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

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

* Xiaochun Zhang The microbiome in sites of the human body

[email protected]

1
Department of Medical Oncology, The Affiliated Hospital of The composition of the human microbiome varies by anatom-
Qingdao University, Qingdao University, Qingdao 266061, China ical sites. In the following sections, we introduce the
2
Cancer Institute, Qingdao 266061, China microbiome in some sites of the human body.
 Eur J Clin Microbiol Infect Dis

Table 1 Examples of human

microbiome research associated Terms Relevant diseases Publications
with some specific diseases
Skin/cutaneous Psoriasis 61
Gut/colon/intestinal Colorectal cancer/inflammatory bowel 3960
disease/obesity/rheumatoid arthritis/liver diseases
Oral/mouth/tongue/tooth/ Oral lichen planus 7
subgingival/supragingival
Lung/airway Asthma/chronic obstructive pulmonary disease/idiopathic 387
pulmonary fibrosis/pneumonia
Other (vaginal/nasal) Bacterial vaginitis/chronic rhinosinusitis 117

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(retrieved 20 March 2018)

The skin microbiome infection [23]. In addition, prior reports have confirmed that
the most important factor controlling cutaneous microbial
As the largest and most exposed organ of the human body, the composition is the ecological zone, followed by the effects
skin is a unique biological barrier to the external environment of ethnicity and the use of particular soaps and shampoos as
[7, 8]. Various microbes, including bacteria, fungi, and viruses, secondary factors [7, 24, 25].
colonize the skin with different distributions [9–11]. Compared
to other body sites, such as the gastro-intestinal tract, the bio- The intestinal microbiome
mass of microbes from cutaneous sites is relatively low [3];
however, the level of bacterial diversity in the skin probably The human intestine harbors numerous microorganisms, in-
approaches that of the colon [12]. Microbes with different skin cluding commensals, symbionts, and some opportunistic path-
locations in humans have disparate richness, abundance, and ogens. As an internalized Bmicrobial organ,^ the intestinal
alpha diversity; however, there is no significant difference in microbiome has a profound influence on human physiology,
alpha diversity among ethnic groups at each skin site [13]. Skin nutrition, and health [26], such as short-chain fatty acid
sites vary with the local conditions of the skin (dry, moist, and (SCFA) production and vitamin synthesis [27, 28]. A previous
sebaceous) and are mainly affiliated with Corynebacterium, study reported that human intestinal microbes comprise
Propionibacteriu, and Staphylococcus [14]. They are primarily 9,879,896 genes by combining 1267 previously and newly se-
influenced by a wealth of intrinsic (host age, diet, gender, im- quenced samples from three continents [29]. Based on micro-
mune status, genetic predisposition, and so on) and extrinsic bial taxa, gene families, and metabolic pathways, the human
(environmental and behavioral) factors [15]. intestinal microbiome is typical for omnivorous primates [30].
These skin microbes play beneficial or harmful roles in the The composition and diversity of the human intestinal
host [16]. We have learned about many diseases in humans microbiome vary greatly with ethnic background, lifestyle,
that are closely linked with the skin microbiome, such as pso- age, and geography [31–33]. Generally, the intestinal
riasis and atopic dermatitis. Psoriasis is associated with exten- microbiome is dominated by members of the divisions
sive variations in the composition and representation of the Bacteroidetes and Firmicutes [34]. However, the intestinal
skin microbiome. Cho and Blaser found that the increased microbiome probably differs in different periods of life. For
ratio of Firmicutes to Actinobacteria species was often ac- example, the structure of the intestinal microbiome varies great-
companied by the occurrence of psoriasis [17]. Atopic derma- ly from the first to the third trimesters of pregnancy, with an
titis is also a common, chronic inflammatory skin disease. The increase in Proteobacteria and Actinobacteria over time [35].
morbidity of atopic dermatitis is often caused by cutaneous The intestinal microbiome, as a complex microbial ecosys-
microbiota infections. For example, Stapbylococcus aureus is tem, has been associated with (inducing or aggravating) many
extremely prevalent on atopic dermatitis skin and has a direct diseases, such as obesity [36], colorectal cancer [37, 38], in-
correlation with atopic dermatitis clinical severity [18]. flammatory bowel disease [39], rheumatoid arthritis [40], and
Meanwhile, parts of the skin microbiome are also involved liver diseases [41]. It has been reported that the intestinal
in the maintenance of skin homeostasis. Studies have found microbiome could act as an ambient factor in regulating fat
that nonpathogenic bacteria, such as Staphylococcus storage in humans [42]. Enterobacter cloacae, which is an
epidermidis and Propionibacterium acnes [19–21], can inhibit obesity-inducing strain in the human intestine, is known to
Staphylococcus aureus to restore balanced communities and cause bacteremia [43]. Akkermansia muciniphila and
alleviate atopic dermatitis-related skin inflammation [22]. Clostridium coccoides have been reported to be closely linked
S. epidermidis could tune the function of resident skin T lym- to decreasing adiposity [44]. Infection with Streptococcus
phocytes and enhance skin defense mechanisms against bovis is a risky sign for colon tumors [45]. Enterotosigenic
Eur J Clin Microbiol Infect Dis

