Human microbiome

Source: Wikipedia, the free encyclopedia.

skin microbiota
, with relative prevalences of various classes of bacteria

The human microbiome is the aggregate of all

human metagenome has the same meaning.[1]

The human body hosts many microorganisms, with approximately the same

FMO3-mediated oxidation.[5][6] Certain microorganisms perform tasks that are known to be useful to the human host, but the role of most of them 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.[2]

During early life, the establishment of a diverse and balanced human microbiota plays a critical role in shaping an individual's long-term health.[7] Studies have shown that the composition of the gut microbiota during infancy is influenced by various factors, including mode of delivery, breastfeeding, and exposure to environmental factors.[8] There are several beneficial species of bacteria and potential probiotics present in breast milk.[9] Research has highlighted the beneficial effects of a healthy microbiota in early life, such as the promotion of immune system development, regulation of metabolism, and protection against pathogenic microorganisms.[10] Understanding the complex interplay between the human microbiota and early life health is crucial for developing interventions and strategies to support optimal microbiota development and improve overall health outcomes in individuals.[11]

The Human Microbiome Project (HMP) 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.[2] It reached a milestone in 2012 when it published its initial results.[12]

Terminology

Though widely known as flora or microflora, this is a

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.[4]

Relative numbers

The number of

Study

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.

ribonucleic acid (RNA), protein and metabolite based studies are also performed.[20][21] 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.[20] 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.[22]

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.[23][24] 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 HMP. It is known that the human microbiome (such as the gut microbiota) is highly variable both within a single subject and among different individuals, a phenomenon which is also observed in mice.[4]

On 13 June 2012, a major milestone of the HMP was announced by the

genera.[27]

Analysis after the processing

The statistical analysis is essential to validate the obtained results (

ANOVA can be used to size the differences between the groups); if it is paired with graphical tools, the outcome is easily visualized and understood.[28]

Once a metagenome is assembled, it is possible to infer the functional potential of the microbiome. The computational challenges for this type of analysis are greater than for single genomes, because usually metagenomes assemblers have poorer quality, and many recovered

orthologs databases.[29]

Marker gene analysis

It is a technique that exploits

phylogenies. The genetic region is characterized by a highly variable region which can confer detailed identification; it is delimited by conserved regions, which function as binding sites for primers used in PCR. The main gene used to characterize bacteria and archaea is 16S rRNA gene, while fungi identification is based on Internal Transcribed Spacer (ITS). The technique is fast and not so expensive and enables to obtain a low-resolution classification of a microbial sample; it is optimal for samples that may be contaminated by host DNA. Primer affinity varies among all DNA sequences, which may result in biases during the amplification reaction; indeed, low-abundance samples are susceptible to overamplification errors, since the other contaminating microorganisms result to be over-represented in case of increasing the PCR cycles. Therefore, the optimization of primer selection can help to decrease such errors, although it requires complete knowledge of the microorganisms present in the sample, and their relative abundances.[30]

Marker gene analysis can be influenced by the primer choice; in this kind of analysis, it is desirable to use a well-validated protocol (such as the one used in the

SNPs because they would get clustered into a single OTU. Another approach is Oligotyping, which includes position-specific information from 16s rRNA sequencing to detect small nucleotide variations and from discriminating between closely related distinct taxa. These methods give as an output a table of DNA sequences and counts of the different sequences per sample rather than OTU.[30]

Another important step in the analysis is to assign a taxonomic name to microbial sequences in the data. This can be done using machine learning approaches that can reach an accuracy at genus-level of about 80%. Other popular analysis packages provide support for taxonomic classification using exact matches to reference databases and should provide greater specificity, but poor sensitivity. Unclassified microorganism should be further checked for organelle sequences.[30]

Phylogenetic analysis

Many methods that exploit phylogenetic inference use the 16SRNA gene for Archea and Bacteria and the 18SRNA gene for Eukaryotes. Phylogenetic comparative methods (PCS) are based on the comparison of multiple traits among microorganisms; the principle is: the closely they are related, the higher number of traits they share. Usually PCS are coupled with phylogenetic generalized least square (PGLS) or other statistical analysis to get more significant results. Ancestral state reconstruction is used in microbiome studies to impute trait values for taxa whose traits are unknown. This is commonly performed with PICRUSt, which relies on available databases. Phylogenetic variables are chosen by researchers according to the type of study: through the selection of some variables with significant biological informations, it is possible to reduce the dimension of the data to analyse.[31]

