A new era in medical science has dawned with the realization of the critical role of the “forgotten organ,” the gut micro-biota, in health and disease. Central to this beneficial interaction between the microbiota and host is the manner in which bacteria and most likely other microorganisms contained within the gut communicate with the host’s immune system and participate in a variety of metabolic processes of mutual benefit to the host and the microbe.
The advent of high-throughput methodologies and the elaboration of sophisticated analytic systems have facilitated the detailed description of the composition of the microbial constituents of the human gut, as never before, and are now enabling comparisons to be made between health and various disease states. Although the latter approach is still in its infancy, some important insights have already been gained about how the microbiota might influence a number of disease processes both within and distant from the gut. These discoveries also lay the groundwork for the development of therapeutic strategies that might modify the microbiota (eg, through the use of probiot-ics). Although this area holds much promise, more high-quality trials of probiotics, prebiotics, and other microbiota-modifying approaches in digestive disorders are needed, as well as laboratory investigations of their mechanisms of action.
The Normal Gut Microbiota: An Essential Factor in Health
Basic Definitions and Development of the Microbiota
The term microbiota is to be preferred to the older term flora, as the latter fails to account for the many nonbacte-rial elements (eg, archea, viruses, and fungi) that are now known to be normal inhabitants of the gut. Given the relatively greater understanding that currently exists of the role of bacteria, in comparison with the other constituents of the microbiota in health and disease, gut bacteria will be the primary focus of this review. Within the human gastrointestinal microbiota exists a complex ecosystem of approximately 300 to 500 bacterial species, comprising nearly 2 million genes (the microbiome).1 Indeed, the number of bacteria within the gut is approximately 10 times that of all of the cells in the human body, and the collective bacterial genome is vastly greater than the human genome.
At birth, the entire intestinal tract is sterile; the infant’s gut is first colonized by maternal and environmental bacteria during birth and continues to be populated through feeding and other contacts.2Factors known to influence colonization include gestational age, mode of delivery (vaginal birth vs assisted delivery), diet (breast milk vs formula), level of sanitation, and exposure to antibiotics. The intestinal microbiota of newborns is characterized by low diversity and a relative dominance of the phyla Proteobacteria and Actinobacteria; thereafter, the microbiota becomes more diverse with the emergence of the dominance of Firmicutes and Bacteroidetes, which characterizes the adult microbiota.By the end of the first year of life, the microbial profile is distinct for each infant; by the age of 2.5 years, the microbiota fully resembles the microbiota of an adult in terms of composition. This period of maturation of the microbiota may be critical; there is accumulating evidence from a number of sources that disruption of the microbiota in early infancy may be a critical determinant of disease expression in later life. It follows that interventions directed at the microbiota later in life may, quite literally, be too late and potentially doomed to failure.
Following infancy, the composition of the intestinal microflora remains relatively constant until later life. Although it has been claimed that the composition of each individual’s flora is so distinctive that it could be used as an alternative to fingerprinting, more recently, 3 differ-ent enterotypes have been described in the adult human microbiome. These distinct enterotypes are dominated by Prevotella, Ruminococcus, and Bacteroides, respectively, and their appearance seems to be independent of sex, age, nationality, and body mass index. The microbiota is thought to remain stable until old age when changes are seen, possibly related to alterations in digestive physiology and diet. Indeed, Claesson and colleagues were able to identify clear correlations in elderly individuals, not only between the composition of the gut microbiota and diet, but also in relation to health status.
Regulation of the Microbiota
Because of the normal motility of the intestine (peristalsis and the migrating motor complex) and the antimicrobial effects of gastric acid, bile, and pancreatic and intestinal secretions, the stomach and proximal small intestine, although certainly not sterile, contain relatively small numbers of bacteria in healthy subjects. Interestingly, commensal organisms with probiotic properties have recently been isolated from the human stomach. The microbiology of the terminal ileum represents a transition zone between the jejunum, containing predominantly aerobic species, and the dense population of anaerobes found in the colon. Bacterial colony counts may be as high as 109 colony-forming units (CFU)/mL in the terminal ileum immediately proximal to the ileocecal valve, with a predominance of gram-negative organisms and anaerobes. On crossing into the colon, the bacterial concentration and variety of the enteric flora change dramatically. Concentrations of 1012 CFU/mL or greater may be found and are comprised mainly of anaerobes such as Bacteroides, Porphyromonas, Bifidobacterium, Lactobacillus, and Clos-tridium, with anaerobic bacteria outnumbering aerobic bacteria by a factor of 100 to 1000:1. The predominance of anaerobes in the colon reflects the fact that oxygen concentrations in the colon are very low; the flora has simply adapted to survive in this hostile environment.
At any given level of the gut, the composition of the flora also demonstrates variation along its diameter, with certain bacteria tending to be adherent to the mucosal surface, while others predominate in the lumen. It stands to reason that bacterial species residing at the mucosal surface or within the mucus layer are those most likely to participate in interactions with the host immune system, whereas those that populate the lumen may be more relevant to metabolic interactions with food or the products of digestion. It is now evident that different bacterial populations may inhabit these distinct domains. Their relative contributions to health and disease have been explored to a limited extent, though, because of the relative inaccessibility of the juxtamucosal populations in the colon and, especially, in the small intestine. However, most studies of the human gut microbiota have been based on analyses of fecal samples, therefore representing a major limitation. Indeed, a number of studies have already shown differ-ences between luminal (fecal) and juxtamucosal populations in disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).
