Human microbiota

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Graphic depicting the human skin microbiota, with relative prevalences of various classes of bacteria.

The human microbiota is the aggregate of microorganisms, a microbiome that resides on or within a number of tissues and biofluids, including the skin, mammary glands, placenta, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, and gastrointestinal tracts. They include bacteria, fungi, and archaea. Micro-animals which live on the human body are excluded. The human microbiome refers to their genomes.[1]

Humans are colonized by many microorganisms; the traditional estimate was that humans live with ten times more non-human cells than human cells; more recent estimates have lowered that to 3:1 and even to approximately the same number; all the numbers are estimates.[2][3][4][5] Some microbiota that colonize humans have not merely a commensal (a non-harmful coexistence), but rather a mutualistic relationship with their human hosts.[1]:700[6] Conversely, some non-pathogenic microbiota can harm human hosts via the metabolites that they produce, like trimethylamine.[7][8] Certain microbiota perform tasks that are known to be useful for the human host; for most, the role is not well understood. Those that are expected to be present, and that under normal circumstances do not cause disease, are deemed normal flora or normal microbiota.[1]

The Human Microbiome Project took on the project of sequencing the genome of the human microbiota, focusing particularly on the microbiota that normally inhabit the skin, mouth, nose, digestive tract, and vagina.[1] It reached a milestone in 2012 when it published initial results.[9]

Terminology[edit]

Though widely known as flora or microflora, this is a misnomer in technical terms, since the word root flora pertains to plants, and biota refers to the total collection of organisms in a particular ecosystem. Recently, the more appropriate term microbiota is applied, though its use has not eclipsed the entrenched use and recognition of flora with regard to bacteria and other microorganisms. Both terms are being used in different literature.[6]

Relative numbers[edit]

As of 2014, it was often reported in popular media and in the scientific literature that there are about 10 times as many microbial cells in the human body than there are human cells; this figure was based on estimates that the human microbiome includes around 100 trillion bacterial cells and an adult human typically has around 10 trillion human cells.[2] In 2014 the American Academy of Microbiology published an FAQ that emphasized that the number of microbial cells and the number of human cells are both estimates, and noted that recent research had arrived at a new estimate of the number of human cells at around 37 trillion cells, meaning that the ratio of microbial to human cells is probably about 3:1.[2][3] In 2016 another group published a new estimate of ratio as being roughly 1:1 (1.3:1, with "an uncertainty of 25% and a variation of 53% over the population of standard 70 kg males").[4][5]

Study[edit]

Flowchart illustrating how the human microbiome is studied on the DNA level.

The problem of elucidating the human microbiome is essentially identifying the members of a microbial community which includes bacteria, eukaryotes, and viruses.[10] This is done primarily using DNA-based studies, though RNA, protein and metabolite based studies are also performed.[10][11] DNA-based microbiome studies typically can be categorized as either targeted amplicon studies or more recently shotgun metagenomic studies. The former focuses on specific known marker genes and is primarily informative taxonomically, while the latter is an entire metagenomic approach which can also be used to study the functional potential of the community.[10] One of the challenges that is present in human microbiome studies but not in other metagenomic studies is to avoid including the host DNA in the study.[12]

Aside from simply elucidating the composition of the human microbiome, one of the major questions involving the human microbiome is whether there is a "core", that is, whether there is a subset of the community that is shared among most humans.[13][14] If there is a core, then it would be possible to associate certain community compositions with disease states, which is one of the goals of the Human Microbiome Project. It is known that the human microbiome is highly variable both within a single subject and between different individuals. For example, the gut microbiota of humans is markedly dissimilar between individuals, a phenomenon which is also observed in mice.[6]

On 13 June 2012, a major milestone of the Human Microbiome Project (HMP) was announced by the NIH director Francis Collins.[9] The announcement was accompanied with a series of coordinated articles published in Nature[15][16] and several journals in the Public Library of Science (PLoS) on the same day. By mapping the normal microbial make-up of healthy humans using genome sequencing techniques, the researchers of the HMP have created a reference database and the boundaries of normal microbial variation in humans. From 242 healthy U.S. volunteers, more than 5,000 samples were collected from tissues from 15 (men) to 18 (women) body sites such as mouth, nose, skin, lower intestine (stool), and vagina. All the DNA, human and microbial, were analyzed with DNA sequencing machines. The microbial genome data were extracted by identifying the bacterial specific ribosomal RNA, 16S rRNA. The researchers calculated that more than 10,000 microbial species occupy the human ecosystem and they have identified 81 – 99% of the genera.

