Human microbiota

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 the surface and in deep layers of skin (including in mammary glands),[1] in the saliva and oral mucosa, in the conjunctiva, and in the 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.

Previous estimates calculated that microbes outnumber human cells 10 to 1,[2] however, the comparative total cell counts may be much closer and that "each defecation event may flip the ratio to favor human cells over bacteria."[3]

Some of these organisms 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 members of the normal flora or normal microbiota.

Most of the microbes associated with humans appear to be not harmful at all, but rather assist in maintaining processes necessary for a healthy body. A surprising finding was that at specific sites on the body, a different set of microbes may perform the same function for different people. For example, on the tongues of two people, two entirely different sets of organisms will break down sugars in the same way. This suggests that medical science may be forced to abandon the "one only" microbe model of infectious disease, and rather pay attention to functions of groups of microbes that have somehow gone awry.[4]

Terminology

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.

Types

Bacteria

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).

In 2012, some 200 researchers from some 80 research institutions comprising the Human Microbiome Project (HMP) Consortium have used advanced DNA-sequencing to identify and catalogue the thousands of microorganisms co-existing with humans. This study examined, amongst other things, the carbohydrate active enzymes from microbial populations from twelve sites on and in the human body, and concluded that microbes colonise each site to utilise the available sugars. Considerable variation was found in the enzymes for carbohydrate metabolism from site to site, and the researchers suggested that the composition of local carbohydrate metabolites may be the most important factor shaping the composition of microbial sub-communities of the human microbiome.

The same project examined the diversity of microbial communities present in multiple sites on the human body, using some 200 healthy persons and examining 18 sites on the body. Healthy individuals were found to 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.[5][6]

It is estimated that 500 to 1,000 species of bacteria live in the human gut[7][8] Bacterial cells are much smaller than human cells, and it is often said that there are at least ten times as many bacteria as human cells in the body, although the actual ratio has not been strictly defined. There is a point of view that human body contains approximately 1014 bacteria cells,[9][10] while the number of human cells has been calculated to be at least 3.72 * 1013.[11] The mass of microorganisms are estimated to account for 1-3% total body mass.[12] Though members of the flora are found on all surfaces exposed to the environment (on the skin and eyes, in the mouth, nose, small intestine), the vast majority of bacteria live in the large intestine.

Many of the bacteria in the digestive tract, collectively referred to as the gut flora, are able to break down certain nutrients such as carbohydrates that humans otherwise could not digest. The majority of these commensal bacteria are anaerobes, meaning they survive in an environment with no oxygen. Normal flora bacteria can act as opportunistic pathogens at times of lowered immunity.[13]

Escherichia coli (a.k.a. E. coli) is a bacterium that lives in the colon; it is an extensively studied model organism and probably the best-understood bacterium of all.[14] Certain mutated strains of these gut bacteria do cause disease; an example is E. coli O157:H7.

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.

Certain bacteria from the Clostridium genus, particularly Clostridium sporogenes, synthesize a highly potent indole-based neuroprotective antioxidant, 3-indolepropionic acid, which is detectable in the blood stream.[15][16][17] This compound is currently being studied for the treatment of Alzheimer's disease.[15][16][17]

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

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.[18] The dominant group are the methanogens, particularly Methanobrevibacter smithii and Methanosphaera stadtmanae.[19] However, colonization by methanogens is variable, and only about 50% of humans have easily detectable populations of these organisms.[20]

As of 2007, no clear examples of archaeal pathogens are known,[21][22] although a relationship has been proposed between the presence of some methanogens and human periodontal disease.[23]

Fungi

Fungi, in particular yeasts, are present in the human gut. The best-studied of these are Candida species. This is because of their ability to become pathogenic in immunocompromised hosts.[24] Yeasts are also present on the skin, particularly Malassezia species, where they consume oils secreted from the sebaceous glands.[25][26]

Anatomical areas

Main article: List of human flora

Skin flora

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%).[27]

Microbial colonization in the human body begins shortly after birth, and average adults possess 10 times more microbial cells than human cells. The skin acts as a barrier to deter the invasion of pathogenic bacteria. 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 bacteria reside on superficial cells on the skin or prefer to associate with glands. These glands such as oil or sweat glands provide the bacteria with water, amino acids, and fatty acids that provide nutrients for the microbes. In addition, resident bacteria can be pathogenic and are characteristically gram positive bacteria. Certain gram positive bacteria can be associated with oil glands that play a role in acne and skin disease.[28] Moreover, human sweat is by nature odorless, but bacteria associated with the skin play a role in producing body odor. Researchers at Wageningen University in Netherlands discovered that humans with a large number of bacteria that possess a low level of diversity are more attractive to a particular species of mosquito. The experiments were conducted with Anopheles gambiae sensu stricto mosquito, which are associated with malaria.[29]

Conjunctival flora

These are sparse in occurrence, but Gram-positive cocci and Gram-negative rods and cocci are present.[30] A small number of bacteria are normally present in the conjunctiva. Staphylococcus epidermidis and certain coryneforms such as Propionibacterium acnes are dominant. Staphylococcus aureus, streptococci, Haemophilus sp. and Neisseria sp. sometimes occur. 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 flora

Main article: Gut flora

The gut flora is the human flora of microorganisms that normally live in the digestive tract and can perform a number of useful functions for their hosts. The bacterial flora of the human gut encompasses a wide variety of microorganisms that aid in digestion, the synthesis of vitamins, and creating enzymes not produced by the human body.[28] According to scientific research, the human gut consists of different enterotypes that have an inconspicuous impact on human health.[31] It is suggested that the intestines of infants are colonized by bacteria that alter the gut to support those specific bacteria.[31] The average human body, consisting of about ten trillion cells, has about ten times that number of microorganisms in the gut.[32][33][34][35] The metabolic activity performed by these bacteria is equal to that of a virtual organ, leading to gut bacteria being termed a "forgotten" organ.[36]

