Microbiome

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https://en.wikipedia.org/wiki/Microbiome

A microbiome (from Ancient Greek μικρός (mikrós) 'small' and βίος (bíos) 'life') is the community of microorganisms that can usually be found living together in any given habitat. It was defined more precisely in 1988 by Whipps et al. as "a characteristic microbial community occupying a reasonably well-defined habitat which has distinct physio-chemical properties. The term thus not only refers to the microorganisms involved but also encompasses their theatre of activity". In 2020, an international panel of experts published the outcome of their discussions on the definition of the microbiome. They proposed a definition of the microbiome based on a revival of the "compact, clear, and comprehensive description of the term" as originally provided by Whipps et al., but supplemented with two explanatory paragraphs, the first pronouncing the dynamic character of the microbiome, and the second clearly separating the term microbiota from the term microbiome.

The microbiota consists of all living members forming the microbiome. Most microbiome researchers agree bacteria, archaea, fungi, algae, and small protists should be considered as members of the microbiome. The integration of phages, viruses, plasmids, and mobile genetic elements is more controversial. Whipps's "theatre of activity" includes the essential role secondary metabolites play in mediating complex interspecies interactions and ensuring survival in competitive environments. Quorum sensing induced by small molecules allows bacteria to control cooperative activities and adapts their phenotypes to the biotic environment, resulting, e.g., in cell–cell adhesion or biofilm formation.

All animals and plants form associations with microorganisms, including protists, bacteria, archaea, fungi, and viruses. In the ocean, animal–microbial relationships were historically explored in single host–symbiont systems. However, new explorations into the diversity of microorganisms associating with diverse marine animal hosts is moving the field into studies that address interactions between the animal host and the multi-member microbiome. The potential for microbiomes to influence the health, physiology, behaviour, and ecology of marine animals could alter current understandings of how marine animals adapt to change. This applies to especially the growing climate-related and anthropogenic-induced changes already impacting the ocean and the phytoplankton microbiome in it. The plant microbiome plays key roles in plant health and food production and has received significant attention in recent years. Plants live in association with diverse microbial consortia, referred to as the plant microbiota, living both inside (the endosphere) and outside (the episphere) plant tissues. They play important roles in the ecology and physiology of plants. The core plant microbiome is thought to contain keystone microbial taxa essential for plant health and for the fitness of the plant holobiont. Likewise, the mammalian gut microbiome has emerged as a key regulator of host physiology, and coevolution between host and microbial lineages has played a key role in the adaptation of mammals to their diverse lifestyles.

Microbiome research originated in microbiology in the seventeenth century. The development of new techniques and equipment boosted microbiological research and caused paradigm shifts in understanding health and disease. The development of the first microscopes allowed the discovery of a new, unknown world and led to the identification of microorganisms. Infectious diseases became the earliest focus of interest and research. However, only a small proportion of microorganisms are associated with disease or pathogenicity. The overwhelming majority of microbes are essential for healthy ecosystem functioning and are known for beneficial interactions with other microbes and organisms. The concept that microorganisms exist as single cells began to change as it became increasingly obvious that microbes occur within complex assemblages in which species interactions and communication are critical. Discovery of DNA, the development of sequencing technologies, PCR, and cloning techniques enabled the investigation of microbial communities using cultivation-independent approaches. Further paradigm shifts occurred at the beginning of this century and still continue, as new sequencing technologies and accumulated sequence data have highlighted both the ubiquity of microbial communities in association within higher organisms and the critical roles of microbes in human, animal, and plant health. These have revolutionised microbial ecology. The analysis of genomes and metagenomes in a high-throughput manner now provides highly effective methods for researching the functioning of individual microorganisms as well as whole microbial communities in natural habitats.

Background

History

Microbiome research originated in microbiology and started back in the seventeenth century. The development of new techniques and equipment has boosted microbiological research and caused paradigm shifts in understanding health and disease. Since infectious diseases have affected human populations throughout most of history, medical microbiology was the earliest focus of research and public interest. Additionally, food microbiology is an old field of empirical applications. The development of the first microscopes allowed the discovery of a new, unknown world and led to the identification of microorganisms.

• Paradigm shift
• 
  Shift of paradigm from microbes as unsocial organisms causing diseases to a holistic view of microorganisms as the centre of the One Health Concept interconnecting all areas of human lives.

Access to the previously invisible world opened the eyes and the minds of the researchers of the seventeenth century. Antonie van Leeuwenhoek investigated diverse bacteria of various shapes, fungi, and protozoa, which he called animalcules, mainly from water, mud, and dental plaque samples, and discovered biofilms as a first indication of microorganisms interacting within complex communities. Robert Koch's explanation of the origin of human and animal diseases as a consequence of microbial infection and development of the concept of pathogenicity was an important milestone in microbiology. These findings shifted the focus of the research community and the public on the role of microorganisms as disease-forming agents that needed to be eliminated.

However, comprehensive research over the past century has shown only a small proportion of microorganisms are associated with disease or pathogenicity. The overwhelming majority of microbes are essential for ecosystem functioning and known for beneficial interactions with other microbes as well as macroorganisms. In fact, maintaining a healthy microbiome is essential for human health and may be a target for new therapeutics. At the end of the nineteenth century, microbial ecology started with the pioneering work by Martinus W. Beijerinck and Sergei Winogradsky. The newly established science of environmental microbiology resulted in another paradigm shift: microorganisms are everywhere in natural environments, often associated with hosts and, for the first time, beneficial effects on their hosts were reported.

Subsequently, the concept that microorganisms exist as single cells began to change as it became increasingly obvious that microbes occur within complex assemblages in which species interactions and communication are critical to population dynamics and functional activities. Discovery of DNA, the development of sequencing technologies, PCR, and cloning techniques enabled the investigation of microbial communities using cultivation-independent, DNA and RNA-based approaches.

A further important step was the introduction of phylogenetic markers such as the 16S rRNA gene for microbial community analysis by Carl Woese and George E. Fox in 1977. Nowadays biologists can barcode bacteria, archaea, fungi, algae, and protists in their natural habitats, e.g., by targeting their 16S and 18S rRNA genes, internal transcribed spacer (ITS), or, alternatively, specific functional regions of genes coding for specific enzymes.

Another major paradigm shift was initiated at the beginning of this century and continues through today, as new sequencing technologies and accumulated sequence data have highlighted both the ubiquity of microbial communities in association within higher organisms and the critical roles of microbes in human, animal, and plant health. These new possibilities have revolutionized microbial ecology, because the analysis of genomes and metagenomes in a high-throughput manner provides efficient methods for addressing the functional potential of individual microorganisms as well as of whole communities in their natural habitats. Multiomics technologies including metatranscriptome, metaproteome and metabolome approaches now provide detailed information on microbial activities in the environment. Based on the rich foundation of data, the cultivation of microbes, which was often ignored or underestimated over the last thirty years, has gained new importance, and high throughput culturomics is now an important part of the toolbox to study microbiomes. The high potential and power of combining multiple "omics" techniques to analyze host-microbe interactions are highlighted in several reviews.

Etymology

The word microbiome (from the Greek micro meaning "small" and bíos meaning "life") was first used by J.L. Mohr in 1952 in The Scientific Monthly to mean the microorganisms found in a specific environment.

Definitions

Microbial communities have commonly been defined as the collection of microorganisms living together. More specifically, microbial communities are defined as multi-species assemblages, in which (micro) organisms interact with each other in a contiguous environment. In 1988, Whipps and colleagues working on the ecology of rhizosphere microorganisms provided the first definition of the term microbiome. They described the microbiome as a combination of the words micro and biome, naming a "characteristic microbial community" in a "reasonably well-defined habitat which has distinct physio-chemical properties" as their "theatre of activity". This definition represents a substantial advancement of the definition of a microbial community, as it defines a microbial community with distinct properties and functions and its interactions with its environment, resulting in the formation of specific ecological niches.

However, many other microbiome definitions have been published in recent decades. By 2020 the most cited definition was by Lederberg, and described microbiomes within an ecological context as a community of commensal, symbiotic, and pathogenic microorganisms within a body space or other environment. Marchesi and Ravel focused in their definition on the genomes and microbial (and viral) gene expression patterns and proteomes in a given environment and its prevailing biotic and abiotic conditions. All these definitions imply that general concepts of macro-ecology could be easily applied to microbe-microbe as well as to microbe-host interactions. However, the extent to which these concepts, developed for macro-eukaryotes, can be applied to prokaryotes with their different lifestyles regarding dormancy, variation of phenotype, and horizontal gene transfer as well as to micro-eukaryotes that is not quite clear. This raises the challenge of considering an entirely novel body of conceptual ecology models and theory for microbiome ecology, particularly in relation to the diverse hierarchies of interactions of microbes with one another and with the host biotic and abiotic environments. Many current definitions fail to capture this complexity and describe the term microbiome as encompassing the genomes of microorganisms only.