Types[edit]

Bacteria[edit]

Populations of microbes (such as bacteria and yeasts) inhabit the skin and mucosal surfaces in various parts of the body. Their role forms part of normal, healthy human physiology, however if microbe numbers grow beyond their typical ranges (often due to a compromised immune system) or if microbes populate (such as through poor hygiene or injury) areas of the body normally not colonized or sterile (such as the blood, or the lower respiratory tract, or the abdominal cavity), disease can result (causing, respectively, bacteremia/sepsis, pneumonia, and peritonitis).

The Human Microbiome Project found that individuals host thousands of bacterial types, different body sites having their own distinctive communities. Skin and vaginal sites showed smaller diversity than the mouth and gut, these showing the greatest richness. The bacterial makeup for a given site on a body varies from person to person, not only in type, but also in abundance. Bacteria of the same species found throughout the mouth are of multiple subtypes, preferring to inhabit distinctly different locations in the mouth. Even the enterotypes in the human gut, previously thought to be well-understood, are from a broad spectrum of communities with blurred taxon boundaries.[17][18]

It is estimated that 500 to 1,000 species of bacteria live in the human gut but belong to just a few phyla: Firmicutes and Bacteroidetes dominate but there are also Proteobacteria, Verrumicrobia, Actinobacteria, Fusobacteria and Cyanobacteria.[19]

A number of types of bacteria, such as Actinomyces viscosus and A. naeslundii, live in the mouth, where they are part of a sticky substance called plaque. If this is not removed by brushing, it hardens into calculus (also called tartar). The same bacteria also secrete acids that dissolve tooth enamel, causing tooth decay.

The vaginal microflora consist mostly of various lactobacillus species. It was long thought that the most common of these species was Lactobacillus acidophilus, but it has later been shown that the most common one is L. iners followed by L. crispatus. Other lactobacilli found in the vagina are L. jensenii, L. delbruekii and L. gasseri. Disturbance of the vaginal flora can lead to infections such as bacterial vaginosis or candidiasis ("yeast infection").

Archaea[edit]

Archaea are present in the human gut, but, in contrast to the enormous variety of bacteria in this organ, the numbers of archaeal species are much more limited.[20] The dominant group are the methanogens, particularly Methanobrevibacter smithii and Methanosphaera stadtmanae.[21] However, colonization by methanogens is variable, and only about 50% of humans have easily detectable populations of these organisms.[22]

As of 2007, no clear examples of archaeal pathogens were known,[23][24] although a relationship has been proposed between the presence of some methanogens and human periodontal disease.[25]

Fungi[edit]

See also: Mycobiome

Fungi, in particular yeasts, are present in the human gut.[26][27][28][29] The best-studied of these are Candida species due to their ability to become pathogenic in immunocompromised and even in healthy hosts.[27][28][29] Yeasts are also present on the skin,[26] such as Malassezia species, where they consume oils secreted from the sebaceous glands.[30][31]

Anatomical areas[edit]

Main article: List of human flora

Skin[edit]

Main article: Skin flora

A study of twenty skin sites on each of ten healthy humans found 205 identified genera in nineteen bacterial phyla, with most sequences assigned to four phyla: Actinobacteria (51.8%), Firmicutes (24.4%), Proteobacteria (16.5%), and Bacteroidetes (6.3%).[32] A large number of fungal genera are present on healthy human skin, with some variability by region of the body; however, during pathological conditions, certain genera tend to dominate in the affected region.[26] For example, Malassezia is dominant in atopic dermatitis and Acremonium is dominant on dandruff-afflicted scalps.[26]

The skin acts as a barrier to deter the invasion of pathogenic microbes. The human skin contains microbes that reside either in or on the skin and can be residential or transient. Resident microorganism types vary in relation to skin type on the human body. A majority of microbes reside on superficial cells on the skin or prefer to associate with glands. These glands such as oil or sweat glands provide the microbes with water, amino acids, and fatty acids. In addition, resident bacteria that associated with oil glands are often Gram-positive and can be pathogenic.[1]

Conjunctiva[edit]

A small number of bacteria and fungi are normally present in the conjunctiva.[26][33] Classes of bacteria include Gram-positive cocci (e.g., Staphylococcus and Streptococcus) and Gram-negative rods and cocci (e.g., Haemophilus and Neisseria) are present.[33] Fungal genera include Candida, Aspergillus, and Penicillium.[26] The lachrymal glands continuously secrete, keeping the conjunctiva moist, while intermittent blinking lubricates the conjunctiva and washes away foreign material. Tears contain bactericides such as lysozyme, so that microorganisms have difficulty in surviving the lysozyme and settling on the epithelial surfaces.