In humans, the composition of the flora is influenced not only by age but also by diet and socioeconomic conditions. In a recent study of elderly individuals, the interaction of diet and age was demonstrated, firstly, by a close relationship between diet and microbiota composition in the subjects and, secondly, by interactions between diet, the microbiota, and health status. It must also be remembered that nondigestible or undigested components of the diet may contribute substantially to bacterial metabolism; for example, much of the increase in stool volume resulting from the ingestion of dietary fiber is based on an augmentation of bacterial mass. The subtleties of interaction between other components of diet and the microbiota are now being explored and will, undoubtedly, yield important information. For example, data indicating a potential role of certain products of bacterial metabolism in colon carcinogenesis have already provided strong hints of the relevance of diet-microbiota interactions to disease. Antibiotics, whether prescribed or in the food chain as a result of their administration to animals, have the potential to profoundly impact the microbiota. In the past, it was thought that these effects were relatively transient, with complete recovery of the microbiota occurring very soon after the course of antibiotic therapy was complete. However, while recent studies have confirmed that recovery is fairly rapid for many species, some species and strains show more sustained effects.
Gut-commensal microbiota interactions play a fundamental role in promoting homeostatic functions such as immunomodulation, upregulation of cytoprotec-tive genes, prevention and regulation of apoptosis, and maintenance of barrier function. The critical role of the microbiota on the development of gut function is amply demonstrated by the fate of the germ-free animal. Not only are virtually all components of the gut-associated and systemic immune systems affected in these animals, but the development of the epithelium, vasculature, neu-romuscular apparatus, and gut endocrine system also is impaired. The subtleties of the interactions between the microbiota and the host are exemplified by studies that demonstrate the ability of a polysaccharide elaborated by the bacterium Bacteroides fragilis to correct T-cell deficien-cies and Th1/Th2 imbalances and direct the development of lymphoid organs in the germ-free animal. Intestinal dendritic cells appear to play a central role in these critical immunologic interactions.
How does the gut immune system differentiate between friend and foe when it comes to the bacteria it encounters?
At the epithelial level, for example, a number of factors may allow the epithelium to tolerate commensal (and thus probiotic) organisms. These include the masking or modification of microbial-associated molecular patterns that are usually recognized by pattern recognition receptors, such as Toll-like receptors,27 and the inhibition of the NFκB inflammatory pathway. Responses to commensals and pathogens also may be distinctly different within the mucosal and systemic immune systems. For example, commensals such as Bifidobacterium infantis and Faecalibacterium prausnitzii have been shown to differentially induce regulatory T cells and result in the production of the anti-inflammatory cytokine interleukin (IL)-10. Other commensals may promote the development of T-helper cells, including TH17 cells, and result in a controlled inflammatory response that is protective against pathogens in part, at least, through the production of IL-17. The induction of a low-grade inflammatory response (physiologic inflammation) by commensals could be seen to prime the host’s immune system to deal more aggressively with the arrival of a pathogen.
Through these and other mechanisms, the microbiota can be seen to play a critical role in protecting the host from colonization by pathogenic species. Some intestinal bacteria produce a variety of substances, ranging from relatively nonspecifc fatty acids and peroxides to highly specific bacteriocins, which can inhibit or kill other potentially pathogenic bacteria, while certain strains produce proteases capable of denaturing bacterial toxins.
The Microbiota and Metabolism
Although the immunologic interactions between the microbiota and the host have been studied in great detail for some time, it has been only recently that the true extent of the metabolic potential of the microbiota has begun to be grasped. Some of these metabolic functions were well known, such as the ability of bacterial disac-charidases to salvage unabsorbed dietary sugars, such as lactose, and alcohols and convert them into short-chain fatty acids (SCFAs) that are then used as an energy source by the colonic mucosa. SCFAs promote the growth of intestinal epithelial cells and control their proliferation and differentiation. It has also been known for some time that enteric bacteria can produce nutrients and vitamins, such as folate and vitamin K, deconjugate bile salts, and metabolize some medications (such as sul-fasalazine) within the intestinal lumen, thereby releasing their active moieties. However, it is only recently that the full metabolic potential of the microbiome has come to be recognized and the potential contributions of the microbiota to the metabolic status of the host in health and in relation to obesity and related disorders have been appreciated. The application of genomics, metabolomics, and transcriptomics can now reveal, in immense detail, the metabolic potential of a given organism.
It is now also known that certain commensal organisms also produce other chemicals, including neurotrans-mitters and neuromodulators, which can modify other gut functions, such as motility or sensation. Most recently and perhaps most surprisingly, it has been proposed that the microbiota can influence the development and func-tion of the central nervous system, thereby leading to the concept of the microbiota-gut-brain axis.
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