New claims are frequently made for a role for the microbiome in a disease or disorder previously considered remote from the gut. The microbiome has been linked to such seemingly unrelated entities as depression, anorexia nervosa, autism, Parkinson disease, allergy, and asthma. Although many of these proposals have been based on animal studies, explorations of the microbiome in human disease continue to proliferate, facilitated by technologies that provide a detailed assessment of the microbial inhabitants of our gastrointestinal tract and their biological activities and metabolic products. With these technologies come new terminologies, which are identified in this article.
Key points
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New claims are frequently made for a role for the microbiome in a disease or disorder previously considered remote from the gut, not to mention its bacterial population.
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The microbiome has been linked to such seemingly unrelated entities as depression, anorexia nervosa, autism, Parkinson disease, allergy, and asthma.
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Although many of these proposals have been based on animal studies, explorations of the microbiome in human disease continue to proliferate, facilitated by the availability of a variety of technologies that rapidly and with ever-increasing economy provide a detailed assessment of the microbial inhabitants of our gastrointestinal tract, their biological activities, and metabolic products.
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With these technologies come new terminology, such as microbiota, microbiome, metagenomics, and metabonomics, which are identified in this article.
To the busy clinician the tsunami of information that hits his or her desk or computer on a daily basis relating to the science and clinical implications of the microbiome has become simply overwhelming. Not a day goes by without a new claim for a role for the microbiome in a disease or disorder previously considered remote from the gut, not to mention its bacterial population. Thus, the microbiome has been liked to such seemingly unrelated entities as depression, anorexia nervosa, autism, Parkinson disease, allergy, and asthma. Although many of these proposals have been based on animal studies, explorations of the microbiome in human disease continue to proliferate, facilitated by the availability of a variety of technologies that rapidly and with ever-increasing economy provide a detailed assessment of the microbial inhabitants of our gastrointestinal tract and their biological activities and metabolic products. With these technologies comes a new terminology:
Microbiota is the assemblage of microorganisms (bacteria, archaea, or lower eukaryotes) present in a defined environment, such as the gastrointestinal tract.
Microbiome is the full complement of microbes (bacteria, viruses, fungi, and protozoa) and their genes and genomes (though strictly speaking different, the terms microbiome and microbiota are often used interchangeably).
Metagenomics is the study of the gene content and encoded functional attributes of the gut microbiome in healthy humans.
Metabonomics is the quantitative measurement of the multiparametric (time related) metabolic responses of complex systems to a pathophysiologic stimulus or genetic modification, often used synonymously with metabolomics .
The term flora , which dates from the time when bacteria were included in the plant kingdom, has now been largely abandoned and replaced by microbiota . Although the focus of the review is on the possible role of the microbiota in gastrointestinal diseases and disorders, one must first briefly review what is known of the microbiota in health.
The microbiome in health: development, influences, and functions
Much of what we know of the composition and functions of the normal gut microbiota comes from large national or multinational consortia. Although the microbiome of each individual is quite distinct at the level of individual bacterial strains, data from a European consortium indicated that, at a higher level of organization, some general patterns can be identified across populations. They identified 3 broad groupings (enterotypes) driven by the predominance of certain species: Prevotella , Bacteroides, and Ruminococcus . Enterotype prevalence seemed independent of age, body mass index, or geographic location but might have been driven by differing dietary habits.
Although the delineation of the full range of normal variations in the composition of the gut microbiota within and between individuals continues to be defined, certain trends have emerged. Traditionally, it was thought that the intestinal tract is sterile at birth; new evidence indicates that the colonization of the infant’s gut may commence in utero from the placenta. However, the balance of evidence indicates that most of the infant’s microbiome is acquired from the mother during birth and continues to be populated through feeding and other contacts. Several factors influence the microbiome over these critical early months and years of life : mode of delivery (vaginal birth vs cesarean delivery), diet (breast milk vs formula), geography, and exposure to antibiotics. By 2 to 3 years of age, the child’s microbiota has come to closely resemble that of an adult in terms of composition ; some further evolution through to adolescence has, however, recently been reported. Thereafter, the microbiota is thought to remain relatively stable until old age when changes are seen, possibly related to alterations in digestive physiology and diet ; further longitudinal studies are required to more precisely define age-related changes in adults.