Phylogenetic aware distance is usually performed with

horizontal gene transmission (HGT), since it can generate errors and lead to the correlation of distant species. There are different ways to reduce the negative impact of HGT: the use of multiple genes or computational tools to assess the probability of putative HGT events.[31]

Ecological Network analysis

Microbial communities develop in a very complex dynamic which can be viewed and analyzed as an ecosystem. The ecological interactions between microbes govern its change, equilibrium and stability, and can be represented by a population dynamic model.[32] The ongoing study of ecological features of the microbiome is growing rapidly and allows to understand the fundamental properties of the microbiome. Understanding the underlying rules of microbial community could help with treating diseases related to unstable microbial communities. A very basic question is if different humans, who share different microbial communities, have the same underlying microbial dynamics.[33] Increasing evidence and indications have found that the dynamics is indeed universal.[34] This question is a basic step that will allow scientists to develop treatment strategies, based on the complex dynamics of human microbial communities. There are more important properties on which considerations should be taken into account for developing interventions strategies for controlling the human microbial dynamics.[35] Controlling the microbial communities could result in solving very bad and harmful diseases.

Types

Bacteria

Commensals vs pathogens mechanism. Mechanisms underlying the inflammation in COPD. Airway epithelium has complex structure: consists of at least seven diverse cell types interacting with each other by means of tight junctions. Moreover, epithelial calls can deliver the signals into the underlying tissues taking part in the mechanisms of innate and adaptive immune defence. The key transmitters of the signals are dendritic cells. Once pathogenic bacterium (e.g., S. pneumoniae, P. aeruginosa) has activated particular pattern recognition receptors on/in epithelial cells, the proinflammatory signaling pathways are activated. This results mainly in IL-1, IL-6 and IL-8 production. These cytokines induce the chemotaxis to the site of infection in its target cells (e.g., neutrophils, dendritic cells and macrophages). On the other hand, representatives of standard microbiota cause only weak signaling preventing the inflammation. The mechanism of distinguishing between harmless and harmful bacteria on the molecular as well as on physiological levels is not completely understood.

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).[36]

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.[37][38]

It is estimated that 500 to 1,000

Actinobacteriota, Fusobacteriota, and "Cyanobacteria".[39]

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.[citation needed]

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 and candiadiasis.[40]

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.[41] The dominant group are the methanogens, particularly Methanobrevibacter smithii and Methanosphaera stadtmanae.[42] However, colonization by methanogens is variable, and only about 50% of humans have easily detectable populations of these organisms.[43]

As of 2007, no clear examples of archaeal pathogens were known,[44][45] although a relationship has been proposed between the presence of some methanogens and human periodontal disease.[46] Methane-dominant small intestinal bacterial overgrowth (SIBO) is also predominently caused by methanogens, and Methanobrevibacter smithii in particular.[47]

Fungi

Fungi, in particular

Candida species due to their ability to become pathogenic in immunocompromised and even in healthy hosts.[49][50][51] Yeasts are also present on the skin,[48] such as Malassezia species, where they consume oils secreted from the sebaceous glands.[52][53]

Viruses

Viruses, especially bacterial viruses (bacteriophages), colonize various body sites. These colonized sites include the skin,[54] gut,[55] lungs,[56] and oral cavity.[57] Virus communities have been associated with some diseases, and do not simply reflect the bacterial communities.[58][59][60]

In January 2024, biologists reported the discovery of "

obelisks", a new class of viroid-like elements, and "oblins", their related group of proteins, in the human microbiome.[61][62]

Anatomical areas

Skin

A study of 20 skin sites on each of ten healthy humans found 205 identified genera in 19 bacterial phyla, with most sequences assigned to four phyla: Actinomycetota (51.8%), Bacillota (24.4%), Pseudomonadota (16.5%), and Bacteroidota (6.3%).[63] 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.[48] For example, Malassezia is dominant in atopic dermatitis and Acremonium is dominant on dandruff-affected scalps.[48]

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.[2]

Conjunctiva

A small number of bacteria and fungi are normally present in 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.

