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Human microbiota

  (Redirected from Human flora)
Graphic depicting the human skin microbiota, with relative prevalences of various classes of bacteria

The human microbiota is the aggregate of microorganisms that resides on or within any of a number of human tissues and biofluids, including the skin, mammary glands, placenta, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, biliary and gastrointestinal tracts. They include bacteria, archaea, protists, fungi and viruses. Though micro-animals also live on the human body, they are typically excluded from this definition. The human microbiome refers specifically to the collective genomes of resident microorganisms.[1]

Humans are colonized by many microorganisms; the traditional estimate is that the average human body is inhabited by ten times as many non-human cells as human cells, but more recent estimates have lowered that ratio to 3:1 or even to approximately the same number.[2][3][4][5] Some microbiota that colonize humans are commensal, meaning they co-exist without harming humans; others have a mutualistic relationship with their human hosts.[1]:700[6] Conversely, some non-pathogenic microbiota can harm human hosts via the metabolites they produce, like trimethylamine.[7][8] Certain microbiota perform tasks that are known to be useful to the human host; but the role of most resident microorganisms is not well understood. Those that are expected to be present, and that under normal circumstances do not cause disease, are sometimes 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 its initial results.[9]

Contents

TerminologyEdit

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 numbersEdit

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 as there are human cells; this figure was based on estimates that the human microbiome includes around 100 trillion bacterial cells and that an adult human typically has around 10 trillion human cells.[2] In 2014, the American Academy of Microbiology published a 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 – approximately 37.2 trillion, meaning that the ratio of microbial-to-human cells, if the original estimate of 100 trillion bacterial cells is correct, is closer to 3:1.[2][3] In 2016, another group published a new estimate of the ratio 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]

StudyEdit

 
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.

TypesEdit

BacteriaEdit

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).[medical citation needed]

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 L. iners is in fact most common, 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").

ArchaeaEdit

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]

FungiEdit

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]

VirusesEdit

Viruses, especially bacterial viruses (bacteriophages), colonize various body sites. These colonized sites include the skin,[32] gut,[33] lungs,[34] and oral cavity.[35] Virus communities have been associated with some diseases, and do not simply reflect the bacterial communities.[36][37][38]

Anatomical areasEdit

SkinEdit

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%).[39] 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]

ConjunctivaEdit

A small number of bacteria and fungi are normally present in the conjunctiva.[26][40] 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.[40] 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.

GutEdit

Tryptophan metabolism by human gastrointestinal microbiota (v · t · e)
Tryptophanase-
expressing
bacteria
Intestinal
immune
cells
Mucosal homeostasis:
TNF-α
Junction protein-
coding mRNAs
Neuroprotectant:
↓Activation of glial cells and astrocytes
4-Hydroxy-2-nonenal levels
DNA damage
Antioxidant
–Inhibits β-amyloid fibril formation
Maintains mucosal reactivity:
IL-22 production
 
This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut.[41] Indole is produced from tryptophan by bacteria that express tryptophanase.[41] Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA),[42] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals.[41][43][44] IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.[41] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer’s disease.[41] 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.[41] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR.[41] 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.[41] 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.[41]

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 composition of gut flora is established during birth.[45] Birth by Cesarean section or vaginal delivery also influences the gut's microbial composition. Babies born through the vaginal canal have non-pathogenic, beneficial gut microbiota similar to those found in the mother.[46] However, the gut microbiota of babies delivered by C-section harbors more pathogenic bacteria such as Escherichia coli and Staphylococcus and it takes longer to develop non-pathogenic, beneficial gut microbiota.[47]

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][48] Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics.[1][48] 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,[48] and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.[6][49]