Microbiome definitions
Definition type	Examples
Ecological	Definitions based on ecology describe the microbiome following the concepts derived from the ecology of multicellular organisms. The main issue here is that the theories from the macro-ecology do not always fit the rules in the microbial world.
	"A convenient ecological framework in which to examine biocontrol systems is that of the microbiome. This may be defined as a characteristic microbial community occupying a reasonably well-defined habitat which has distinct physio-chemical properties. The term thus not only refers to the microorganisms involved but also encompasses their theatre of activity". "This term refers to the entire habitat, including the microorganisms (bacteria, archaea, lower and higher eurkaryotes, and viruses), their genomes (i.e., genes), and the surrounding environmental conditions. This definition is based on that of "biome," the biotic and abiotic factors of given environments. Others in the field limit the definition of microbiome to the collection of genes and genomes of members of a microbiota. It is argued that this is the definition of metagenome, which combined with the environment constitutes the microbiome. The microbiome is characterized by the application of one or combinations of metagenomics, metabonomics, metatranscriptomics, and metaproteomics combined with clinical or environmental metadata". "others use the term microbiome to mean all the microbes of a community, and in particular, for the plant microbiome, those microbial communities associated with the plant which can live, thrive, and interact with different tissues such as roots, shoots, leaves, flowers, and seeds".  "Ecological community of commensal, symbiotic and pathogenic microorganisms within a body space or other environment".
Organisms/host-dependent	The host-dependent definitions are based on the microbial interactions with the host. The main gaps here concern the question whether the microbial-host interaction data gained from one host can be transferred to another. The understanding of coevolution and selection in the host-dependent definitions is also underrepresented.
	"A community of microorganisms (such as bacteria, fungi, and viruses) that inhabit a particular environment and especially the collection of microorganisms living in or on the human body". "Human Microbiome Project (HMP): [...] The Human Microbiome is the collection of all the microorganisms living in association with the human body. These communities consist of a variety of microorganisms including eukaryotes, archaea, bacteria and viruses".
Genomic/ method-driven	There is a variety of microbiome definitions available that are driven by the methods applied. Mostly, these definitions rely on DNA sequence-based analysis and describe microbiome as a collective genome of microorganisms in a specific environment. The main bottleneck here is that every new available technology will result in a need for a new definition.
	"The collective genomes of microorganisms inhabiting a particular environment and especially the human body".  "The microbiome comprises all of the genetic material within a microbiota (the entire collection of microorganisms in a specific niche, such as the human gut). This can also be referred to as the metagenome of the microbiota".  "Microbiome is a term that describes the genome of all the microorganisms, symbiotic and pathogenic, living in and on all vertebrates. The gut microbiome consists of the collective genome of microbes inhabiting the gut including bacteria, archaea, viruses, and fungi".  "Different approaches to define the population provide different information. a | Microbiota: 16S rRNA surveys are used to taxonomically identify the microorganisms in the environment. b | Metagenome: the genes and genomes of the microbiota, including plasmids, highlighting the genetic potential of the population. c | Microbiome: the genes and genomes of the microbiota, as well as the products of the microbiota and the host environment".  "Totality of genomes of a microbiota. Often used to describe the entity of microbial traits (=functions) encoded by a microbiota."
Combined	There are some microbiome definitions available that fit several categories with their advantages and disadvantages.
	"A microbiome is the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share our body space."  "The microbiome is the sum of the microbes and their genomic elements in a particular environment".  "The genes and genomes of the microbiota, as well as the products of the microbiota and the host environment".

In 2020, a panel of international experts, organised by the EU-funded MicrobiomeSupport project, published the results of their deliberations on the definition of the microbiome. The panel was composed of about 40 leaders from diverse microbiome areas, and about one hundred further experts from around the world contributed through an online survey. They proposed a definition of the microbiome based on a revival of what they characterised as the "compact, clear, and comprehensive description of the term" as originally provided by Whipps et al. in 1988, amended with a set of recommendations considering subsequent technological developments and research findings. They clearly separate the terms microbiome and microbiota and provide a comprehensive discussion considering the composition of microbiota, the heterogeneity and dynamics of microbiomes in time and space, the stability and resilience of microbial networks, the definition of core microbiomes, and functionally relevant keystone species as well as co-evolutionary principles of microbe-host and inter-species interactions within the microbiome.

The term microbiome encompasses both the microbiota (community of microorganisms) and their "theatre of activity" (structural elements, metabolites/signal molecules, and the surrounding environmental conditions.

The panel extended the Whipps et al. definition, which contains all important points that are valid even 30 years after its publication in 1988, by two explanatory paragraphs differentiating the terms microbiome and microbiota and pronouncing its dynamic character, as follows:

• The microbiome is defined as a characteristic microbial community occupying a reasonable well-defined habitat which has distinct physio-chemical properties. The microbiome not only refers to the microorganisms involved but also encompass their theatre of activity, which results in the formation of specific ecological niches. The microbiome, which forms a dynamic and interactive micro-ecosystem prone to change in time and scale, is integrated in macro-ecosystems including eukaryotic hosts, and here crucial for their functioning and health.

• The microbiota consists of the assembly of microorganisms belonging to different kingdoms (prokaryotes (bacteria, archaea), eukaryotes (algae, protozoa, fungi etc), while "their theatre of activity" includes microbial structures, metabolites, mobile genetic elements (such as transposons, phages, and viruses), and relic DNA embedded in the environmental conditions of the habitat.

Membership

Microbiota

Main article: microbiota

The microbiota comprises all living members forming the microbiome. Most microbiome researchers agree bacteria, archaea, fungi, algae, and small protists should be considered as members of the microbiome. The integration of phages, viruses, plasmids, and mobile genetic elements is a more controversial issue in the definition of the microbiome. There is also no clear consensus as to whether extracellular DNA derived from dead cells, so-called "relic DNA", belongs to the microbiome. Relic DNA can be up to 40% of the sequenced DNA in soil, and was up to 33% of the total bacterial DNA on average in a broader analysis of habitats with the highest proportion of 80% in some samples. Despite its omnipresence and abundance, relic DNA had a minimal effect on estimates of taxonomic and phylogenetic diversity.

When it comes to the use of specific terms, a clear differentiation between microbiome and microbiota helps to avoid the controversy concerning the members of a microbiome. Microbiota is usually defined as the assemblage of living microorganisms present in a defined environment. As phages, viruses, plasmids, prions, viroids, and free DNA are usually not considered as living microorganisms, they do not belong to the microbiota.

The term microbiome, as it was originally postulated by Whipps and coworkers, includes not only the community of the microorganisms but also their "theatre of activity". The latter involves the whole spectrum of molecules produced by the microorganisms, including their structural elements (nucleic acids, proteins, lipids, polysaccharides), metabolites (signalling molecules, toxins, organic, and inorganic molecules), and molecules produced by coexisting hosts and structured by the surrounding environmental conditions. Therefore, all mobile genetic elements, such as phages, viruses, and "relic" and extracellular DNA, should be included in the term microbiome, but are not a part of microbiota. The term microbiome is also sometimes confused with the metagenome. Metagenome is, however, clearly defined as a collection of genomes and genes from the members of a microbiota.

Microbiome studies sometimes focus on the behaviour of a specific group of microbiota, generally in relation to or justified by a clear hypothesis. More and more terms like bacteriome, archaeome, mycobiome, or virome have started appearing in the scientific literature, but these terms do not refer to biomes (a regional ecosystem with a distinct assemblage of (micro) organisms, and physical environment often reflecting a certain climate and soil) as the microbiome itself. Consequently, it would be better to use the original terms (bacterial, archaeal, or fungal community). In contrast to the microbiota, which can be studied separately, the microbiome is always composed by all members, which interact with each other, live in the same habitat, and form their ecological niche together. The well-established term virome is derived from virus and genome and is used to describe viral shotgun metagenomes consisting of a collection of nucleic acids associated with a particular ecosystem or holobiont. Viral metagenomes can be suggested as a semantically and scientifically better term.

Networks

• 
  Co-occurrence networks help visualising microbial interactions
  Nodes usually represent taxa of microorganisms, and edges represent statistically significant associations between nodes.
  –––––––––––––––––––––––––––
  Testing of the hypotheses resulted from the network analyses is required for a comprehensive study of microbial interactions.

Microbes interact with one another, and these symbiotic interactions have diverse consequences for microbial fitness, population dynamics, and functional capacities within the microbiome. The microbial interactions can either be between microorganisms of the same species or between different species, genera, families, and domains of life. The interactions can be separated into positive, negative, and neutral types. Positive interactions include mutualism, synergism, and commensalism. Negative interactions include amensalism, predation, parasitism, antagonism, and competition. Neutral interactions are interactions where there is no observed effect on the functional capacities or fitness of interacting species microbial life strategy concepts.

• 
  Co-occurrence networks show difference in gut microbiota between herbivorous and carnivorous cichlids
  Nodes coloured according to phylum. The herbivore network has higher complexity (156 nodes and 339 edges) compared to the carnivore network (21 nodes and 70 edges).