Gastrointestinal tract

Tryptophan metabolism by
human gastrointestinal microbiota (
)
Tryptophanase-
expressing
bacteria
AST-120
Intestinal
immune
cells
Mucosal homeostasis:
TNF-α
Junction protein-
coding mRNAs
β-amyloid
fibril formation
Maintains mucosal reactivity:
IL-22 production
Associated with
calcification
Associated with
Uremic toxin
The image above contains clickable links
This diagram shows the biosynthesis of
activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.[65]

In humans, the composition of the gastrointestinal microbiome is established during birth.

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.[70] 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.[71]

The relationship between some

hormones and the gut flora itself appears to function like an endocrine organ,[72] and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.[4][73]

The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes.

autism spectrum disorder, and obsessive–compulsive disorder – and improves certain aspects of memory.[74]

Urethra and bladder

The genitourinary system appears to have a microbiota,[75][76] which is an unexpected finding in light of the long-standing use of standard clinical microbiological culture methods to detect bacteria in urine when people show signs of a urinary tract infection; it is common for these tests to show no bacteria present.[77] It appears that common culture methods do not detect many kinds of bacteria and other microorganisms that are normally present.[77] As of 2017, sequencing methods were used to identify these microorganisms to determine if there are differences in microbiota between people with urinary tract problems and those who are healthy.[75][76][78] To properly assess the microbiome of the bladder as opposed to the genitourinary system, the urine specimen should be collected directly from the bladder, which is often done with a catheter.[79]

Vagina

Vaginal microbiota refers to those species and genera that colonize the vagina. These organisms play an important role in protecting against infections and maintaining vaginal health.

species composition and ratios vary depending on the stage of the menstrual cycle.[82][83][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.[84] Other influential factors such as sexual intercourse and antibiotics have been linked to the loss of lactobacilli.[81] 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.[81] Changes in the normal, healthy vaginal microbiota is an indication of infections,[85] such as candidiasis or bacterial vaginosis.[81] 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.[48][50][51]

Fungal genera that have been detected in the vagina include Candida, Pichia, Eurotium, Alternaria, Rhodotorula, and Cladosporium, among others.[48]

Placenta

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.[86][87][88] However, the existence of a microbiome in the placenta is controversial as criticized in several researches. So called "placental microbiome" is likely derived from contamination of regents because low-biomass samples are easily contaminated.[89][90][91]

Uterus

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.[92]

Oral cavity

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.[2] 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.[2][50]

Anaerobic bacteria in the oral cavity include:

Selenomonas, Treponema, and Veillonella.[93][needs update] Genera of fungi that are frequently found in the mouth include Candida, Cladosporium, Aspergillus, Fusarium, Glomus, Alternaria, Penicillium, and Cryptococcus, among others.[48]

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.[94] Saliva plays a key biofilm homeostatic role allowing recolonization of bacteria for formation and controlling growth by detaching biofilm buildup.[95] It also provides a means of nutrients and temperature regulation. The location of the biofilm determines the type of exposed nutrients it receives.[96]

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.[97]

This dynamic between host oral cavity and oral microbes plays a key role in health and disease as it provides entry into the body.[98] 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.

dental caries and periodontal disease.[97] Pathogen colonization at the periodontium cause an excessive immune response resulting in a periodontal pocket- a deepened space between the tooth and gingiva.[94] This acts as a protected blood-rich reservoir with nutrients for anaerobic pathogens.[94] Systemic disease at various sites of the body can result from oral microbes entering the blood bypassing periodontal pockets and oral membranes.[98]

Persistent proper oral hygiene is the primary method for preventing oral and systemic disease.[98] It reduces the density of biofilm and overgrowth of potential pathogenic bacteria resulting in disease.[96] 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.[96] Use of antibiotics could treat already spreading infection but ineffective against bacteria within biofilms.[96]

