European Journal of Clinical Microbiology & Infectious Diseases

https://doi.org/10.1007/s10096-018-3263-1

REVIEW

How human microbiome talks to health and disease

Jing Cong 1,2 & Xiaochun Zhang 1,2

Received: 20 March 2018 / Accepted: 12 April 2018

# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Microbes are ubiquitous in the human body. They usually live in communities, and each of these communities has a distinct
taxonomical structure. Due to its close relationship with human health and disease, the human microbiome has received great
attention and is probably considered to be the most valuable biomarker in preventing and solving human diseases. In this paper,
we first review the value of the human microbiome. Then, we focus on the role of the human microbiome in influencing human
health and disease. Furthermore, we intensively discuss the relationship between intestinal microbiota and cancer therapy.
Finally, we briefly summarize the significance of the human microbiome based on the development of sequencing and bioin-
formatic techniques.

Keywords Human microbiome . Health and disease . Intestinal microbiota . Cancer therapy . Technique

Introduction [3]. The human microbiome contains an enormous group of

Based on human evolutionary history, we know that the envi-
ronment has played a main role in the way that we have
evolved. Microbes follow the premise of Beverything is ev-
erywhere, but the environment selects^ [1]. Certainly, mi-
crobes can colonize both outside and inside the human body.
They have evolved with humans and have established a com-
plex host-microbial relationship. As humans, we provide
Broom and board^ for these microbes; in turn, they can me-
tabolize molecules that we cannot metabolize ourselves. This
symbiotic relationship not only influences human health but
also causes a risk of disease occurrence.
Recently, many researchers have considered the human
microbiome as an Borgan^ [2]. The human microbiome is
estimated to include 100 trillion cells in total, which is ten
times greater than the number of human cells. The aggregate
of microbial genes greatly surpasses the number of genes in
the human genome by orders of magnitude. Therefore, the
microbiome is referred to as Ba second genome^ in humans
prokaryotes, viruses, and eukaryotes that have close relation-
ships to human health and disease. Different microbial com-
munities occupy different habitats of the human body. We rely
on these microbes to aid in nutrition, combat pathogens, and
modulate our immune system [4]. Therefore, the human
microbiome is valuable in human health and disease.
Overall, how does the microbiome influence human health
or trigger disease? Is there a causal relationship between mi-
crobial variation and pathology? Recently, numerous studies
have been conducted on the human microbial variations that
occur in specific disease states, or temporal microbial changes.
For example, the occurrence of psoriasis could be related to an
increased ratio of Firmicutes to Actinobacteria [5], whereas a
reduced ratio of Bacteroidetes to Firmicutes may cause obe-
sity [6]. A combination of recent technological advances and
bioinformatics development has driven a surge of interest in
the human microbiome (Table 1). The purpose of this review
is to help us better understand the role of human microbiome
in the health and disease.

* Xiaochun Zhang The microbiome in sites of the human body

zhangxiaochun9670@126.com

1
Department of Medical Oncology, The Affiliated Hospital of
Qingdao University, Qingdao University, Qingdao 266061, China
2
Cancer Institute, Qingdao 266061, China
The composition of the human microbiome varies by anatom-
ical sites. In the following sections, we introduce the
microbiome in some sites of the human body.