Microbiomes exhibit different adaptive strategies. Oligotrophs are organisms that can live in an environment offering very low levels of nutrients, particularly carbon. They are characterised by slow growth, low rates of metabolism, and generally low population density. Oligotrophic environments include deep oceanic sediments, caves, glacial and polar ice, deep subsurface soil, aquifers, ocean waters, and leached soils. In contrast are the copiotrophs, which thrive in much higher carbon concentrations, and do well in high organic substrate conditions such as sewage lagoons.

In addition to oligotrophic and copiotrophic strategists, the competitor–stress tolerator–ruderals framework can influence the outcomes of interactions. For example, microorganisms competing for the same source can also benefit from each other when competing for the same compound at different trophic levels. Stability of a complex microbial ecosystem depends on trophic interactions for the same substrate at different concentration levels. As of 2020 microbial social adaptations in nature have been understudied. Here molecular markers can provide insight into social adaptations by supporting the theories, e.g., of altruists and cheaters in native microbiomes.

Coevolution

• Shift in the understanding of the microbial-host coevolution
• 
  from "separation" theories to a holistic approach

  In a holistic approach, the hosts and their associated microbiota are assumed to have coevolved with each other 

See also: Holobiont and Hologenome theory of evolution

According to the "separation" approach, the microorganisms can be divided into pathogens, neutral, and symbionts, depending on their interaction with their host. The coevolution between host and its associated microbiota may be accordingly described as antagonistic (based on negative interactions) or mutualistic (based on positive interactions).

As of 2020, the emergence in publications about opportunistic pathogens and pathobionts has produced a shift towards a holistic approach in the coevolutions theory. The holistic approach sees the host and its associated microbiota as one unit (the so-called holobiont), that coevolves as one entity. According to the holistic approach, holobiont's disease state is linked to dysbiosis, low diversity of the associated microbiota, and their variability: a so-called pathobiome state. The healthy state, on the other hand, is accompanied with eubiosis, high diversity, and uniformity of the respective microbiota.

Types

Terrestrial

Plant

• 
  Microbiomes in the plant ecosystem 

Main article: Plant microbiome

The plant microbiome plays roles in plant health and food production and has received significant attention in recent years. Plants live in association with diverse microbial consortia. These microbes, referred to as the plant's microbiota, live both inside (the endosphere) and outside (the episphere) of plant tissues, and play important roles in the ecology and physiology of plants. "The core plant microbiome is thought to comprise keystone microbial taxa that are important for plant fitness and established through evolutionary mechanisms of selection and enrichment of microbial taxa containing essential functions genes for the fitness of the plant holobiont".

Plant microbiomes are shaped by both factors related to the plant itself, such as genotype, organ, species and health status, as well as factors related to the plant's environment, such as management, land use and climate. The health status of a plant has been reported in some studies to be reflected by or linked to its microbiome.

Plant and plant-associated microbiota colonise different niches on and inside the plant tissue. All the above-ground plant parts together, called the phyllosphere, are a continuously evolving habitat due to ultraviolet (UV) radiation and altering climatic conditions. It is primarily composed of leaves. Below-ground plant parts, mainly roots, are generally influenced by soil properties. Harmful interactions affect the plant growth through pathogenic activities of some microbiota members. On the other hand, beneficial microbial interactions promote plant growth.

The addition of synthetic nitrogen fertiliser may have little impact on soil microbiome structure or composition, but drastically reduces the microbiome network connectivity.

Animal

• 
  Principal coordinate analysis of animal gut microbiome data 

The mammalian gut microbiome has emerged as a key regulator of host physiology, and coevolution between host and microbial lineages has played a key role in the adaptation of mammals to their diverse lifestyles. Diet, especially herbivory, is an important correlate of microbial diversity in mammals. Most mammalian microbiomes are also strongly correlated with host phylogeny, despite profound shifts in diet. This suggests host factors that themselves change across host phylogeny, such as gut physiology, play an important role in structuring the gut microbiomes across mammals. The vertebrate adaptive immune system is even speculated to have evolved as just such a factor for selective maintenance of symbiotic homeostasis.

The importance of phylogeny-correlated factors to the diversity of vertebrate microbiomes more generally is still poorly understood. Phylosymbiosis, or the observation that more closely related host species have more similar microbiomes, has been described in a number of nonmammalian taxa. Other analyses have found substantial variation in phylosymbiotic signals among mammalian taxa, sometimes with conflicting results. The presence of a robust phylosymbiotic correlation implies that host factors control microbial assembly. Even if the specific mechanisms are unknown, variation in the strength or presence of a measurable phylosymbiotic signal across host phylogeny could prove useful for identifying such mechanisms through comparative studies. However, as of 2020 most studies have focused on just a few taxa at a time, and variable methods for both surveying the microbiome and measuring phylosymbiosis and host specificity (or the restriction of microbes to specific host lineages) have made generalisations difficult.

Without broader evolutionary context, it is unclear how universally conserved patterns of host-microbe phylosymbiosis actually are. Growing evidence indicates that the strong patterns identified in mammals are the exception rather than the rule in vertebrates. Meta-analyses of fish  and birds  have failed to detect the strength of correlations to diet and phylogeny reported in mammals. A recent analysis of samples from more than 100 vertebrate species also found the strength of phylogenetic correlation to be much higher in mammals than in birds, reptiles, amphibians, or fish. It is increasingly appreciated in nonvertebrate animals that fundamental aspects of the host's relationship to its symbiotic community can change drastically between taxa: many insects depend entirely on microbes for key metabolites, while others seem to be devoid of resident gut microbes.

Human

Main article: Human microbiome

The human microbiome is the aggregate of all microbiota that reside on or within human tissues and biofluids along with the corresponding anatomical sites in which they reside, including the skin, mammary glands, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, biliary tract, and gastrointestinal tract. Types of human microbiota include bacteria, archaea, fungi, protists and viruses. Though micro-animals can also live on the human body, they are typically excluded from this definition. In the context of genomics, the term human microbiome is sometimes used to refer to the collective genomes of resident microorganisms; the term human metagenome has the same meaning.

Humans are colonised by many microorganisms, with approximately the same order of magnitude of non-human cells as human cells. Some microorganisms that colonize humans are commensal, meaning they co-exist without harming or benefiting humans; others have a mutualistic relationship with their human hosts. Conversely, some non-pathogenic microorganisms can harm human hosts via the metabolites they produce, like trimethylamine, which the human body converts to trimethylamine N-oxide via FMO3-mediated oxidation. 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.

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. It reached a milestone in 2012 when it published its initial results.

Marine

• Marine animal host-microbiome relationship
• 
  Relationships are generally thought to exist in a symbiotic state, and are normally exposed to environmental and animal-specific factors that may cause natural variations. Some events may change the relationship into a functioning but altered symbiotic state, whereas extreme stress events may cause dysbiosis or a breakdown of the relationship and interactions.

Main article: Marine microbiome

All animals on Earth form associations with microorganisms, including protists, bacteria, archaea, fungi, and viruses. In the ocean, animal–microbial relationships were historically explored in single host–symbiont systems. However, new explorations into the diversity of microorganisms associating with diverse marine animal hosts is moving the field into studies that address interactions between the animal host and a more multi-member microbiome. The potential for microbiomes to influence the health, physiology, behavior, and ecology of marine animals could alter current understandings of how marine animals adapt to change, and especially the growing climate-related and anthropogenic-induced changes already impacting the ocean environment.

The microbiomes of diverse marine animals are currently under study, from simplistic organisms including sponges and ctenophores to more complex organisms such as sea squirts and sharks.

The relationship between the Hawaiian bobtail squid and the bioluminescent bacterium Aliivibrio fischeri is one of the best studied symbiotic relationships in the sea and is a choice system for general symbiosis research. This relationship has provided insight into fundamental processes in animal-microbial symbioses, and especially biochemical interactions and signaling between the host and bacterium.

The gutless marine oligochaete worm Olavius algarvensis is another relatively well-studied marine host to microbes. These three centimetre long worms reside within shallow marine sediments of the Mediterranean Sea. The worms do not contain a mouth or a digestive or excretory system, but are instead nourished with the help of a suite of extracellular bacterial endosymbionts that reside upon coordinated use of sulfur present in the environment. This system has benefited from some of the most sophisticated 'omics and visualization tools. For example, multi-labeled probing has improved visualization of the microbiome and transcriptomics and proteomics have been applied to examine host–microbiome interactions, including energy transfer between the host and microbes and recognition of the consortia by the worm's innate immune system. The major strength of this system is that it does offer the ability to study host–microbiome interactions with a low diversity microbial consortium, and it also offers a number of host and microbial genomic resources

Stylophora pistillata coral colony and the bacteria Endozoicomonas (Ez) probed cells (yellow) within the tentacles of S. pistillata residing in aggregates (Ez agg) as well as just outside the aggregate (b).