Nasal cavity

The healthy nasal microbiome is dominated by Corynebacterium, and Staphylococcus. The mucosal microbiome plays a critical role in modulating viral infection.[99]

Lung

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.[2] In addition, a bactericidal effect is generated by nasal mucus which contains the enzyme lysozyme.[2] The upper and lower respiratory tract appears to have its own set of microbiota.[100] 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.[48]

Unusual distributions of bacterial and fungal genera in the respiratory tract is observed in people with cystic fibrosis.[48][101] Their bacterial flora often contains antibiotic-resistant and slow-growing bacteria, and the frequency of these pathogens changes in relation to age.[101]

Biliary tract

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.[102]

Disease and death

Human bodies rely on the innumerable bacterial genes as the source of essential nutrients.[103] Both metagenomic and epidemiological studies indicate vital roles for the human microbiome in preventing a wide range of diseases, from type 2 diabetes and obesity to inflammatory bowel disease, Parkinson's disease, and even mental health conditions like depression.[104] A symbiotic relationship between the gut microbiota and different bacteria may influence an individual's immune response.[105] Metabolites generated by gut microbes appear to be causative factors in type 2 diabetes.[106] Although in its infancy, microbiome-based treatment is also showing promise, most notably for treating drug-resistant C. difficile[dead link] infection[107] and in diabetes treatment.[108]

Clostridioides difficile infection

An overwhelming presence of the bacteria, C. difficile, leads to an infection of the gastrointestinal tract, normally associated to dysbiosis with the microbiota believed to have been caused by the administration of antibiotics. Use of antibiotics eradicates the beneficial gut flora within the gastrointestinal tract, which normally prevents pathogenic bacteria from establishing dominance.[109] Traditional treatment for C. difficile infections includes an additional regime of antibiotics, however, efficacy rates average between 20 and 30%.[110] Recognizing the importance of healthy gut bacteria, researchers turned to a procedure known as fecal microbiota transplant (FMT), where patients experiencing gastrointestinal diseases, such as C. difficile infection (CDI), receive fecal content from a healthy individual in hopes of restoring a normal functioning intestinal microbiota.[111] Fecal microbiota transplant is approximately 85–90% effective in people with CDI for whom antibiotics have not worked or in whom the disease recurs following antibiotics.[112][113] Most people with CDI recover with one FMT treatment.[114][109][115]

Cancer

Although cancer is generally a disease of host genetics and environmental factors, microorganisms are implicated in some 20% of human cancers.

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.[117] Microbial density may be used as a prognostic tool in assessment of colorectal cancers.[117]

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.

down-regulate the host immune system including driving acute or chronic inflammation in ways that contribute to carcinogenesis.[116]

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.[116] For example, cancer-associated microbes appear to activate NF-κΒ signaling within the tumor microenvironment. 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.[116] Likewise Helicobacter pylori appears to increase the risk of gastric cancer, due to its driving a chronic inflammatory response in the stomach.[116][117]

Inflammatory bowel disease

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,[118][119] and is correlated to defects in host genes that changes the innate immune response in individuals.[118]

Human immunodeficiency virus

The

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.[120]

Vaginal microbiota plays a role in the infectivity of HIV, with an increased risk of infection and transmission when the woman has

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.[120]

Gut microbiome of centenarians

Humans who are 100 years old or older, called centenarians, have a distinct gut microbiome. This microbiome is characteristically enriched in microorganisms that are able to synthesize novel secondary bile acids.[122] These secondary bile acids include various isoforms of lithocholic acid that may contribute to healthy aging.[122]

Death

With death, the microbiome of the living body collapses and a different composition of microorganisms named necrobiome establishes itself as an important active constituent of the complex physical decomposition process. Its predictable changes over time are thought to be useful to help determine the time of death.[123][124]

Environmental health

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.[125]

Changes, modulation and transmission

Microbiome-based interventions to modulate gut ecology and the immune system[126]

can change the human microbiome across various anatomical systems or regions such as skin and gut.

Person-to-person transmission

The human microbiome is transmitted between a

children, as well as between people living in the same household.[138][139]

Research

Migration

Cellulose digestion

A 2024 study suggests that

See also

Bibliography

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

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