Table 1 Examples of human
microbiome research associated Terms
with some specific diseases
Skin/cutaneous
Gut/colon/intestinal
Oral/mouth/tongue/tooth/
subgingival/supragingival
Lung/airway
Other (vaginal/nasal)
Number of results obtained by searching for B(microbiota/microbiome/microflora)^ (<Terms>)^ on PubMed
(retrieved 20 March 2018)
The skin microbiome
As the largest and most exposed organ of the human body, the
skin is a unique biological barrier to the external environment
[7, 8]. Various microbes, including bacteria, fungi, and viruses,
colonize the skin with different distributions [9–11]. Compared
to other body sites, such as the gastro-intestinal tract, the bio-
mass of microbes from cutaneous sites is relatively low [3];
however, the level of bacterial diversity in the skin probably
approaches that of the colon [12]. Microbes with different skin
locations in humans have disparate richness, abundance, and
alpha diversity; however, there is no significant difference in
alpha diversity among ethnic groups at each skin site [13]. Skin
sites vary with the local conditions of the skin (dry, moist, and
sebaceous) and are mainly affiliated with Corynebacterium,
Propionibacteriu, and Staphylococcus [14]. They are primarily
influenced by a wealth of intrinsic (host age, diet, gender, im-
mune status, genetic predisposition, and so on) and extrinsic
(environmental and behavioral) factors [15].
These skin microbes play beneficial or harmful roles in the
host [16]. We have learned about many diseases in humans
that are closely linked with the skin microbiome, such as pso-
riasis and atopic dermatitis. Psoriasis is associated with exten-
sive variations in the composition and representation of the
skin microbiome. Cho and Blaser found that the increased
ratio of Firmicutes to Actinobacteria species was often ac-
companied by the occurrence of psoriasis [17]. Atopic derma-
titis is also a common, chronic inflammatory skin disease. The
morbidity of atopic dermatitis is often caused by cutaneous
microbiota infections. For example, Stapbylococcus aureus is
extremely prevalent on atopic dermatitis skin and has a direct
correlation with atopic dermatitis clinical severity [18].
Meanwhile, parts of the skin microbiome are also involved
in the maintenance of skin homeostasis. Studies have found
that nonpathogenic bacteria, such as Staphylococcus
epidermidis and Propionibacterium acnes [19–21], can inhibit
Staphylococcus aureus to restore balanced communities and
alleviate atopic dermatitis-related skin inflammation [22].
S. epidermidis could tune the function of resident skin T lym-
phocytes and enhance skin defense mechanisms against
Eur J Clin Microbiol Infect Dis
Relevant diseases Publications
Psoriasis 61
Colorectal cancer/inflammatory bowel 3960
disease/obesity/rheumatoid arthritis/liver diseases
Oral lichen planus 7
Asthma/chronic obstructive pulmonary disease/idiopathic 387
pulmonary fibrosis/pneumonia
Bacterial vaginitis/chronic rhinosinusitis 117
infection [23]. In addition, prior reports have confirmed that
the most important factor controlling cutaneous microbial
composition is the ecological zone, followed by the effects
of ethnicity and the use of particular soaps and shampoos as
secondary factors [7, 24, 25].
The intestinal microbiome
The human intestine harbors numerous microorganisms, in-
cluding commensals, symbionts, and some opportunistic path-
ogens. As an internalized Bmicrobial organ,^ the intestinal
microbiome has a profound influence on human physiology,
nutrition, and health [26], such as short-chain fatty acid
(SCFA) production and vitamin synthesis [27, 28]. A previous
study reported that human intestinal microbes comprise
9,879,896 genes by combining 1267 previously and newly se-
quenced samples from three continents [29]. Based on micro-
bial taxa, gene families, and metabolic pathways, the human
intestinal microbiome is typical for omnivorous primates [30].
The composition and diversity of the human intestinal
microbiome vary greatly with ethnic background, lifestyle,
age, and geography [31–33]. Generally, the intestinal
microbiome is dominated by members of the divisions
Bacteroidetes and Firmicutes [34]. However, the intestinal
microbiome probably differs in different periods of life. For
example, the structure of the intestinal microbiome varies great-
ly from the first to the third trimesters of pregnancy, with an
increase in Proteobacteria and Actinobacteria over time [35].
The intestinal microbiome, as a complex microbial ecosys-
tem, has been associated with (inducing or aggravating) many
diseases, such as obesity [36], colorectal cancer [37, 38], in-
flammatory bowel disease [39], rheumatoid arthritis [40], and
liver diseases [41]. It has been reported that the intestinal
microbiome could act as an ambient factor in regulating fat
storage in humans [42]. Enterobacter cloacae, which is an
obesity-inducing strain in the human intestine, is known to
cause bacteremia [43]. Akkermansia muciniphila and
Clostridium coccoides have been reported to be closely linked
to decreasing adiposity [44]. Infection with Streptococcus
bovis is a risky sign for colon tumors [45]. Enterotosigenic
Eur J Clin Microbiol Infect Dis
Bacteroides fragilis and Fusobacterium nucletum have been