Corals are one of the more common examples of an animal host whose symbiosis with microalgae can turn to dysbiosis, and is visibly detected as bleaching. Coral microbiomes have been examined in a variety of studies, which demonstrate how variations in the ocean environment, most notably temperature, light, and inorganic nutrients, affect the abundance and performance of the microalgal symbionts, as well as calcification and physiology of the host. Studies have also suggested that resident bacteria, archaea, and fungi additionally contribute to nutrient and organic matter cycling within the coral, with viruses also possibly playing a role in structuring the composition of these members, thus providing one of the first glimpses at a multi-domain marine animal symbiosis. The gammaproteobacterium Endozoicomonas is emerging as a central member of the coral's microbiome, with flexibility in its lifestyle. Given the recent mass bleaching occurring on reefs, corals will likely continue to be a useful and popular system for symbiosis and dysbiosis research.

Sponges are common members of the ocean's diverse benthic habitats and their abundance and ability to filter large volumes of seawater have led to the awareness that these organisms play critical roles in influencing benthic and pelagic processes in the ocean. They are one of the oldest lineages of animals, and have a relatively simple body plan that commonly associates with bacteria, archaea, algal protists, fungi, and viruses. Sponge microbiomes are composed of specialists and generalists, and complexity of their microbiome appears to be shaped by host phylogeny. Studies have shown that the sponge microbiome contributes to nitrogen cycling in the oceans, especially through the oxidation of ammonia by archaea and bacteria. Most recently, microbial symbionts of tropical sponges were shown to produce and store polyphosphate granules, perhaps enabling the host to survive periods of phosphate depletion in oligotrophic marine environments. The microbiomes of some sponge species do appear to change in community structure in response to changing environmental conditions, including temperature and ocean acidification, as well as synergistic impacts.

• 
  Collecting a sample of blow from a blue whale using a helicopter drone 
• 
  Relative abundance of bacterial classes from whale blow, air and seawater samples.

Cetacean microbiomes can be difficult to assess because of difficulties accessing microbial samples. For example, many whale species are rare and are deep divers. There are different techniques for sampling a cetacean's gut microbiome. The most common is collecting fecal samples from the environment and taking a probe from the center that is non-contaminated. The skin is a barrier protecting marine mammals from the outside world. The epidermal microbiome on the skin is an indicator of how healthy the animal is, and is also an ecological indicator of the state of the surrounding environment. Knowing what the microbiome of the skin of marine mammals looks like under typical conditions allows understanding of how these communities different from free microbial communities found in the sea. Cetaceans are in danger because they are affected by multiple stress factors which make them more vulnerable to various diseases. They have been high susceptibility to airway infections, but little is known about their respiratory microbiome. Sampling the exhaled breath or "blow" of cetaceans can provide an assessment of their state of health. Blow is composed of a mixture of microorganisms and organic material, including lipids, proteins, and cellular debris derived from the linings of the airways which, when released into the relatively cooler outdoor air, condense to form a visible mass of vapor, which can be collected. There are various methods for collecting exhaled breath samples, one of the most recent is through the use of aerial drones. This method provides a safer, quieter, and less invasive alternative and often a cost-effective option for monitoring fauna and flora. Blow samples are taken to the laboratory where the respiratory tract microbiota are amplified and sequenced. The use of aerial drones has been more successful with large cetaceans due to slow swim speeds and larger blow sizes.

Assessment

Currently available methods for studying microbiomes, so-called multi-omics, range from high throughput isolation (culturomics) and visualization (microscopy), to targeting the taxonomic composition (metabarcoding), or addressing the metabolic potential (metabarcoding of functional genes, metagenomics) to analyze microbial activity (metatranscriptomics, metaproteomics, metabolomics). Based on metagenome data, microbial genomes can be reconstructed. While first metagenome-assembled genomes were reconstructed from environmental samples, in recent years, several thousands of bacterial genomes were binned without culturing the organisms behind. For example, 154,723 microbial genomes of the global human microbiome were reconstructed in 2019 from 9,428 metagenomes.

• Methods for assessing microbial functioning
• 
  Methods for assessing microbial functioning

  Complex microbiome studies cover various areas, starting from the level of complete microbial cells (microscopy, culturomics), followed by the DNA (single cell genomics, metabarcoding, metagenomics), RNA (metatranscriptomics), protein (metaproteomics), and metabolites (metabolomics). In that order, the focus of the studies shifts from the microbial potential (learning about available microbiota in the given habitat) over the metabolic potential (deciphering available genetic material) towards microbial functioning (e.g., the discovery of the active metabolic pathways).

Computational modeling of microbiomes has been used to complement experimental methods for investigating microbial function by utilizing multi-omic data to predict complex inter-species and host-species dynamics. A popular in silico method is to combine metabolic network models of microbial taxa present in a community and use a mathematical modeling strategy such as flux balance analysis to predict the metabolic function of the microbial community at a taxon and community-level.

As of 2020, understanding remains limited due to missing links between the massive availability of microbiome DNA sequence data on the one hand and limited availability of microbial isolates needed to confirm metagenomic predictions of gene function on the other hand. Metagenome data provides a playground for new predictions, yet much more data is needed to strengthen the links between sequence and rigorous functional predictions. This becomes obvious when considering that the replacement of one single amino acid residue by another may lead to a radical functional change, resulting in an incorrect functional assignment to a given gene sequence. Additionally, cultivation of new strains is needed to help identify the large fraction of unknown sequences obtained from metagenomics analyses, which for poorly studied ecosystems can be more than 70%. Depending on the applied method, even in well-studied microbiomes, 40–70% of the annotated genes in fully sequenced microbial genomes have no known or predicted function. As of 2019, 85 of the then established 118 phyla had not had a single species described, presenting a challenge to understanding prokaryotic functional diversity.

The number of prokaryotic phyla may reach hundreds, and archaeal ones are among the least studied. The growing gap between the diversity of Bacteria and Archaea held in pure culture and those detected by molecular methods has led to the proposal to establish a formal nomenclature for not-yet cultured taxa, primarily based on sequence information. According to this proposal, the concept of Candidatus species would be extended to the groups of closely related genome sequences, and their names would be published following established rules of bacterial nomenclature.

Each microbiome system is suited to address different types of questions based on the culturability of microbes, genetic tractability of microbes and host (where relevant), ability to maintain system in laboratory setting, and ability to make host/environment germfree.

• Underlying complexity
• 
  Tradeoffs between experimental questions and complexity of microbiome systems 
  (A) Pairwise interactions between the soil bacteria Bacillus subtilis and Streptomyces spp. are well-suited for characterizing the functions of secondary metabolites in microbial interactions.
  (B) The symbiosis between bobtail squid and the marine bacterium Aliivibrio fischeri is fundamental to understanding host and microbial factors that influence colonization.
  (C) The use of gnotobiotic mice is crucial for making links between host diet and the effects on specific microbial taxa in a community.

Gut microbiota

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Gut_microbiota

Escherichia coli, one of the many species of bacteria present in the human gut

Gut microbiota, gut microbiome, or gut flora are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals.The gastrointestinal metagenome is the aggregate of all the genomes of the gut microbiota. The gut is the main location of the human microbiome. The gut microbiota has broad impacts, including effects on colonization, resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the gut–brain axis.

The microbial composition of the gut microbiota varies across regions of the digestive tract. The colon contains the highest microbial density of any human-associated microbial community studied so far, representing between 300 and 1000 different species. Bacteria are the largest and to date, best studied component and 99% of gut bacteria come from about 30 or 40 species. About 55% of the dry mass of feces is bacteria. Over 99% of the bacteria in the gut are anaerobes, but in the cecum, aerobic bacteria reach high densities. It is estimated that the human gut microbiota has around a hundred times as many genes as there are in the human genome.

Overview

Composition and distribution of gut microbiota in human body

In humans, the gut microbiota has the highest numbers and species of bacteria compared to other areas of the body. The approximate number of bacteria composing the gut microbiota is about 10¹³–10¹⁴ (10,000 to 100,000 billion). In humans, the gut flora is established at birth and gradually transitions towards a state resembling that of adults by the age of two, coinciding with the development and maturation of the intestinal epithelium and intestinal mucosal barrier. This barrier is essential for supporting a symbiotic relationship with the gut flora while providing protection against pathogenic organisms.

The relationship between some gut microbiota and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship. Some human gut microorganisms benefit the host by fermenting dietary fiber into short-chain fatty acids (SCFAs), such as acetic acid and butyric acid, which are then absorbed by the host. Intestinal bacteria also play a role in synthesizing certain B vitamins and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics. 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. Dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.

The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes. A systematic review from 2016 examined the preclinical and small human trials that have been conducted with certain commercially available strains of probiotic bacteria and identified those that had the most potential to be useful for certain central nervous system disorders. It should also be highlighted that the Mediterranean diet, rich in vegetables and fibers, stimulates the activity and growth of beneficial bacteria for the brain.

Classifications

The microbial composition of the gut microbiota varies across the digestive tract. In the stomach and small intestine, relatively few species of bacteria are generally present. Fungi, protists, archaea, and viruses are also present in the gut flora, but less is known about their activities.