Bacteroides fragilis and Fusobacterium nucletum have been Unlike the intestinal microbiome, the lung microbiome on-
identified to be closely associated with colorectal cancer tissue ly has a density of 10–100 bacterial cells per 1000 human cells
[46]. Patients with colorectal cancer often have a lower micro- [58]. The lung microbiome has a low microbial concentration,
bial diversity and Clostridia abundance [47]. Rather than a but it is important to host immunity. A study showed that
simple causal relationship, there is probably a complex and healthy adults exposed to higher levels of particulates tended
dynamic relationship between intestinal microbial dysbiosis to have a higher level of potentially pathogenic bacteria in
and inflammatory bowel disease (IBD). IBD patients usually their lungs [59]. An imbalanced microbial ecosystem in the
have dysbiosis with reduced numbers of SCFAs-producing lung may incur the development of respiratory diseases [60],
bacteria, which is a factor in the emergence and severity of such as asthma, chronic obstructive pulmonary disease
IBD [48]. Furthermore, dysregulation of host responses in the (COPD), idiopathic pulmonary fibrosis, and pneumonia.
intestinal lumen could influence distant anatomical sites by Adult asthmatics exhibit changes in their lower respiratory
the activation of host immune responses, which occurs in tract microbiome, typically showing enhanced community di-
rheumatoid arthritis [40]. In addition, the liver is the first organ versity and abundance in the Proteobacteria phylum [61]. The
to be exposed to the metabolic products generated by the lung microbiome of advanced COPD patients has been ob-
intestinal microbiome. Many observations have suggested that served to shift from the Bacteroidetes to Proteobacteria phy-
there are close links between intestinal microbial composition lum [62], potentially including its familiar pathogenic mem-
and liver diseases [49]. 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-
The oral microbiome
crobial community members Staphylococcus spp. and
Streptococcus spp. and the progression of idiopathic pulmo-
The complexity of the oral microbiome is similar to that of the
nary fibrosis [64]. Most pneumonia cases resulting from a
intestinal microbiome, but it is comprised of different species
single pathogen are characterized by high microbial biomass,
and tends to be dominated by Streptococcus spp. [50]. The oral
low microbial diversity, and host inflammation [65].
microbiome is a valuable asset and plays an important role in
Therefore, quantitative and/or qualitative changes in the lung
oral health and disease [51]. Oral microbial communities vary
microbiome may be closely linked with many pulmonary
from childhood to adulthood [52]. Zheng et al. found that there
diseases.
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
Other microbiomes
from healthy implant status to peri-implant disease [53]. The
researchers also compared microbial taxa in oral lichen planus
Except for the skin microbiome, intestinal microbiome, oral
(OLP) patients and healthy individuals and identified the
microbiome, and lung microbiome, microbiomes in other
dysbiosis in the oral microbial community of OLP patients,
sites of the body have also been explored. For example,
indicating a potential microbial role in the progression of OLP.
the vaginal microbiome not only influences human repro-
Dental caries have a polymicrobial etiology caused by various
ductive physiology, but also is potentially affected by host
oral bacterial consortia. Some differentially abundant taxa, such
physiology during puberty and menopause [66, 67]. A
as Lactobacillus, Cryptobacterium, Atopobium, Ochrobactrum,
healthy vagina contains at least five reproducible commu-
Centipeda, and Mycoplasma, are considered to be potential bio-
nity types, each dominated by a single species of
markers to better diagnose dental caries occurrence.
Lactobacillus or by a mixture of other microbes, including
Gardnerella [68]. The nostril microbiome varies seasonally
The lung microbiome in young children [69] and is also very valuable in human
health and disease [70].
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, Intestinal microbiota and cancer therapy
Actinobacteria, and Firmicutes, that drive and reflect immune
function and mucosal inflammation [54, 55]. The lung Intestinal microbiota can modulate host physiological func-
microbiome resembles the microbiome of the mouth more tion, inflammation, and immunity to influence health status
closely than the microbiomes of other body sites [56]. and disease occurrence and/or progression [71]. There is
Meanwhile, mouth-lung microbial similarity may be related to growing awareness regarding the role of the intestinal micro-
circadian rhythms, peaking overnight and waning daytime [57]. 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