identified to be closely associated with colorectal cancer tissue
[46]. Patients with colorectal cancer often have a lower micro-
bial diversity and Clostridia abundance [47]. Rather than a
simple causal relationship, there is probably a complex and
dynamic relationship between intestinal microbial dysbiosis
and inflammatory bowel disease (IBD). IBD patients usually
have dysbiosis with reduced numbers of SCFAs-producing
bacteria, which is a factor in the emergence and severity of
IBD [48]. Furthermore, dysregulation of host responses in the
intestinal lumen could influence distant anatomical sites by
the activation of host immune responses, which occurs in
rheumatoid arthritis [40]. In addition, the liver is the first organ
to be exposed to the metabolic products generated by the
intestinal microbiome. Many observations have suggested that
there are close links between intestinal microbial composition
and liver diseases [49].
The oral microbiome
The complexity of the oral microbiome is similar to that of the
intestinal microbiome, but it is comprised of different species
and tends to be dominated by Streptococcus spp. [50]. The oral
microbiome is a valuable asset and plays an important role in
oral health and disease [51]. Oral microbial communities vary
from childhood to adulthood [52]. Zheng et al. found that there
was higher subgingival microbial diversity in ailing dental im-
plant patients than in healthy implant patients, indicating that
periodontal pathogens could play key roles in the progression
from healthy implant status to peri-implant disease [53]. The
researchers also compared microbial taxa in oral lichen planus
(OLP) patients and healthy individuals and identified the
dysbiosis in the oral microbial community of OLP patients,
indicating a potential microbial role in the progression of OLP.
Dental caries have a polymicrobial etiology caused by various
oral bacterial consortia. Some differentially abundant taxa, such
as Lactobacillus, Cryptobacterium, Atopobium, Ochrobactrum,
Centipeda, and Mycoplasma, are considered to be potential bio-
markers to better diagnose dental caries occurrence.
The lung microbiome
Previously, healthy lungs were assumed to be a sterile environ-
ment. However, extensive sequencing analyses from the lungs
of healthy individuals have identified microbial organisms,
such as those in the phyla Bacteroidetes, Proteobacteria,
Actinobacteria, and Firmicutes, that drive and reflect immune
function and mucosal inflammation [54, 55]. The lung
microbiome resembles the microbiome of the mouth more
closely than the microbiomes of other body sites [56].
Meanwhile, mouth-lung microbial similarity may be related to
circadian rhythms, peaking overnight and waning daytime [57].
Unlike the intestinal microbiome, the lung microbiome on-
ly has a density of 10–100 bacterial cells per 1000 human cells
[58]. The lung microbiome has a low microbial concentration,
but it is important to host immunity. A study showed that
healthy adults exposed to higher levels of particulates tended
to have a higher level of potentially pathogenic bacteria in
their lungs [59]. An imbalanced microbial ecosystem in the
lung may incur the development of respiratory diseases [60],
such as asthma, chronic obstructive pulmonary disease
(COPD), idiopathic pulmonary fibrosis, and pneumonia.
Adult asthmatics exhibit changes in their lower respiratory
tract microbiome, typically showing enhanced community di-
versity and abundance in the Proteobacteria phylum [61]. The
lung microbiome of advanced COPD patients has been ob-
served to shift from the Bacteroidetes to Proteobacteria phy-
lum [62], potentially including its familiar pathogenic mem-
bers (e.g., Haemophilus spp., Pseudomonas spp.) and occa-
sionally to Firmicutes phylum [63]. There is a positive rela-
tionship between the relative abundance of specific lung mi-
crobial community members Staphylococcus spp. and
Streptococcus spp. and the progression of idiopathic pulmo-
nary fibrosis [64]. Most pneumonia cases resulting from a
single pathogen are characterized by high microbial biomass,
low microbial diversity, and host inflammation [65].
Therefore, quantitative and/or qualitative changes in the lung
microbiome may be closely linked with many pulmonary
diseases.
Other microbiomes
Except for the skin microbiome, intestinal microbiome, oral
microbiome, and lung microbiome, microbiomes in other
sites of the body have also been explored. For example,
the vaginal microbiome not only influences human repro-
ductive physiology, but also is potentially affected by host
physiology during puberty and menopause [66, 67]. A
healthy vagina contains at least five reproducible commu-
nity types, each dominated by a single species of
Lactobacillus or by a mixture of other microbes, including
Gardnerella [68]. The nostril microbiome varies seasonally
in young children [69] and is also very valuable in human
health and disease [70].
Intestinal microbiota and cancer therapy
Intestinal microbiota can modulate host physiological func-
tion, inflammation, and immunity to influence health status
and disease occurrence and/or progression [71]. There is
growing awareness regarding the role of the intestinal micro-
biota in cancer therapy (Table 2).
 Eur J Clin Microbiol Infect Dis