Candida albicans, a yeast found in the gut

Many species in the gut have not been studied outside of their hosts because they cannot be cultured. While there are a small number of core microbial species shared by most individuals, populations of microbes can vary widely. Within an individual, their microbial populations stay fairly constant over time, with some alterations occurring due to changes in lifestyle, diet and age. The Human Microbiome Project has set out to better describe the microbiota of the human gut and other body locations.

The four dominant bacterial phyla in the human gut are Bacillota (Firmicutes), Bacteroidota, Actinomycetota, and Pseudomonadota. Most bacteria belong to the genera Bacteroides, Clostridium, Faecalibacterium, Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, and Bifidobacterium. Other genera, such as Escherichia and Lactobacillus, are present to a lesser extent. Species from the genus Bacteroides alone constitute about 30% of all bacteria in the gut, suggesting that this genus is especially important in the functioning of the host.

Fungal genera that have been detected in the gut include Candida, Saccharomyces, Aspergillus, Penicillium, Rhodotorula, Trametes, Pleospora, Sclerotinia, Bullera, and Galactomyces, among others. Rhodotorula is most frequently found in individuals with inflammatory bowel disease while Candida is most frequently found in individuals with hepatitis B cirrhosis and chronic hepatitis B.

Archaea constitute another large class of gut flora which are important in the metabolism of the bacterial products of fermentation.

Industrialization is associated with changes in the microbiota and the reduction of diversity could drive certain species to extinction; in 2018, researchers proposed a biobank repository of human microbiota.

Enterotype

An enterotype is a classification of living organisms based on its bacteriological ecosystem in the human gut microbiome not dictated by age, gender, body weight, or national divisions. There are indications that long-term diet influences enterotype. Three human enterotypes have been proposed, but their value has been questioned.

Composition

See also: Human microbiome § Gastrointestinal tract

Diagram of human gastrointestinal tract microbiota depicted in various regions

Bacteria

Stomach

Due to the high acidity of the stomach, most microorganisms cannot survive there. The main bacteria of the gastric microbiota belong to five major phyla: Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteriota, and Proteobacteria. The dominant genera are Prevotella, Streptococcus, Veillonella, Rothia, and Haemophilus. The interaction between the pre-existing gastric microbiota with the introduction of H. pylori may influence disease progression. When there is a presence of H. pylori it becomes the dominant species of the microbiota.

Intestines

Bacteria commonly found in the human colon
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 enterica	3–7
Faecalibacterium prausnitzii	?common
Peptostreptococcus sp.	?common
Peptococcus sp.	?common

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. However, in the distal portion of the small intestine alkaline conditions support gram-negative bacteria of the Enterobacteriaceae. 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. In addition the large intestine contains the largest bacterial ecosystem in the human body. About 99% of the large intestine and feces flora are made up of obligate anaerobes such as Bacteroides and Bifidobacterium. Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites.

Bacteria make up most of the flora in the colon and account for 60% of fecal nitrogen. This fact makes feces an ideal source of 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.

Five phyla dominate the intestinal microbiota: Bacteroidota, Bacillota (Firmicutes), Actinomycetota, Pseudomonadota, and Verrucomicrobiota – with Bacteroidota and Bacillota constituting 90% of the composition. Somewhere between 300 and 1000 different species live in the gut, with most estimates at about 500. However, it is probable that 99% of the bacteria come from about 30 or 40 species, with Faecalibacterium prausnitzii (phylum firmicutes) being the most common species in healthy adults.

Research suggests that the relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship. Though people can survive with no gut flora, the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system via end products of metabolism like propionate and acetate, preventing growth of harmful species, 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. However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host.

Fungi

Further information: Mycobiome

Fungi also make up a part of the gut flora, but less is known about their activities.

Due to the prevalence of fungi in the natural environment, determining which genera and species are permanent members of the gut mycobiome is difficult. Research is underway as to whether Penicillium is a permanent or transient member of the gut flora, obtained from dietary sources such as cheese, though several species in the genus are known to survive at temperatures around 37 °C, about the same as the core body temperature. Saccharomyces cerevisiae, brewer's yeast, is known to reach the intestines after being ingested and can be responsible for the condition auto-brewery syndrome in cases where it is overabundant, while Candida albicans is likely a permanent member, and is believed to be acquired at birth through vertical transmission.

Viruses

Further information: Virome

The human virome includes all viruses associated with the human body, ranging from viruses that infect native cells to bacteriophages that infect bacteria in the microbiome. Among these, bacteriophages are by far the most numerous.

Variation

Age

There are common patterns of microbiome composition evolution during life. In general, the diversity of microbiota composition of fecal samples is significantly higher in adults than in children, although interpersonal differences are higher in children than in adults. Much of the maturation of microbiota into an adult-like configuration happens during the first three years of life.

As the microbiome composition changes, so does the composition of bacterial proteins produced in the gut. In adult microbiomes, a high prevalence of enzymes involved in fermentation, methanogenesis and the metabolism of arginine, glutamate, aspartate and lysine have been found. In contrast, in infant microbiomes the dominant enzymes are involved in cysteine metabolism and fermentation pathways.

Geography

Gut microbiome composition depends on the geographic origin of populations. Variations in a trade-off of Prevotella, the representation of the urease gene, and the representation of genes encoding glutamate synthase/degradation or other enzymes involved in amino acids degradation or vitamin biosynthesis show significant differences between populations from the US, Malawi, or Amerindian origin.

The US population has a high representation of enzymes encoding the degradation of glutamine and enzymes involved in vitamin and lipoic acid biosynthesis; whereas Malawi and Amerindian populations have a high representation of enzymes encoding glutamate synthase and they also have an overrepresentation of α-amylase in their microbiomes. As the US population has a diet richer in fats than Amerindian or Malawian populations which have a corn-rich diet, the diet is probably the main determinant of the gut bacterial composition.

Further studies have indicated a large difference in the composition of microbiota between European and rural African children. The fecal bacteria of children from Florence were compared to that of children from the small rural village of Boulpon in Burkina Faso. The diet of a typical child living in this village is largely lacking in fats and animal proteins and rich in polysaccharides and plant proteins. The fecal bacteria of European children were dominated by Firmicutes and showed a marked reduction in biodiversity, while the fecal bacteria of the Boulpon children was dominated by Bacteroidetes. The increased biodiversity and different composition of the gut microbiome in African populations may aid in the digestion of normally indigestible plant polysaccharides and also may result in a reduced incidence of non-infectious colonic diseases.

On a smaller scale, it has been shown that sharing numerous common environmental exposures in a family is a strong determinant of individual microbiome composition. This effect has no genetic influence and it is consistently observed in culturally different populations.

Malnourishment

Malnourished children have less mature and less diverse gut microbiota than healthy children, and changes in the microbiome associated with nutrient scarcity can in turn be a pathophysiological cause of malnutrition. Malnourished children also typically have more potentially pathogenic gut flora, and more yeast in their mouths and throats. Altering diet may lead to changes in gut microbiota composition and diversity.

Race and ethnicity

Researchers with the American Gut Project and Human Microbiome Project found that twelve microbe families varied in abundance based on the race or ethnicity of the individual. The strength of these associations is limited by the small sample size: the American Gut Project collected data from 1,375 individuals, 90% of whom were white. The Healthy Life in an Urban Setting (HELIUS) study in Amsterdam found that those of Dutch ancestry had the highest level of gut microbiota diversity, while those of South Asian and Surinamese descent had the lowest diversity. The study results suggested that individuals of the same race or ethnicity have more similar microbiomes than individuals of different racial backgrounds.

Socioeconomic status

As of 2020, at least two studies have demonstrated a link between an individual's socioeconomic status (SES) and their gut microbiota. A study in Chicago found that individuals in higher SES neighborhoods had greater microbiota diversity. People from higher SES neighborhoods also had more abundant Bacteroides bacteria. Similarly, a study of twins in the United Kingdom found that higher SES was also linked with a greater gut diversity.

Antibiotic use

As of 2023, a study suggests that antibiotics, especially those used in the treatment of broad-spectrum bacterial infections, have negative effects on the gut microbiota. The study also states that there are many experts on intestinal health concerned that antibody usage has reduced the diversity of the gut microbiota, many of the strains are lost, and if there is a re-emergence of the bacteria, it is gradual and long-term.

Functions

When the study of gut flora began in 1995, it was thought to have three key roles: direct defense against pathogens, fortification of host defense by its role in developing and maintaining the intestinal epithelium and inducing antibody production there, and metabolizing otherwise indigestible compounds in food. Subsequent work discovered its role in training the developing immune system, and yet further work focused on its role in the gut–brain axis. The gut microbiota not only influences intestinal health but also plays a role in systemic immune regulation, including interactions with the pulmonary immune environment through what is known as the 'gut–lung axis'.