Several factors influence the composition of the microbiota in health and must be accounted for in the interpretation of findings in disease. Foremost among these is diet. General characteristics of the diet (total calories, highly processed vs vegetable and fruit based) as well as the relative concentrations of specific components, such as carbohydrate, protein, fat, fiber, and vitamins, have all been shown to influence the composition of the microbiota. It has been assumed that diet-related changes reflect the long-term effects of a particular dietary pattern over a lifetime ; it is now evident that relatively acute, albeit drastic, changes in dietary habit may also result in shifts in microbial populations. All of these observations are highly relevant to the study of gastrointestinal diseases given the restrictions that gut ill health per se may impose on eating patterns and of the propensity for individuals afflicted by gastrointestinal symptoms to alter their diet, sometimes drastically, in an attempt to alleviate these same symptoms.
Other factors that may independently influence the structure of the microbiome (in the short- and long-term) include antibiotic use, acid suppression, and cultural and geographic factors. It is now apparent that other prescription drugs, such as metformin, may also influence microbiota architecture. It has been postulated (and supported by some evidence) that antibiotic and other exposures during the early years of life, when the microbiome is in evolution, may be especially deleterious and could result in metabolic and inflammatory disorders later in life. Two recent population-based studies from the Netherlands and Belgium have emphasized the influence of diet, medications, smoking habit, and disease state on the composition of the gut microbiome in adults. The last observation is especially noteworthy; studies of the microbiome in disease states have assumed, for the most part, that the relationship is unidirectional, that is, that an altered microbiome causes the disease. This approach fails to consider the alternative possibility: that the disease alters the microbiome, as exemplified by the impact of inflammatory processes on the microbiome.
A detailed exploration of the many proven and postulated functions of the gut microbiome is beyond the scope of this review; the reader is referred to several excellent reviews for a detailed discussion. Suffice it to say that a vast amount of laboratory and clinical research has already provided abundant justification for the gut microbiota to be considered “the forgotten organ.” Experiments in germ-free animals have convinced us that an intact microbiome is essential for the development and function of many, if not all, of the components of an intact gastrointestinal tract: the mucosa- or, gut-associated immune system (mucosa-associated lymphoid tissue or gut-associated lymphoid tissue), immunologic tolerance, epithelial and barrier function, motility, and vascularity. The resident commensal microbiota continues to contribute to such homeostatic functions during life as pathogen exclusion, immunomodulation, upregulation of cytoprotective genes, prevention and regulation of apoptosis, and maintenance of barrier function.
The sophistication of the relationship between the microbiota and its host is elegantly illustrated by the manner in which the immune system of the gut differentiates between friend and foe when it encounters bacteria. Various phenomena operative at the level of the intestinal epithelium lead to the recognition (tolerance) of commensals as friend and differentiate them from pathogens (foe): the masking or modification of microbial-associated molecular patterns that are usually recognized by pattern recognition receptors, such as Toll-like receptors, the preferential induction of regulatory T cells resulting in the production of the antiinflammatory cytokine, interleukin 10, and the associated inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells inflammatory pathway.
The metabolic functions of the microbiome continue to be revealed and are now seen to extend well beyond its long-recognized ability to salvage unabsorbed dietary sugars and convert them into short-chain fatty acids; synthesize nutrients and vitamins, such as folate and vitamin K; deconjugate bile salts ; and metabolize dietary xenobiotics as well as an expanding list of commonly used drugs. Thus, metabolic products of the microbiome, including neurotransmitters and neuromodulators, impact not just on the enteric neuromodulatory apparatus but also seem capable of influencing the development and function of the central nervous system, thereby, leading to the concept of the microbiota-gut-brain axis.
The microbiome in health: development, influences, and functions
Much of what we know of the composition and functions of the normal gut microbiota comes from large national or multinational consortia. Although the microbiome of each individual is quite distinct at the level of individual bacterial strains, data from a European consortium indicated that, at a higher level of organization, some general patterns can be identified across populations. They identified 3 broad groupings (enterotypes) driven by the predominance of certain species: Prevotella , Bacteroides, and Ruminococcus . Enterotype prevalence seemed independent of age, body mass index, or geographic location but might have been driven by differing dietary habits.