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Intestinal microbiota and cancer chemotherapy responder patients in response to immunotherapy are differ-
ent; however, these results still show the close relationship
Mucositis, which is one of the most debilitating side effects of between the intestinal microbiota and cancer immunotherapy.
chemotherapy, often results in a higher mortality in cancer
patients [79]. Chemotherapy has a detrimental effect on intes- Intestinal microbiota and cancer radiotherapy
tinal microbial composition, which increases in potentially
pathogenic bacteria and decreases in commensal anaerobes The effects of radiotherapy on the intestinal microbiota have
[80]. Significant reductions in Faecalibacterium prausnitzii not been studied extensively; however, radiation-induced
and Clostridium cluster XIVa have been reported during che- bowel injury is influenced by the intestinal microbiota. It has
motherapy, which were thought to contribute to chemotherapy- been reported first that the intestinal microbiota is a key mod-
associated intestinal inflammation and mucositis [72]. ifier of radiation-induced intestinal injury, showing marked
However, Fusobacterium nucleatum was demonstrated to pro- resistance to lethal radiation enteritis [82]. Then, probiotic
mote colorectal cancer resistance to chemotherapy [73]. The Lactobacillus was found to exert protective effects in a pre-
broad-spectrum antibiotics vancomycin and colistin can influ- clinical model of radiation-induced intestinal epithelium inju-
ence the intestinal microbiota, so the efficacy of chemotherapy ry in a TLR-2/cyclo-oxygenase-2-dependent manner [83].
is closely associated with the intestinal microbiota [81]. In There are many studies about ameliorating radiation-induced
addition, antibiotics combined with chemotherapy may work diarrhea using Lactobacillus acidophilus, Bifidobacterium
synergistically to increase bacterial translocation from the gut. bifidum, and other probiotics [77, 78]. Radiotherapy for gyne-
Therefore, an intact intestinal microbiota appears to be required cological cancer patients could result in a decrease in the
for optimal efficacy in cancer chemotherapy. abundance and diversity of intestinal microbiota [84]. In ad-
dition, radiotherapy-induced intestinal injuries promote the
Intestinal microbiota and cancer immunotherapy intestinal microbiota to partly activate the immune reaction,
which is closely correlated with treatment efficacy.
The studies of Gopalakrishnan V et al., Routy B et al., and Therefore, targeting intestinal microbiota with strategies
Matson V et al. have reported that the composition of the such as nutrition, probiotics and prebiotics, or antibiotic selec-
intestinal microbiota could modulate the tumor response to tion may be an effective way to conduct precision medicine in
immunotherapy with blocking antibodies against PD-1 or cancer patients.
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- Microbial sequencing and analytical
tors. Akkermansia muciniphila, which belongs to the technique
Verrucomicrobiaceae family, is more abundant in responder
patients in response to immunotherapy than in non-responders Although microbes are responsible for key functions in the
[74]. Significantly higher alpha diversity and relative abun- determination of human health and disease, high microbial
dance of Ruminococcaceae species are found to be in re- diversity has made it difficult to explore specific functions,
sponder patients with melanoma in response to anti-PD-1 im- especially in the complex human system. Fortunately, techno-
munotherapy [75], whereas Bifidobacterium longum, logical and analytical advances have greatly facilitated studies
Enterococcus faecium, and Collinsella aureofaciens seem to on the composition and function of complex microbes in
be key in another study on responder patients with melanoma humans [85]. DNA sequencing technology developments have
[76]. Due to distinct organ sites, metagenomics technologies, made many discoveries related to the identities and potential
statistical methods, and others, the dominant species of functions of microbes in our own bodies. Previously,
Eur J Clin Microbiol Infect Dis

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With improvements in sequencing technology and bioinfor- 1638
13. Perez Perez GI, Gao Z, Jourdain R, Ramirez J, Gany F, Clavaud C,
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Bouffard GG, Blakesley RW, Murray PR, Green ED (2009)
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by China Postdoctoral Science Foundation (2016M602094), Qingdao bacterial infections of the skin. J Investig Dermatol Symp Proc 6(3):
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Compliance with ethical standards 19. Iwase T, Uehara Y, Shinji H, Tajima A, Seo H, Takada K, Agata T,
Mizunoe Y (2010) Staphylococcus epidermidis Esp inhibits
Conflict of interest The authors declare that they have no competing Staphylococcus aureus biofilm formation and nasal colonization.
interests. Nature 465(7296):346–349
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Hooper LV, Schmidt RR, Von AS (2009) Commensal bacteria reg-
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