Direct inhibition of pathogens

The gut flora community plays a direct role in defending against pathogens by fully colonising the space, making use of all available nutrients, and by secreting compounds known as cytokines that kill or inhibit unwelcome organisms that would compete for nutrients with it. Different strains of gut bacteria cause the production of different cytokines. Cytokines are chemical compounds produced by our immune system for initiating the inflammatory response against infections. Disruption of the gut flora allows competing organisms like Clostridioides difficile to become established that otherwise are kept in abeyance.

Development of enteric protection and immune system

Microfold cells transfer antigens (Ag) from the lumen of the gut to gut-associated lymphoid tissue (GALT) via transcytosis and present them to different innate and adaptive immune cells.

Gut flora in infants becomes similar to an adult within one to two years of birth. As the gut flora establishes, the lining of the intestines – the intestinal epithelium and the intestinal mucosal barrier that it secretes – develop a symbiosis with microorganisms. Specifically, goblet cells that produce the mucosa proliferate, and the mucosa layer thickens, providing an outside mucosal layer in which favorable microorganisms can anchor and feed, and an inner layer that these organisms cannot penetrate. Additionally, the development of gut-associated lymphoid tissue (GALT), which forms part of the intestinal epithelium and which detects and reacts to pathogens, develops during the time that the gut flora becomes established. The GALT that develops is tolerant to gut flora species, but not to other microorganisms. GALT also normally becomes tolerant to food the infant consumes, and the gut flora metabolites (molecules formed from metabolism) produced from food.

The human immune system creates cytokines that can drive the immune system to produce inflammation in order to protect itself, and that can tamp down the immune response to maintain homeostasis and allow healing after insult or injury. Different bacterial species that appear in gut flora have been shown to be able to drive the immune system to create cytokines selectively; for example Bacteroides fragilis and some Clostridia species appear to drive an anti-inflammatory response, while some segmented filamentous bacteria drive the production of inflammatory cytokines. Gut flora can also regulate the production of antibodies by the immune system. One function of this regulation is to cause B cells to class switch to IgA. In most cases B cells need activation from T helper cells to induce class switching; however, in another pathway, gut flora cause NF-kB signaling by intestinal epithelial cells which results in further signaling molecules being secreted. These signaling molecules interact with B cells to induce class switching to IgA. IgA is an important type of antibody that is used in mucosal environments like the gut. It has been shown that IgA can help diversify the gut community and helps in getting rid of bacteria that cause inflammatory responses. Ultimately, IgA maintains a healthy environment between the host and gut bacteria. These cytokines and antibodies can have effects outside the gut, in the lungs and other tissues.

A 2022 review indicated that various mechanisms are under preliminary research to assess how gut microbes may modulate vaccine immunogenicity, including effects on antigen presentation and cytokine profiles.

Metabolism

Tryptophan metabolism by human gut microbiota Tryptophan Clostridium sporogenes Lacto- bacilli Tryptophanase- expressing bacteria IPA I3A Indole Liver Brain IPA I3A Indole Indoxyl sulfate AST-120 AhR Intestinal immune cells Intestinal epithelium PXR Mucosal homeostasis: ↓TNF-α ↑Junction protein- coding mRNAs L cell GLP-1 T J 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 Associated with vascular disease: ↑Oxidative stress ↑Smooth muscle cell proliferation ↑Aortic wall thickness and calcification Associated with chronic kidney disease: ↑Renal dysfunction –Uremic toxin Kidneys This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut. Indole is produced from tryptophan by bacteria that express tryptophanase. Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA), a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals. IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function. Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease. Lactobacillaceae (Lactobacillus s.l.) 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. Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR. 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. 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.

Without gut flora, the human body would be unable to utilize some of the undigested carbohydrates it consumes, because some types of gut flora have enzymes that human cells lack for breaking down certain polysaccharides. Rodents raised in a sterile environment and lacking in gut flora need to eat 30% more calories just to remain the same weight as their normal counterparts. Carbohydrates that humans cannot digest without bacterial help include certain starches, fiber, oligosaccharides, and sugars that the body failed to digest and absorb like lactose in the case of lactose intolerance and sugar alcohols, mucus produced by the gut, and proteins.

Bacteria turn carbohydrates they ferment into short-chain fatty acids by a form of fermentation called saccharolytic fermentation. Products include acetic acid, propionic acid and butyric acid. These materials can be used by host cells, providing a major source of energy and nutrients. Gases (which are involved in signaling and may cause flatulence) and organic acids, such as lactic acid, are also produced by fermentation. Acetic acid is used by muscle, propionic acid facilitates liver production of ATP, and butyric acid provides energy to gut cells.

Gut flora also synthesize vitamins like biotin and folate, and facilitate absorption of dietary minerals, including magnesium, calcium, and iron. Methanobrevibacter smithii is unique because it is not a species of bacteria, but rather a member of domain Archaea, and is the most abundant methane-producing archaeal species in the human gastrointestinal microbiota.

Gut microbiota also serve as a source of vitamins K and B₁₂, which are not produced by the body or produced in little amount.

Cellulose degradation

Bacteria that degrade cellulose (such as Ruminococcus) are prevalent among great apes, ancient human societies, hunter-gatherer communities, and even modern rural populations. However, they are rare in industrialized societies. Human-associated strains have acquired genes that can degrade specific plant fibers such as maize, rice, and wheat. Bacterial strains found in primates can also degrade chitin, a polymer abundant in insects, which are part of the diet of many nonhuman primates. The decline of these bacteria in the human gut were likely influenced by the shift toward western lifestyles.

Pharmacomicrobiomics

The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals. Since the total number of microbial cells in the human body (over 100 trillion) greatly outnumbers Homo sapiens cells (tens of trillions),^{[note 1][76][78]} there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile.

Apart from carbohydrates, gut microbiota can also metabolize other xenobiotics such as drugs, phytochemicals, and food toxicants. More than 30 drugs have been shown to be metabolized by gut microbiota. The microbial metabolism of drugs can sometimes inactivate the drug.

Contribution to drug metabolism

The gut microbiota is an enriched community that contains diverse genes with huge biochemical capabilities to modify drugs, especially those taken by mouth. Gut microbiota can affect drug metabolism via direct and indirect mechanisms. The direct mechanism is mediated by the microbial enzymes that can modify the chemical structure of the administered drugs. Conversely, the indirect pathway is mediated by the microbial metabolites which affect the expression of host metabolizing enzymes such as cytochrome P450. The effects of the gut microbiota on the pharmacokinetics and bioavailability of the drug have been investigated a few decades ago. These effects can be varied; it could activate the inactive drugs such as lovastatin, inactivate the active drug such as digoxin or induce drug toxicity as in irinotecan. Since then, the impacts of the gut microbiota on the pharmacokinetics of many drugs were heavily studied.

The human gut microbiota plays a crucial role in modulating the effect of the administered drugs on the human. Directly, gut microbiota can synthesize and release a series of enzymes with the capability to metabolize drugs such as microbial biotransformation of L-dopa by decarboxylase and dehydroxylase enzymes. On the contrary, gut microbiota may also alter the metabolism of the drugs by modulating the host drug metabolism. This mechanism can be mediated by microbial metabolites or by modifying host metabolites which in turn change the expression of host metabolizing enzymes.

A large number of studies have demonstrated the metabolism of over 50 drugs by the gut microbiota. For example, lovastatin (a cholesterol-lowering agent) which is a lactone prodrug is partially activated by the human gut microbiota forming active acid hydroxylated metabolites. Conversely, digoxin (a drug used to treat Congestive Heart Failure) is inactivated by a member of the gut microbiota (i.e. Eggerthella lanta). Eggerthella lanta has a cytochrome-encoding operon up-regulated by digoxin and associated with digoxin-inactivation. Gut microbiota can also modulate the efficacy and toxicity of chemotherapeutic agents such as irinotecan. This effect is derived from the microbiome-encoded β-glucuronidase enzymes which recover the active form of the irinotecan causing gastrointestinal toxicity.

Secondary metabolites

This microbial community in the gut has a huge biochemical capability to produce distinct secondary metabolites that are sometimes produced from the metabolic conversion of dietary foods such as fibers, endogenous biological compounds such as indole or bile acids. Microbial metabolites especially short chain fatty acids (SCFAs) and secondary bile acids (BAs) play important roles for the human in health and disease states.

One of the most important bacterial metabolites produced by the gut microbiota is secondary bile acids (BAs). These metabolites are produced by the bacterial biotransformation of the primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) into secondary bile acids (BAs) lithocholic acid (LCA) and deoxy cholic acid (DCA) respectively. Primary bile acids which are synthesized by hepatocytes and stored in the gall bladder possess hydrophobic characters. These metabolites are subsequently metabolized by the gut microbiota into secondary metabolites with increased hydrophobicity. Bile salt hydrolases (BSH) which are conserved across gut microbiota phyla such as Bacteroides, Firmicutes, and Actinobacteria responsible for the first step of secondary bile acids metabolism. Secondary bile acids (BAs) such as DCA and LCA have been demonstrated to inhibit both Clostridioides difficile germination and outgrowth.