Gut[edit]

Main article: Gut flora
Tryptophan metabolism by human gastrointestinal microbiota (v · t · e)
Tryptophan metabolism diagram
This diagram shows the biosynthesis of bioactive compounds (indole and certain derivatives) from tryptophan by bacteria in the gut.[34] Indole is produced from tryptophan by bacteria that express tryptophanase.[34] Clostridium sporogenes metabolizes indole into 3-indolepropionic acid (IPA),[35] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals.[34][36][37] In the intestine, IPA binds to pregnane X receptors (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.[34] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer’s disease.[34] Lactobacillus species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production.[34] Indole itself acts as a glucagon-like peptide-1 (GLP-1) secretagogue in intestinal L cells and as a ligand for AhR.[34] Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction.[34] AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.[34]

The gut flora has the largest numbers of bacteria and the greatest number of species compared to other areas of the body.[6] In humans the gut flora is established at one to two years after birth, and by that time the intestinal epithelium and the intestinal mucosal barrier that it secretes have co-developed in a way that is tolerant to, and even supportive of, the gut flora and that also provides a barrier to pathogenic organisms.[19][38]

The relationship between some gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship.[1] Some human gut microorganisms benefit the host by fermentating dietary fiber into short-chain fatty acids (SCFAs), such as acetic acid and butyric acid, which are then absorbed by the host.[6][39] Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics.[1][39] The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ,[39] and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.[6][40]

The composition of human gut flora changes over time, when the diet changes, and as overall health changes.[6][40]

Vagina[edit]

Main article: Vaginal flora

Vaginal microbiota refers to those species and genera that colonize the lower reproductive tract of women. These organisms play an important role in protecting against infections and maintaining vaginal health.[41] The most abundant vaginal microorganisms found in premenopausal women are from the genus Lactobacillus, which suppress pathogens by producing hydrogen peroxide and lactic acid.[28][41][42] Bacterial species composition and ratios vary depending on the stage of the menstrual cycle.[43][44][needs update] Ethnicity also influences vaginal flora. The occurrence of hydrogen peroxide-producing lactobacilli is lower in African American women and vaginal pH is higher.[45] Other influential factors such as sexual intercourse and antibiotics have been linked to the loss of lactobacilli.[42] Moreover, studies have found that sexual intercourse with a condom does appear to change lactobacilli levels, and does increase the level of Escherichia coli within the vaginal flora.[42] Changes in the normal, healthy vaginal microbiota is an indication of infections, such as candidiasis or bacterial vaginosis.[42] Candida albicans inhibits the growth of Lactobacillus species, while Lactobacillus species which produce hydrogen peroxide inhibit the growth and virulence of Candida albicans in both the vagina and the gut.[26][28][29]

Fungal genera that have been detected in the vagina include Candida, Pichia, Eurotium, Alternaria, Rhodotorula, and Cladosporium, among others.[26]

Placenta[edit]

Main article: Placental microbiome

Until recently the placenta was considered to be a sterile organ but commensal, nonpathogenic bacterial species and genera have been identified that reside in the placental tissue.[46][46][47]

Uterus[edit]

Main article: Uterine microbiome

Until recently, the upper reproductive tract of women was considered to be a sterile environment. A variety of microorganisms inhabit the uterus of healthy, asymptomatic women of reproductive age. The microbiome of the uterus differs significantly from that of the vagina and gastrointestinal tract.[48]

Oral cavity[edit]

Main article: Oral microbiology

The environment present in the human mouth allows the growth of characteristic microorganisms found there. It provides a source of water and nutrients, as well as a moderate temperature.[1] Resident microbes of the mouth adhere to the teeth and gums to resist mechanical flushing from the mouth to stomach where acid-sensitive microbes are destroyed by hydrochloric acid.[1][28]

Anaerobic bacteria in the oral cavity include: Actinomyces, Arachnia, Bacteroides, Bifidobacterium, Eubacterium, Fusobacterium, Lactobacillus, Leptotrichia, Peptococcus, Peptostreptococcus, Propionibacterium, Selenomonas, Treponema, and Veillonella.[49][needs update] Genera of fungi that are frequently found in the mouth include Candida, Cladosporium, Aspergillus, Fusarium, Glomus, Alternaria, Penicillium, and Cryptococcus, among others.[26] Bacteria accumulate on both the hard and soft oral tissues in biofilms. Bacterial adhesion is particularly important for oral bacteria.