Although the delineation of the full range of normal variations in the composition of the gut microbiota within and between individuals continues to be defined, certain trends have emerged. Traditionally, it was thought that the intestinal tract is sterile at birth; new evidence indicates that the colonization of the infant’s gut may commence in utero from the placenta. However, the balance of evidence indicates that most of the infant’s microbiome is acquired from the mother during birth and continues to be populated through feeding and other contacts. Several factors influence the microbiome over these critical early months and years of life : mode of delivery (vaginal birth vs cesarean delivery), diet (breast milk vs formula), geography, and exposure to antibiotics. By 2 to 3 years of age, the child’s microbiota has come to closely resemble that of an adult in terms of composition ; some further evolution through to adolescence has, however, recently been reported. Thereafter, the microbiota is thought to remain relatively stable until old age when changes are seen, possibly related to alterations in digestive physiology and diet ; further longitudinal studies are required to more precisely define age-related changes in adults.
Several factors influence the composition of the microbiota in health and must be accounted for in the interpretation of findings in disease. Foremost among these is diet. General characteristics of the diet (total calories, highly processed vs vegetable and fruit based) as well as the relative concentrations of specific components, such as carbohydrate, protein, fat, fiber, and vitamins, have all been shown to influence the composition of the microbiota. It has been assumed that diet-related changes reflect the long-term effects of a particular dietary pattern over a lifetime ; it is now evident that relatively acute, albeit drastic, changes in dietary habit may also result in shifts in microbial populations. All of these observations are highly relevant to the study of gastrointestinal diseases given the restrictions that gut ill health per se may impose on eating patterns and of the propensity for individuals afflicted by gastrointestinal symptoms to alter their diet, sometimes drastically, in an attempt to alleviate these same symptoms.
Other factors that may independently influence the structure of the microbiome (in the short- and long-term) include antibiotic use, acid suppression, and cultural and geographic factors. It is now apparent that other prescription drugs, such as metformin, may also influence microbiota architecture. It has been postulated (and supported by some evidence) that antibiotic and other exposures during the early years of life, when the microbiome is in evolution, may be especially deleterious and could result in metabolic and inflammatory disorders later in life. Two recent population-based studies from the Netherlands and Belgium have emphasized the influence of diet, medications, smoking habit, and disease state on the composition of the gut microbiome in adults. The last observation is especially noteworthy; studies of the microbiome in disease states have assumed, for the most part, that the relationship is unidirectional, that is, that an altered microbiome causes the disease. This approach fails to consider the alternative possibility: that the disease alters the microbiome, as exemplified by the impact of inflammatory processes on the microbiome.
A detailed exploration of the many proven and postulated functions of the gut microbiome is beyond the scope of this review; the reader is referred to several excellent reviews for a detailed discussion. Suffice it to say that a vast amount of laboratory and clinical research has already provided abundant justification for the gut microbiota to be considered “the forgotten organ.” Experiments in germ-free animals have convinced us that an intact microbiome is essential for the development and function of many, if not all, of the components of an intact gastrointestinal tract: the mucosa- or, gut-associated immune system (mucosa-associated lymphoid tissue or gut-associated lymphoid tissue), immunologic tolerance, epithelial and barrier function, motility, and vascularity. The resident commensal microbiota continues to contribute to such homeostatic functions during life as pathogen exclusion, immunomodulation, upregulation of cytoprotective genes, prevention and regulation of apoptosis, and maintenance of barrier function.
The sophistication of the relationship between the microbiota and its host is elegantly illustrated by the manner in which the immune system of the gut differentiates between friend and foe when it encounters bacteria. Various phenomena operative at the level of the intestinal epithelium lead to the recognition (tolerance) of commensals as friend and differentiate them from pathogens (foe): the masking or modification of microbial-associated molecular patterns that are usually recognized by pattern recognition receptors, such as Toll-like receptors, the preferential induction of regulatory T cells resulting in the production of the antiinflammatory cytokine, interleukin 10, and the associated inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells inflammatory pathway.
The metabolic functions of the microbiome continue to be revealed and are now seen to extend well beyond its long-recognized ability to salvage unabsorbed dietary sugars and convert them into short-chain fatty acids; synthesize nutrients and vitamins, such as folate and vitamin K; deconjugate bile salts ; and metabolize dietary xenobiotics as well as an expanding list of commonly used drugs. Thus, metabolic products of the microbiome, including neurotransmitters and neuromodulators, impact not just on the enteric neuromodulatory apparatus but also seem capable of influencing the development and function of the central nervous system, thereby, leading to the concept of the microbiota-gut-brain axis.