The composition of human gut flora changes over time, when the diet changes, and as overall health changes.[6][49] A systematic review of 15 human randomized controlled trials from July 2016 found that certain commercially available strains of probiotic bacteria from the Bifidobacterium and Lactobacillus genera (B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei), when taken by mouth in daily doses of 109–1010 colony forming units (CFU) for 1–2 months, possess treatment efficacy (i.e., improved behavioral outcomes) in certain central nervous system disorders – including anxiety, depression, autism spectrum disorder, and obsessive–compulsive disorder – and improved certain aspects of memory.[50] However, changes in the composition of gut microbiota has also been found to be correlated with harmful effects on health. In an article published by Musso et al., it was found that the gut microbiota of obese invidividuals had more Firmicutes and less Bacteroidetes than healthy individuals.[51] Furthermore, a study done by Gordon et al., confirmed that it was the composition of the microbiota that causes obesity rather than the other way around. This was done by transplanting the gut microbiota from diet-induced obese(DIO) mice or lean control mice into lean germ-free mice that do not have a microbiome. They found that the mice transplanted with DIO mouse gut microbiota had significantly higher total body fat than the mice transplanted with lean mouse microbiota when fed with the same diet.[52]

VaginaEdit

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.[53] 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][53][54] Bacterial species composition and ratios vary depending on the stage of the menstrual cycle.[55][56][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.[57] Other influential factors such as sexual intercourse and antibiotics have been linked to the loss of lactobacilli.[54] 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.[54] Changes in the normal, healthy vaginal microbiota is an indication of infections, such as candidiasis or bacterial vaginosis.[54] 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]

PlacentaEdit

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.[58][59][60]

UterusEdit

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.[61]

Oral cavityEdit

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.[62][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 biofilm allowing them to adhere and strive in the oral environment while protected from the environmental factors and antimicrobial agents.[63] Saliva plays a key biofilm homeostatic role allowing recolonization of bacteria for formation and controlling growth by detaching biofilm buildup.[64] It also provides a means of nutrients and temperature regulation. The location of the biofilm determines the type of exposed nutrients it receives.[65]

Oral bacteria have evolved mechanisms to sense their environment and evade or modify the host. 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.[66]

This dynamic between host oral cavity and oral microbes plays a key role in health and disease as it provides entry into the body.[67] A healthy equilibrium presents a symbiotic relationship where oral microbes limit growth and adherence of pathogens while the host provides an environment for them to flourish.[67][63] Ecological changes such as change of immune status, shift of resident microbes and nutrient availability shift from a mutual to parasitic relationship resulting in the host being prone to oral and systemic disease.[63] Systemic diseases such as diabetes and cardiovascular diseases has been correlated to poor oral health.[67] Of particular interest is the role of oral microorganisms in the two major dental diseases: dental caries and periodontal disease.[66] Pathogen colonization at the periodontium cause an excessive immune response resulting in a periodontal pocket- a deepened space between the tooth and gingiva.[63] This acts as a protected blood-rich reservoir with nutrients for anaerobic pathogens.[63] Systemic disease at various sites of the body can result from oral microbes entering the blood bypassing periodontal pockets and oral membranes.[67]

Persistent proper oral hygiene is the primary method for preventing oral and systemic disease.[67] It reduces the density of biofilm and overgrowth of potential pathogenic bacteria resulting in disease.[65] However, proper oral hygiene may not be enough as the oral microbiome, genetics, and changes to immune response play a factor in developing chronic infections.[65] Use of antibiotics could treat already spreading infection but ineffective against bacteria within biofilms.[65]

LungEdit

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] The upper and lower respiratory tract appears to have its own set of microbiota.[68] 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.[citation needed] 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 people with cystic fibrosis.[26][69] Their bacterial flora often contains antibiotic-resistant and slow-growing bacteria, and the frequency of these pathogens changes in relation to age.[69]

Biliary tractEdit

Traditionally the biliary tract has been considered to be normally sterile, and the presence of microorganisms in bile is a marker of pathological process. This assumption was confirmed by failure in allocation of bacterial strains from the normal bile duct. Papers began emerging in 2013 showing that the normal biliary microbiota is a separate functional layer which protects a biliary tract from colonization by exogenous microorganisms.[70]