Oral bacteria have evolved mechanisms to sense their environment and evade or modify the host. Bacteria occupy the ecological niche provided by both the tooth surface and gingival epithelium. However, a highly efficient innate host defense system constantly monitors the bacterial colonization and prevents bacterial invasion of local tissues. A dynamic equilibrium exists between dental plaque bacteria and the innate host defense system.[50] Of particular interest is the role of oral microorganisms in the two major dental diseases: dental caries and periodontal disease.[50] Additionally, research has correlated poor oral heath and the resulting ability of the oral microbiota to invade the body to affect cardiac health as well as cognitive function.[51]

Lung[edit]

Main article: Lung microbiome

Much like the oral cavity, the upper and lower respiratory system possess mechanical deterrents to remove microbes. Goblet cells produce mucous which traps microbes and moves them out of the respiratory system via continuously moving ciliated epithelial cells.[1] In addition, a bactericidal effect is generated by nasal mucus which contains the enzyme lysozyme.[1]

Nonetheless, the upper and lower respiratory tract appears to have their own set of microbiota. Pulmonary bacterial microbiota belong to 9 major bacterial genera: Prevotella, Sphingomonas, Pseudomonas, Acinetobacter, Fusobacterium, Megasphaera, Veillonella, Staphylococcus, and Streptococcus. Some of the bacteria considered "normal biota" in the respiratory tract can cause serious disease especially in immunocompromised individuals; these include Streptococcus pyogenes, Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, and Staphylococcus aureus.

Fungal genera that compose the pulmonary mycobiome include Candida, Malassezia, Neosartorya, Saccharomyces, and Aspergillus, among others.[26]

Unusual distributions of bacterial and fungal genera in the respiratory tract is observed in patients with cystic fibrosis.[26][52] The bacterial flora found in the lungs of patients with cystic fibrosis often contains antibiotic-resistant and slow-growing bacteria, and the frequency of these pathogens changes in relation to age.[52]

Disease[edit]

Communities of microflora have been shown to change their behavior in diseased individuals.[53]

Cancer[edit]

Although cancer is generally a disease of host genetics and environmental factors, microorganisms are implicated in ~20% of human malignancies. Mucosal microbes can become part of the tumor microenvironment (TME) of aerodigestive tract malignancies. Intratumoral microbes can affect cancer growth and spread. Gut microbiota also detoxify dietary components, reducing inflammation and balancing host cell growth and proliferation. Coley's toxins were one of the earliest forms of cancer bacteriotherapy. Synthetic biology employs designer microbes and microbiota transplants against tumors.[54]

Microbes and the microbiota affect carcinogenesis in three broad ways: (i) altering the balance of tumor cell proliferation and death, (ii) regulating immune system function and (iii) influencing metabolism of host-produced factors, foods and pharmaceuticals.[54]

Modes of action[edit]

Ten microbes are designated by the International Agency for Research on Cancer (IARC) as human carcinogens. Most of these microbes colonize large percentages of the human population, although only genetically susceptible individuals develop cancer. Tumors arising at boundary surfaces, such as the skin, oropharynx and respiratory, digestive and urogenital tracts, harbor a microbiota, which complicates cancer-microbe causality. Substantial microbe presence at a tumor site does not establish association or causal links. Instead, microbes may find the tumor's oxygen tension or nutrient profile supportive. Decreased populations of specific microbes may also increase risks.[54]

Human oncoviruses can drive carcinogenesis by integrating oncogenes into host genomes. Human papillomaviruses (HPV) express oncoproteins such as E6 and E7. Viral integration selectively amplifies host genes in pathways with established cancer roles.[54]

Microbes affect genomic stability, resistance to cell death and proliferative signaling. Many bacteria can damage DNA, to kill competitors/survive. These defense factors can lead to mutational events that contribute to carcinogenesis. Examples include colibactin encoded by the pks locus (expressed by B2 group Escherichia coli as well as by other Enterobacteriaceae), Bacteroides fragilis toxin (Bft) produced by enterotoxigenic B. fragilis and cytolethal distending toxin (CDT) produced by several ε- and γ-proteobacteria. Colibactin is of interest in colorectal carcinogenesis, given the detection of pks+ E. coli in human colorectal cancers and the ability of colibactin-expressing E. coli to potentiate intestinal tumorigenesis in mice. Data also support a role for enterotoxigenic B. fragilis in both human and animal models of colon tumors. Both colibactin and CDT can cause double-stranded DNA damage in mammalian cells. In contrast, Bft acts indirectly by eliciting high levels of reactive oxygen species (ROS), which in turn damage host DNA. Chronically high ROS levels can outpace DNA repair mechanisms, leading to DNA damage and mutations.[54]

