The human body is inhabited by a diverse and populous array of microorganisms, termed the microbiome, including bacteria, viruses, fungi, and archaea. The genetic material from this collection of microbes, termed the metagenome, is now estimated to be 150 times larger than that of the human genome. The gastrointestinal tract contains the majority of commensal microbes; however, the urogenital tract, skin, and oral cavity provide niche environments for additional species. Microbes colonize the sterile gastrointestinal tract during birth and are implicated in early- life programming of the immune and metabolic systems, protection from infection, and the synthesis of vitamins, minerals, and fatty acids, which continues throughout the lifespan of an individual. Given its size, diversity of physiological functions, and interactions with other organ systems, the microbiome can be considered as an organ in its own right.
Revised estimates suggest close to 2000 different bacterial species may persist in the gut, with the number of bacterial cells exceeding 1013 and being as numerous as the total number of host cells in the body. Given the dominance of anaerobic species, early attempts to characterize the diversity of the intestinal microbiome were limited by available sample collection methods and culture techniques. Advances in molecular biology techniques, including use of deep- and next- generation sequencing, have facilitated several large- scale projects, including the European MetaHIT Project and the National Institutes of Health Human Microbiome Project, which have provided additional insights into the diversity of the commensal species. Initially these projects classified 90% of gut bacteria as belonging to either one of two phyla, namely Bacteroides or Firmicutes. Within these two divisions three enterotypes were defined based on variation in either Bacteroidetes (enterotype 1), Prevotella (enterotype 2), or Ruminococcus (enterotype 3) that appeared stable across continents. Classification of stable enterotypes is now considered oversimplified, with the abundance of resident species along the gastrointestinal tract alone displaying up to 90% diversity between individuals in similar geographical locations and thought to be shaped by age, hygiene, medication use, and diet.
The microbial species resident in the gastrointestinal tract are increasingly recognized as playing critical roles in host function and subsequently health and disease. The synergistic relationship between the intestinal microbiota and host provide several benefits to the host, including (i) resistance to infection by pathogenic microorganisms through direct competition for nutrients and attachment sites and production of antimicrobial substances; (ii) promotion of epithelial cell proliferation and differentiation to maintain an intact mucosal surface; (iii) promotion of the development of the gut- associated lymphoid tissue via initiation of dendritic cell maturation and B- and T- lymphocyte differentiation; and (iv) energy harvest from non- digestible dietary starches (Figure 1).
Fig1. A synergistic relationship between the intestinal microbiome and post provides a number of benefits, including (1) competitive exclusion of pathogenic strains; (2) energy harvest; (3) promotion of barrier integrity; and (4) immune education. SCFA, short- chain fatty acids. Source: Modified from Cox et al. 2014.
Bacterial fermentation of non- digestible dietary starch occurs predominantly in the colon and produces short- chain fatty acids (SCFAs; primarily acetate, propionate, and butyrate), which have received particular attention as mediating the beneficial effects provided by the intestinal microbiome. Butyrate in particular is recognized as the main energy source for colonic epithelial cells, and is thought to stimulate blood flow and the secretion of gut hormones, enhance fluid and electrolyte uptake, and increase mucin release, all of which contribute to a local tropic effect, epithelial cell proliferation and differentiation, and maintaining integrity of the intestinal mucosa. The application of ‘- omics’ technologies has further broadened knowledge of the roles of the commensal microbial species in host function, with bacterial communities identified with specific roles in regulating biochemical and metabolic pathways.
Greater understanding of the role of the microbiota in regulating metabolic function and immune homeostasis has also led to a growing focus on the contribution of the microbiota to risk for diabetes. The composition of the microbiota is altered in obesity and may promote increased extraction of energy from food, altered intestinal permeability, and upregulation of inflammatory signal ling. Links between the microbiota and the biochemical processes underpinning the onset and progression of diabetes offer promise that microbial manipulation may be a strategy to reduce the growing burden of associated disease. This chapter will explore the ways in which the intestinal microbiota contribute to diabetes by promoting the accumulation of adipose tissue and altering metabolic and immune homeostasis.