DiseaseEdit

A symbiotic relationship between the gut microbiota and different bacteria may influence an individual's immune response.[71]

CancerEdit

Although cancer is generally a disease of host genetics and environmental factors, microorganisms are implicated in some 20% of human cancers.[72] Particularly for potential factors in colon cancer, bacterial density is one million times higher than in the small intestine, and approximately 12-fold more cancers occur in the colon compared to the small intestine, possibly establishing a pathogenic role for microbiota in colon and rectal cancers.[73] Microbial density may be used as a prognostic tool in assessment of colorectal cancers.[73]

The microbiota may 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.[72] Tumors arising at boundary surfaces, such as the skin, oropharynx and respiratory, digestive and urogenital tracts, harbor a microbiota. Substantial microbe presence at a tumor site does not establish association or causal links. Instead, microbes may find tumor oxygen tension or nutrient profile supportive. Decreased populations of specific microbes or induced oxidative stress may also increase risks.[72][73] Of the around 1030 microbes on earth, ten are designated by the International Agency for Research on Cancer as human carcinogens.[72] Microbes may secrete proteins or other factors directly drive cell proliferation in the host, or may up- or down-regulate the host immune system including driving acute or chronic inflammation in ways that contribute to carcinogenesis.[72]

Concerning the relationship of immune function and development of inflammation, mucosal surface barriers are subject to environmental risks and must rapidly repair to maintain homeostasis. Compromised host or microbiota resiliency also reduce resistance to malignancy, possibly inducing inflammation and cancer. Once barriers are breached, microbes can elicit proinflammatory or immunosuppressive programs through various pathways.[72] For example, cancer-associated microbes appear to activate NF-κΒ signaling within the tumor microenviroment. 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.[72] Likewise Helicobacter pylori appears to increase the risk of gastric cancer, due to its driving a chronic inflammatory response in the stomach.[72][73]

Inflammatory bowel diseaseEdit

Inflammatory bowel disease consists of two different diseases: ulcerative colitis and Crohn’s disease and both of these diseases present with disruptions in the gut microbiota (also known as dysbiosis). This dysbiosis presents itself in the form of decreased microbial diversity in the gut,[74][75] and is correlated to defects in host genes that changes the innate immune response in individuals.[74]

Human immunodeficiency virusEdit

The HIV disease progression influences the composition and function of the gut microbiota, with notable differences between HIV-negative, HIV-positive, and post-ART HIV-positive populations.[citation needed] HIV decreases the integrity of the gut epithelial barrier function by affecting tight junctions. This breakdown allows for translocation across the gut epithelium, which is thought to contribute to increases in inflammation seen in people with HIV.[76]

Vaginal microbiota plays a role in the infectivity of HIV, with an increased risk of infection and transmission when the woman has bacterial vaginosis, a condition characterized by an abnormal balance of vaginal bacteria.[77] The enhanced infectivity is seen with the increase in pro-inflammatory cytokines and CCR5 + CD4+ cells in the vagina. However, a decrease in infectivity is seen with increased levels of vaginal Lactobacillus, which promotes an anti-inflammatory condition.[76]

ResearchEdit

Diabetic foot ulcers develop their own, distinctive microbiota.[78] Periodontal disease and urinary tract infections are often linked to bacteria, such as Helicobacter pylori and Chlamydia pneumonia), numerous viral agents (Cytomegalo-virus, herpes simplex virus type-2, HIV), and parasites (Plasmodium spp. and Toxoplasma gondii).[79]

Environmental healthEdit

Studies in 2009 questioned whether the decline in biota (including microfauna) as a result of human intervention might impede human health, hospital safety procedures, food product design, and treatments of disease.[80]

See alsoEdit

BibliographyEdit

  • Ed Yong. I Contain Multitudes: The Microbes Within Us and a Grander View of Life. 368 pages, Published August 9, 2016 by Ecco, ISBN 0062368591.

ReferencesEdit

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    Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
    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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