β-catenin[edit]

Several microbes possess proteins that engage host pathways involved in carcinogenesis. The Wnt/β-catenin signaling pathway, which regulates cells' polarity, growth and differentiation, is one example and is altered in many malignancies. Multiple cancer-associated bacteria can influence β-catenin signaling. Oncogenic type 1 strains of Helicobacter pylori express CagA, which is injected directly into the cytoplasm of host cells and modulates β-catenin to drive gastric cancer. This modulation leads to up-regulation of cellular proliferation, survival and migration genes, as well as angiogenesis—all processes central to carcinogenesis. Oral microbiota Fusobacterium nucleatum is associated with human colorectal adenomas and adenocarcinomas and amplified intestinal tumorigenesis in mice. F. nucleatum expresses FadA, a bacterial cell surface adhesion component that binds host E-cadherin, activating β-catenin. Enterotoxigenic B. fragilis, which is enriched in some human colorectal cancers, can stimulate E-cadherin cleavage via Btf, leading to β-catenin activation. Salmonella Typhi strains that maintain chronic infections secrete AvrA, which can activate epithelial β-catenin signaling and are associated with hepatobiliary cancers.[54]

Several of these bacteria are normal microbiota constituents. The presence of these cancer-potentiating microbes and their access to E-cadherin in evolving tumors demonstrate that a loss of appropriate boundaries and barrier maintenance between host and microbe is a critical step in the development of some tumors.[54]

Inflammation[edit]

Mucosal surface barriers are subject to environmental insult and must rapidly repair to maintain homeostasis. Compromised host or microbiota resiliency also reduce resistance to malignancy. Cancer and inflammatory disorders can then arise. Once barriers are breached, microbes can elicit proinflammatory or immunosuppressive programs.[54]

Inflammation, whether high-grade as in inflammatory disorders or low-grade as in malignancies and obesity, drive a tumor-permissive milieu. Pro-inflammatory factors such as reactive oxygen and nitrogen species, cytokines and chemokines can also drive tumor growth and spread. Tumors can up-regulate and activate pattern recognition receptors (e.g. toll-like receptors), driving feedforward loops of activation of cancer-associated inflammation regulator NF-κΒ. Cancer-associated microbes appear to activate NF-κΒ signaling within the TME. The activation of NF-κΒ by F. nucleatum may be the result of pattern recognition receptor engagement or FadA engagement of E-cadherin. Other pattern recognition receptors, such as nucleotide-binding oligomerization domain–like receptor (NLR) family members NOD-2, NLRP3, NLRP6 and NLRP12, may play a role in mediating colorectal cancer.[54]

Immune system TME engagement is not restricted to the innate immune system. Once the innate immune system is activated, adaptive immune responses ensue, often with tumor progression. The interleukin-23 (IL-23)–IL-17 axis, tumor necrosis factor–α (TNF-α)–TNF receptor signaling, IL-6–IL-6 family member signaling, and STAT3 activation all represent innate and adaptive pathways contributing to tumor progression and growth.[54]

The microbiota adapts to host changes such as inflammation. Adaptation shift microbiota to a vulnerable tissue site. Genotoxin azoxymethane and colon barrier–disrupting agent dextran sodium sulfate independently result in colon tumors in susceptible mouse strains; combining them accelerates tumorigenesis.[54]

Perturbations to a host immune system coupled with inflammatory stimulus may enrich bacterial clades that attach to host surfaces, invade host tissue, or trigger host inflammatory mediators. Fecal microbiota from NOD2- or NLRP6-deficient mice acquire features that enhance the susceptibility of wild-type mice to caCRC. In mice, gut microbiota modulate colon tumorigenesis, independent of genetic deficiencies. Germ-free mice developed more tumors when colonized from donors with caCRC, once followed by treatments that induced caCRC.[54]

Research[edit]

Diabetic foot ulcers develop their own, distinctive microbiota. Investigations into characterizing and identifying the phyla, genera and species of bacteria or other microorganisms populating these ulcers may help identify one group of microbiota that promotes healing.[55]

Environmental health[edit]

Studies in 2009 questioned whether the decline in biota (including microfauna) as a result of human intervention might impede human health.[56]

See also[edit]

References[edit]

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    Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
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    IPA metabolism diagram
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    Origin:  • Endogenous  • Microbial
     
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