Dysbiosis

The gut microbiota is important for maintaining homeostasis in the intestine. Development of intestinal cancer is associated with an imbalance in the natural microflora (dysbiosis). The secondary bile acid deoxycholic acid is associated with alterations of the microbial community that lead to increased intestinal carcinogenesis. Increased exposure of the colon to secondary bile acids resulting from dysbiosis can cause DNA damage, and such damage can produce carcinogenic mutations in cells of the colon. The high density of bacteria in the colon (about 10¹² per ml.) that are subject to dysbiosis compared to the relatively low density in the small intestine (about 10² per ml.) may account for the greater than 10-fold higher incidence of cancer in the colon compared to the small intestine.

Gut–brain axis

Main article: Gut–brain axis

The gut microbiota contributes to digestion and immune modulation, as it plays a role in the gut-brain axis, where microbial metabolites such as short-chain fatty acids and neurotransmitters influence brain function and behavior. The gut–brain axis is the biochemical signaling that takes place between the gastrointestinal tract and the central nervous system. That term has been expanded to include the role of the gut flora in the interplay; the term "microbiome––brain axis" is sometimes used to describe paradigms explicitly including the gut flora. Broadly defined, the gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems including the hypothalamic–pituitary–adrenal axis (HPA axis), sympathetic and parasympathetic arms of the autonomic nervous system including the enteric nervous system, the vagus nerve, and the gut microbiota.

A 2016 systematic review of preclinical studies and small human trials conducted with certain commercially available strains of probiotic bacteria found that Bifidobacterium and Lactobacillus genera (B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei), were of interest for certain central nervous system disorders.

Alterations in microbiota balance

Effects of antibiotic use

Altering the numbers of gut bacteria, for example by taking broad-spectrum antibiotics, may affect the host's health and ability to digest food. Antibiotics can cause antibiotic-associated diarrhea by irritating the bowel directly, changing the levels of microbiota, or allowing pathogenic bacteria to grow. Another harmful effect of antibiotics is the increase in numbers of antibiotic-resistant bacteria found after their use, which, when they invade the host, cause illnesses that are difficult to treat with antibiotics.

Changing the numbers and species of gut microbiota can reduce the body's ability to ferment carbohydrates and metabolize bile acids and may cause diarrhea. Carbohydrates that are not broken down may absorb too much water and cause runny stools, or lack of SCFAs produced by gut microbiota could cause diarrhea.

A reduction in levels of native bacterial species also disrupts their ability to inhibit the growth of harmful species such as C. difficile and Salmonella Kedougou, and these species can get out of hand, though their overgrowth may be incidental and not be the true cause of diarrhea. Emerging treatment protocols for C. difficile infections involve fecal microbiota transplantation of donor feces (see Fecal transplant). Initial reports of treatment describe success rates of 90%, with few side effects. Efficacy is speculated to result from restoring bacterial balances of bacteroides and firmicutes classes of bacteria.

The composition of the gut microbiome also changes in severe illnesses, due not only to antibiotic use but also to such factors as ischemia of the gut, failure to eat, and immune compromise. Negative effects from this have led to interest in selective digestive tract decontamination, a treatment to kill only pathogenic bacteria and allow the re-establishment of healthy ones.

Antibiotics alter the population of the microbiota in the gastrointestinal tract, and this may change the intra-community metabolic interactions, modify caloric intake by using carbohydrates, and globally affect host metabolic, hormonal, and immune homeostasis.

There is reasonable evidence that taking probiotics containing Lactobacillus species may help prevent antibiotic-associated diarrhea and that taking probiotics with Saccharomyces (e.g., Saccharomyces boulardii ) may help to prevent Clostridioides difficile infection following systemic antibiotic treatment.^[112]

Pregnancy

The gut microbiota of a woman changes as pregnancy advances, with the changes similar to those seen in metabolic syndromes such as diabetes. The change in gut microbiota causes no ill effects. The newborn's gut microbiota resemble the mother's first-trimester samples. The diversity of the microbiome decreases from the first to third trimester, as the numbers of certain species go up.

Probiotics, prebiotics, synbiotics, and pharmabiotics

Probiotics contain live microorganisms. When consumed, they are believed to provide health benefits by altering the microbiome composition. Current research explores using probiotics as a way to restore the microbial balance of the intestine by stimulating the immune system and inhibiting pro-inflammatory cytokines.

With regard to gut microbiota, prebiotics are typically non-digestible, fiber compounds that pass undigested through the upper part of the gastrointestinal tract and stimulate the growth or activity of advantageous gut flora by acting as substrate for them.

Synbiotics refers to food ingredients or dietary supplements combining probiotics and prebiotics in a form of synergism.

The term "pharmabiotics" is used in various ways, to mean: pharmaceutical formulations (standardized manufacturing that can obtain regulatory approval as a drug) of probiotics, prebiotics, or synbiotics; probiotics that have been genetically engineered or otherwise optimized for best performance (shelf life, survival in the digestive tract, etc.); and the natural products of gut flora metabolism (vitamins, etc.).

There is some evidence that treatment with some probiotic strains of bacteria may be effective in treatment of irritable bowel syndrome, inflammatory bowel disease, and abdominal bloating. Those organisms most likely to result in a decrease of symptoms have included:

• Bifidobacterium breve
• Bifidobacterium infantis
• Enterococcus faecium
• Lactobacillus plantarum
• Lactobacillus reuteri
• Lactobacillus rhamnosus
• Lactobacillus salivarius
• Propionibacterium freudenreichii
• Saccharomyces boulardii
• Escherichia coli Nissle 1917
• Streptococcus thermophilus

Research

Tests for whether non-antibiotic drugs may impact human gut-associated bacteria were performed by in vitro analysis on more than 1000 marketed drugs against 40 gut bacterial strains, demonstrating that 24% of the drugs inhibited the growth of at least one of the bacterial strains.

Role in disease

Bacteria in the digestive tract can contribute to and be affected by disease in various ways. The presence or overabundance of some kinds of bacteria may contribute to inflammatory disorders such as inflammatory bowel disease. Additionally, metabolites from certain members of the gut flora may influence host signalling pathways, contributing to disorders such as obesity and colon cancer. Some gut bacteria may also cause infections and sepsis, for example when they are allowed to pass from the gut into the rest of the body.

Ulcers

Helicobacter pylori infection can initiate formation of stomach ulcers when the bacteria penetrate the stomach epithelial lining, then causing an inflammatory phagocytotic response. In turn, the inflammation damages parietal cells which release excessive hydrochloric acid into the stomach and produce less of the protective mucus. Injury to the stomach lining, leading to ulcers, develops when gastric acid overwhelms the defensive properties of cells and inhibits endogenous prostaglandin synthesis, reduces mucus and bicarbonate secretion, reduces mucosal blood flow, and lowers resistance to injury. Reduced protective properties of the stomach lining increase vulnerability to further injury and ulcer formation by stomach acid, pepsin, and bile salts.

Bowel perforation

Normally-commensal bacteria can harm the host if they extrude from the intestinal tract. Translocation, which occurs when bacteria leave the gut through its mucosal lining, can occur in a number of different diseases. If the gut is perforated, bacteria invade the interstitium, causing a potentially fatal infection.

Inflammatory bowel diseases

The two main types of inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gut; the causes of these diseases are unknown and issues with the gut flora and its relationship with the host have been implicated in these conditions.Additionally, it appears that interactions of gut flora with the gut–brain axis have a role in IBD, with physiological stress mediated through the hypothalamic–pituitary–adrenal axis driving changes to intestinal epithelium and the gut flora in turn releasing factors and metabolites that trigger signaling in the enteric nervous system and the vagus nerve.

The diversity of gut flora appears to be significantly diminished in people with inflammatory bowel diseases compared to healthy people; additionally, in people with ulcerative colitis, Proteobacteria and Actinobacteria appear to dominate; in people with Crohn's, Enterococcus faecium and several Proteobacteria appear to be over-represented.

There is reasonable evidence that correcting gut flora imbalances by taking probiotics with Lactobacilli and Bifidobacteria can reduce visceral pain and gut inflammation in IBD.

Irritable bowel syndrome

Irritable bowel syndrome is a result of stress and chronic activation of the HPA axis; its symptoms include abdominal pain, changes in bowel movements, and an increase in proinflammatory cytokines. Overall, studies have found that the luminal and mucosal microbiota are changed in irritable bowel syndrome individuals, and these changes can relate to the type of irritation such as diarrhea or constipation. Also, there is a decrease in the diversity of the microbiome with low levels of fecal Lactobacilli and Bifidobacteria, high levels of facultative anaerobic bacteria such as Escherichia coli, and increased ratios of Firmicutes: Bacteroidetes.