Stomach flora

Due to the high acidity of the stomach, most microorganisms cannot survive. The main bacterial inhabitants of the stomach include: Streptococcus, Staphylococcus, Lactobacillus, Peptostreptococcus, and types of yeast.[28] Helicobacter pylori is a Gram-negative spiral organism that establishes on gastric mucosa causing chronic gastritis and peptic ulcer disease.[37] H. pylori has also been classified as a carcinogen for gastric cancer.[37]

Intestinal flora

The small intestine contains a trace amount of microorganisms due to the proximity and influence of the stomach. Gram positive cocci and rod shaped bacteria are the predominant microorganisms found in the small intestine.[28] However, in the distal portion of the small intestine alkaline conditions support gram-positive bacteria of the Enterobacteriaceae.[28] The bacterial flora of the small intestine aid in a wide range of intestinal functions. The bacterial flora provide regulatory signals that enable the development and utility of the gut. Overgrowth of bacteria in the small intestine can lead to intestinal failure.[38] In addition the large intestine contains the largest bacterial ecosystem in the human body.[28] Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites.[28]

Bacteria make up most of the flora in the colon[39] and 60% of the dry mass of feces.[34] This fact makes feces an ideal source to test for gut flora for any tests and experiments by extracting the nucleic acid from fecal specimens, and bacterial 16S rRNA gene sequences are generated with bacterial primers. This form of testing is also often preferable to more invasive techniques, such as biopsies. Somewhere between 300[34] and 1000 different species live in the gut,[32] with most estimates at about 500.[35][40] However, it is probable that 99% of the bacteria come from about 30 or 40 species, with Faecalibacterium prausnitzii being the most common species in healthy adults.[41][42] Fungi and protozoa also make up a part of the gut flora, but little is known about their activities.

Research suggests that the relationship between gut flora[43] and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship.[32] Though people can (barely) survive with no gut flora,[35] the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system, preventing growth of harmful species,[34] regulating the development of the gut, producing vitamins for the host (such as biotin and vitamin K), and producing hormones to direct the host to store fats. Extensive modification and imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity.[44] However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host.[34][39]

Bacteria commonly found in the human colon[30]
Bacterium Incidence (%)
Bacteroides fragilis 100
Bacteroides melaninogenicus 100
Bacteroides oralis 100
Enterococcus faecalis 100
Escherichia coli 100
Enterobacter sp. 40-80
Klebsiella sp. 40-80
Bifidobacterium bifidum 30-70
Staphylococcus aureus 30-50
Lactobacillus 20-60
Clostridium perfringens 25-35
Proteus mirabilis 5-55
Clostridium tetani 1-35
Clostridium septicum 5-25
Pseudomonas aeruginosa 3-11
Salmonella enteritidis 3-7
Faecalibacterium prausnitzii ?common
Peptostreptococcus sp. ?common
Peptococcus sp. ?common

Vaginal microbiota

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.[45] The most abundant vaginal microorganisms found in premenopausal women are from the genus Lactobacillus, which suppress pathogens by producing lactic acid.[45][46] Bacterial species composition and ratios vary depending on the stage of the menstrual cycle.[47][48] Ethnicity also influences vaginal flora. The occurrence of hydrogen peroxide-producing lactobacilli is lower in African American women and vaginal pH is higher.[49] Other influential factors such as sexual intercourse and antibiotics have been linked to the loss of lactobacilli.[46] 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.[46] Changes in the normal, healthy vaginal microbiota is an indication of infections, such as candidiasis or bacterial vaginosis.[46]

Oral cavity

Main article: Oral microbiology

The human mouth is an ideal environment of the existence and growth of microorganisms. It provides a source of water and nutrients, as well as a moderate temperature.[28] Resident bacteria of the mouth adhere to the teeth and gums to resist mechanical flushing from the mouth to stomach where they are destroyed by hydrochloric acid.[28] Anaerobic bacteria in the oral cavity include: Actinomyces, Arachnia, Bacteroides, Bifidobacterium, Eubacterium, Fusobacterium, Lactobacillus, Leptotrichia, Peptococcus, Peptostreptococcus, Propionibacterium, Selenomonas, Treponema, and Veillonella.[50]

Respiratory flora

Main article: Lung microbiome

Much like the oral cavity, the upper and lower respiratory system possess mechanical deterrents to remove bacteria. Goblet cells produce mucous which traps bacteria and moves them out of the respiratory system via continuously moving ciliated epithelial cells.[28] In addition, a bactericidal effect is generated by nasal mucus which contains the enzyme lysozyme.[28]

Nonetheless, the upper and lower respiratory tract appears to have a normal bacterial flora. A significant portion of the normal biota belongs to 9 major bacterial genera: Prevotella, Sphingomonas, Pseudomonas, Acinetobacter, Fusobacterium, Megasphaera, Veillonella, Staphylococcus, and Streptococcus. Note that some 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.

Unusual bacterial flora in the respiratory system can be detrimental and has been seen in patients with cystic fibrosis[51] 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.[51]

Airborne

A human body emits bacteria into the air, to create a microbial cloud around the body, which may be used to uniquely identify the person.[52]

Disease

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

Cancer

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

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

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

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]

Environmental health

Studies in 2009 questioned whether the decline in biota (including microfauna) as a result of human intervention might impede human health.[55]

See also

References

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