Table 2 Lists of publications

about intestinal microbiota and Cancer therapy Key intestinal microbiota Publications
cancer therapy 2013–2018

Chemotherapy Faecalibacterium prausnitzii [72], Clostridium cluster 97

XIVa [72], Fusobacterium nucleatum [73]
Immunotherapy Akkermansia muciniphila [74], Ruminococcacea [75], 84
Bifidobacterium longum [76], Enterococcus faecium [76],
Collinsella aerofaciens [76]
Radiotherapy Lactobacillus acidophilus, Bifidobacterium bifidum [77, 78] 18

Number of results obtained by searching for B(microbiota/microbiome/microflora)^ (<Terms>)^ on PubMed

(retrieved 20 March 2018)

Intestinal microbiota and cancer chemotherapy
Mucositis, which is one of the most debilitating side effects of
chemotherapy, often results in a higher mortality in cancer
patients [79]. Chemotherapy has a detrimental effect on intes-
tinal microbial composition, which increases in potentially
pathogenic bacteria and decreases in commensal anaerobes
[80]. Significant reductions in Faecalibacterium prausnitzii
and Clostridium cluster XIVa have been reported during che-
motherapy, which were thought to contribute to chemotherapy-
associated intestinal inflammation and mucositis [72].
However, Fusobacterium nucleatum was demonstrated to pro-
mote colorectal cancer resistance to chemotherapy [73]. The
broad-spectrum antibiotics vancomycin and colistin can influ-
ence the intestinal microbiota, so the efficacy of chemotherapy
is closely associated with the intestinal microbiota [81]. In
addition, antibiotics combined with chemotherapy may work
synergistically to increase bacterial translocation from the gut.
Therefore, an intact intestinal microbiota appears to be required
for optimal efficacy in cancer chemotherapy.
Intestinal microbiota and cancer immunotherapy
The studies of Gopalakrishnan V et al., Routy B et al., and
Matson V et al. have reported that the composition of the
intestinal microbiota could modulate the tumor response to
immunotherapy with blocking antibodies against PD-1 or
PD-L1 in patients with melanoma cancer [74–76]. There is a
significant association between commensal microbial compo-
sition and the clinical response to immune checkpoint inhibi-
tors. Akkermansia muciniphila, which belongs to the
Verrucomicrobiaceae family, is more abundant in responder
patients in response to immunotherapy than in non-responders
[74]. Significantly higher alpha diversity and relative abun-
dance of Ruminococcaceae species are found to be in re-
sponder patients with melanoma in response to anti-PD-1 im-
munotherapy [75], whereas Bifidobacterium longum,
Enterococcus faecium, and Collinsella aureofaciens seem to
be key in another study on responder patients with melanoma
[76]. Due to distinct organ sites, metagenomics technologies,
statistical methods, and others, the dominant species of
responder patients in response to immunotherapy are differ-
ent; however, these results still show the close relationship
between the intestinal microbiota and cancer immunotherapy.
Intestinal microbiota and cancer radiotherapy
The effects of radiotherapy on the intestinal microbiota have
not been studied extensively; however, radiation-induced
bowel injury is influenced by the intestinal microbiota. It has
been reported first that the intestinal microbiota is a key mod-
ifier of radiation-induced intestinal injury, showing marked
resistance to lethal radiation enteritis [82]. Then, probiotic
Lactobacillus was found to exert protective effects in a pre-
clinical model of radiation-induced intestinal epithelium inju-
ry in a TLR-2/cyclo-oxygenase-2-dependent manner [83].
There are many studies about ameliorating radiation-induced
diarrhea using Lactobacillus acidophilus, Bifidobacterium
bifidum, and other probiotics [77, 78]. Radiotherapy for gyne-
cological cancer patients could result in a decrease in the
abundance and diversity of intestinal microbiota [84]. In ad-
dition, radiotherapy-induced intestinal injuries promote the
intestinal microbiota to partly activate the immune reaction,
which is closely correlated with treatment efficacy.
Therefore, targeting intestinal microbiota with strategies
such as nutrition, probiotics and prebiotics, or antibiotic selec-
tion may be an effective way to conduct precision medicine in
cancer patients.
Microbial sequencing and analytical
technique
Although microbes are responsible for key functions in the
determination of human health and disease, high microbial
diversity has made it difficult to explore specific functions,
especially in the complex human system. Fortunately, techno-
logical and analytical advances have greatly facilitated studies
on the composition and function of complex microbes in
humans [85]. DNA sequencing technology developments have
made many discoveries related to the identities and potential
functions of microbes in our own bodies. Previously,
Eur J Clin Microbiol Infect Dis
sequencing was performed on only a single bacterial genome
using the Sanger approach, which took years to complete. With
developments in the speed and throughput of nucleic acid se-
quencing technologies, complete bacterial genome sequencing
can be completed in a short time. Next-generation sequencing
of community DNA has made it possible to determine the
specific microbial groups in the human body. Both 16S
rRNA sequencing and whole-genome sequencing are com-
monly used to explore the taxonomical structure and functional
profile of microbial communities. Metatranscriptomics,
metaproteomics, and metabolomics have also offered a wealth
of knowledge about the human microbiome. In addition, the
extraordinarily large datasets of human microbiome studies
show that bioinformatics approaches are indispensable for
analyses. With applications ranging from dissecting microbial
structures by tracking microbial states, functions, and intercel-
lular interactions to probing individual cells, analytical
methods will continue to be a key driving force in human
microbiome science.
Conclusions
With improvements in sequencing technology and bioinfor-
matic approaches, deciphering the roles of the human
microbiome is very important for the treatment and care in
human health. Importantly, a more complete knowledge of
the human microbiome will contribute to a better understand-
ing of how diseases influence microbial functions, enabling
better predictions of impacts and facilitating improved human
health strategies.
Funding This study was supported by funding from the project funded
by China Postdoctoral Science Foundation (2016M602094), Qingdao
Application Research Project (2016047), Youth Research Fund Project,
and Qingdao People’s Livelihood Science and Technology Program (16-
6-2-3-nsh).
Compliance with ethical standards
Conflict of interest The authors declare that they have no competing
interests.
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