Asthma

With asthma, two hypotheses have been posed to explain its rising prevalence in the developed world. The hygiene hypothesis posits that children in the developed world are not exposed to enough microbes and thus may contain lower prevalence of specific bacterial taxa that play protective roles. The second hypothesis focuses on the Western pattern diet, which lacks whole grains and fiber and has an overabundance of simple sugars. Both hypotheses converge on the role of short-chain fatty acids (SCFAs) in immunomodulation. These bacterial fermentation metabolites are involved in immune signalling that prevents the triggering of asthma and lower SCFA levels are associated with the disease. Lacking protective genera such as Lachnospira, Veillonella, Rothia and Faecalibacterium has been linked to reduced SCFA levels. Further, SCFAs are the product of bacterial fermentation of fiber, which is low in the Western pattern diet. SCFAs offer a link between gut flora and immune disorders, and as of 2016, this was an active area of research. Similar hypotheses have also been posited for the rise of food and other allergies.

Diabetes mellitus type 1

The connection between the gut microbiota and diabetes mellitus type 1 has also been linked to SCFAs, such as butyrate and acetate. Diets yielding butyrate and acetate from bacterial fermentation show increased T_reg expression. T_reg cells downregulate effector T cells, which in turn reduces the inflammatory response in the gut. Butyrate is an energy source for colon cells. butyrate-yielding diets thus decrease gut permeability by providing sufficient energy for the formation of tight junctions. Additionally, butyrate has also been shown to decrease insulin resistance, suggesting gut communities low in butyrate-producing microbes may increase chances of acquiring diabetes mellitus type 2. Butyrate-yielding diets may also have potential colorectal cancer suppression effects.

Type 2 diabetes

The gut microbiota are very important for the host health because they play role in degradation of non-digestible polysaccharides (fermentation of resistant starch, oligosaccharides, inulin) strengthening gut integrity or shaping the intestinal epithelium, harvesting energy, protecting against pathogens, and regulating host immunity.

Several studies showed that the gut bacterial composition in diabetic patients became altered with increased levels of Lactobacillus gasseri, Streptococcus mutans and Clostridiales members, with decrease in butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii. This alteration is due to many factors such as antibiotic abuse, diet, and age.

The decrease in butyrate production is associated with defects in intestinal permeability, which could lead to endotoxemia, which is the increased level of circulating Lipopolysaccharides from gram negative bacterial cells wall. It is found that endotoxemia has association with development of insulin resistance.

In addition that butyrate production affects serotonin level. Elevated serotonin level has contribution in obesity, which is known to be a risk factor for development of diabetes.

Cancer

The human gut microbial composition is modulated by dietary bile acids. There appears to be a metabolic link between cancer associated gut microbes and a fat- and meat rich diet. In rodents, elevated levels of bile acids produced by the gut microbiota in response to a high fat diet are associated with an increased the risk of colorectal cancer. The secondary bile acid deoxycholic acid, produced from the primary bile acid cholic acid by the gut microbiota, is elevated in the colonic contents of humans in response to a high fat diet. In populations that have a high incidence of colorectal cancer fecal concentrations of bile acids, particularly deoxycholic acid produced by the action of gut microbiota, are higher.

Development and antibiotics

The colonization of the human gut microbiota may start already before birth. There are multiple factors in the environment that affects the development of the microbiota with birthmode being one of the most impactful.

Another factor that has been observed to cause huge changes in the gut microbiota, particularly in children, is the use of antibiotics, associating with health issues such as higher BMI, and further an increased risk towards metabolic diseases such as obesity. In infants it was observed that amoxicillin and macrolides cause significant shifts in the gut microbiota characterized by a change in the bacterial classes Bifidobacteria, Enterobacteria and Clostridia. A single course of antibiotics in adults causes changes in both the bacterial and fungal microbiota, with even more persistent changes in the fungal communities. The bacteria and fungi live together in the gut and there is most likely a competition for nutrient sources present. Seelbinder et al. found that commensal bacteria in the gut regulate the growth and pathogenicity of Candida albicans by their metabolites, particularly by propionate, acetic acid and 5-dodecenoate. Candida has previously been associated with IBD and further it has been observed to be increased in non-responders to a biological drug, infliximab, given to IBD patients with severe IBD. Propionate and acetic acid are both short-chain fatty acids (SCFAs) that have been observed to be beneficial to gut microbiota health. When antibiotics affect the growth of bacteria in the gut, there might be an overgrowth of certain fungi, which might be pathogenic when not regulated.

Blood–brain barrier dysfunction

The gut microbiome regulates the function of the blood–brain barrier (BBB) throughout life, at least partially due to microbial metabolites. The BBB is a selectively permeable membrane that tightly regulates the transfer of substances between the circulation and the brain parenchyma. During development, germ-free mice exhibit increased BBB permeability from embryonic stages through adulthood with reduced tight junction proteins, while colonization with mature microbiota restores barrier function through SCFAs like butyrate. This developmental impact persists, as mice with gut microbiota associated with preterm birth show early-life BBB hyperpermeability and cognitive deficits, whereas those with microbiota associated with full-term birth maintain an intact BBB. During aging, altered microbiota composition with increased Firmicutes/Bacteroidetes ratio correlates with compromised BBB function, reduced P-glycoprotein activity, and cognitive impairment. These effects may be mediated by microbial metabolites including SCFAs that enhance barrier integrity and methylamines, where trimethylamine N-oxide protects BBB function while its precursor trimethylamine disrupts it.

Obesity and metabolic syndrome

The gut flora have been implicated in obesity and metabolic syndrome due to a key role in the digestive process; the Western pattern diet appears to drive and maintain changes in the gut flora that in turn change how much energy is derived from food and how that energy is used. One aspect of a healthy diet that is often lacking in the Western-pattern diet is fiber and other complex carbohydrates that a healthy gut flora require flourishing; changes to gut flora in response to a Western-pattern diet appear to increase the amount of energy generated by the gut flora which may contribute to obesity and metabolic syndrome. There is also evidence that microbiota influence eating behaviours based on the preferences of the microbiota, which can lead to the host consuming more food eventually resulting in obesity. It has generally been observed that with higher gut microbiome diversity, the microbiota will spend energy and resources on competing with other microbiota and less on manipulating the host. The opposite is seen with lower gut microbiome diversity, and these microbiotas may work together to create host food cravings.

Additionally, the liver plays a dominant role in blood glucose homeostasis by maintaining a balance between the uptake and storage of glucose through the metabolic pathways of glycogenesis and gluconeogenesis. Intestinal lipids regulate glucose homeostasis involving a gut–brain–liver axis. The direct administration of lipids into the upper intestine increases the long chain fatty acyl-coenzyme A (LCFA-CoA) levels in the upper intestines and suppresses glucose production even under subdiaphragmatic vagotomy or gut vagal deafferentation. This interrupts the neural connection between the brain and the gut and blocks the upper intestinal lipids' ability to inhibit glucose production. The gut–brain–liver axis and gut microbiota composition can regulate the glucose homeostasis in the liver and provide potential therapeutic methods to treat obesity and diabetes.

Just as gut flora can function in a feedback loop that can drive the development of obesity, there is evidence that restricting intake of calories (i.e., dieting) can drive changes to the composition of the gut flora.

Other animals

The composition of the human gut microbiome is similar to that of the other great apes. However, humans' gut biota has decreased in diversity and changed in composition since our evolutionary split from Pan. Humans display increases in Bacteroidetes, a bacterial phylum associated with diets high in animal protein and fat, and decreases in Methanobrevibacter and Fibrobacter, groups that ferment complex plant polysaccharides. These changes are the result of the combined dietary, genetic, and cultural changes humans have undergone since evolutionary divergence from Pan (chimpanzees and bonobos).

In addition to humans and vertebrates, some insects also have complex and diverse gut microbiota that play key nutritional roles. Microbial communities associated with termites can constitute a majority of the weight of the individuals and perform important roles in the digestion of lignocellulose and nitrogen fixation. It is known that the disruption of gut microbiota of termites using agents like antibiotics or boric acid (a common agent used in preventative treatment) causes severe damage to digestive function and leads to the rise of opportunistic pathogens. These communities are host-specific, and closely related insect species share comparable similarities in gut microbiota composition. In cockroaches, gut microbiota have been shown to assemble in a deterministic fashion, irrespective of the inoculum; the reason for this host-specific assembly remains unclear. Bacterial communities associated with insects like termites and cockroaches are determined by a combination of forces, primarily diet, but there is some indication that host phylogeny may also be playing a role in the selection of lineages.

For more than 51 years it has been known that the administration of low doses of antibacterial agents promotes the growth of farm animals to increase weight gain.

In a study carried out on mice the ratio of Firmicutes and Lachnospiraceae was significantly elevated in animals treated with subtherapeutic doses of different antibiotics. By analyzing the caloric content of faeces and the concentration of small chain fatty acids (SCFAs) in the GI tract, it was concluded that the changes in the composition of microbiota lead to an increased capacity to extract calories from otherwise indigestible constituents, and to an increased production of SCFAs. These findings provide evidence that antibiotics perturb not only the composition of the GI microbiome but also its metabolic capabilities, specifically with respect to SCFAs.