapy.
In conclusion, however, the poor study design and the
small sample size of the majority of the studies available
do not allow us to reach a definitive conclusion regarding
the therapeutic use of probiotics.
Therapeutic Side Effects of the Different
Therapeutic Strategies
Only a few studies [59, 64, 70, 71] have reported the side
effects of SUDD treatment. The rate of side effects with
either fiber, Rifaximin, mesalazine, probiotics or their
combination ranges from 1.5 to 10 %, including nausea,
headache, and weakness [59, 64].
Conclusions
A growing body of knowledge is shifting the paradigm of
diverticular disease from an acute surgical illness to a
chronic bowel disorder. Although there are standardized
guidelines for the management of acute diverticulitis, less
is known about how to adequately manage chronic bowel
symptoms related to symptomatic uncomplicated divertic-
ular disease and how to prevent diverticulitis recurrence.
Better understanding of inflammatory pathways and gut
Dig Dis Sci (2016) 61:673–683
microbiota has increased therapeutic options, including the
use of gut-directed antibiotics, mesalazine, and probiotics,
although more research is necessary to validate the safety,
effectiveness, and cost-effectiveness of these interventions.
Current evidence enhances the therapeutic role of
Rifaximin and mesalazine in the treatment of SUDD
symptoms, while only inconclusive results are available for
probiotic use. Fiber supplementation is still recommended
for SUDD treatment by the majority of the international
guidelines, even if its use is not supported by recent and
strong evidence.
Data regarding the prevention of acute diverticulitis are
still conflicting.
For these reasons, future studies are need to individu-
alize drug therapy, tailoring drug selection, and drug dos-
ing to a given patient, in order to optimize the efficacy of a
drug and minimize its toxicity.
Compliance with ethical standards
Conflict of interest The authors declare no conflict of interest.
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