Given the documented relationship between excess body mass and risk for type 2 diabetes, links between the intestinal microbiome and excess body mass are of interest when considering the role of the microbiome in diabetes pathogenesis. In animal models, lower body mass and body fat in germ- free mice compared to wild- type counterparts, even following exposure to a high- fat and sugar- rich Western- style diet, suggest that the absence of microbial colonization in the gastrointestinal tract impairs energy harvest. Studies involving transplantation of the intestinal microbiota further implicate the microbiome as a contributor to excess body mass; transplantation of wild- type microbiota to germ- free mice normalizes body weight between groups, while transplantation of microbiota from obese mice results in an increase in fat mass in germ- free animals. Research examining the transplantation of microbiota from obese or lean human donors into germ- free mice is mixed. One investigation has reported greater weight gain over 50 days in recipient animals receiving obesity- associated microbiota. However, a comparison of three diets including a control diet, Western diet, or 45% high- fat diet in mice with gut microbiota from lean or obese human donors found that after 22 weeks, final body weight or body composition of animals did not significantly differ based on source of human- donor material (lean or obese). Collectively, these data suggest that particular microbiome profiles may favour accumulation of excess body weight, itself a risk factor for type 2 diabetes.
In humans, direct comparison of the composition of the intestinal microbiota between individuals with overweight and lean individuals has produced mixed findings, likely to be the result of modest sample sizes examined in early studies and inherent variability between individuals in response to other environmental factors, in addition to host genetics. A significant decrease in the relative abundance of Bacteroidetes, but an increase in Firmicutes in individuals with obesity, has been reported. Similarly, reductions in overall bacterial diversity and reductions in relative abundance of Bacteroidetes, increased relative abundance of Actino bacteria, but no significant change in Firmicutes between individuals with obesity and lean individuals have also been observed. However, others report no difference in the dominant phyla, and an increased relative abundance of Bacteroidetes in individuals with obesity compared to lean individuals. While these inconsistencies are increasingly acknowledged, these studies have revealed that the intestinal microbiota is not static and that the composition of the microbiome can vary both within and between populations.
Dietary intervention studies further support the dynamic nature of the intestinal microbiome. Increased caloric content (2400 or 3400 kcal/d at similar macronutrient profiles; 24% protein, 16% fat, and 60% carbohydrates) in otherwise healthy humans for as little as three days has been reported to increase the abundance of Firmicutes and decrease the abundance of Bacteroidetes. Even more acute changes have been suggested, with a subsequent study in otherwise healthy adults noting changes in the composition of the intestinal microbiota within 24 hours of initiation of a high- fat diet. Changes in the intestinal microbiota in response to weight- reducing diets have also been reported, including reduction in the abundance of some specific Firmicutes species following a four- week low- carbohydrate weight- reducing diet in men with obesity and a decreased relative abundance of Bacteroidetes in men with obesity following a four- week high- protein low- carbohydrate diet. It remains to be determined if alterations in the intestinal microbiota that promote energy harvest are a cause or a consequence of Western diets and excess body mass. However, given the functions of the intestinal microbiota beyond energy harvest, additional mechanisms may also contribute to the risk for obesity and associated disease.
Composition of the intestinal microbiome is altered in type 2 diabetes
Potential contributions of the gut microbiota to the pathogenesis of metabolic syndrome and type 2 diabetes are increasingly recognized. Comparison of intestinal microbial composition between individuals with and without type 2 diabetes has tradition ally relied on 16s rRNA characterization. Conflicting outcomes in terms of overall microbial diversity are noted; some groups report no difference in overall microbial diversity between individuals with type 2 diabetes and controls, while others suggest a decrease in microbial diversity in people with type 2 diabetes. Despite the discrepancies relating to microbial diversity, the majority of studies report differences in the relative abundance of specific microbial taxa between people with and without type 2 diabetes, including decreased relative abundance of specific Bacteroidetes species, such as Bifidobacteria and Bacteroides. The modest sample sizes (groups from 8 to 64 individuals) employed in some of the earlier studies and the degree of species identification possible using 16s rRNA method ologies are recognized limitations in the field and have limited the wider application of such observations.
However, the adoption of full metagenome sequencing method ologies in response to reduced costs has provided greater insights into altered microbial composition in type 2 diabetes. Notable studies include those performed in an ethnic Chinese type 2 diabetes case control cohort (n = 345) in a two- stage design; in a cohort of almost 3000 European women classified into those with type 2 diabetes, impaired glucose tolerance, or normal glucose metabolism; in a cohort of people with treatment- naïve type 2 diabetes, pre- diabetes, and normal glucose tolerance (n = 254); and a multi ethnic cohort (n = 784) with stratification of individuals with type 2 diabetes based on metformin treatment. All studies report differences in the abundance of specific bacterial taxa in individuals with type 2 diabetes compared to those without diabetes. Consistent observations include enrichment of opportunistic pathogens, including Eggerthella species and Escherichia coli, as well as Lactobacillus species and depletion of known butyrate producers including Faecalibacterium prasnitzii, Roseburia species, and Eubacteria species in individuals with type 2 diabetes relative to controls. Beyond microbial composition, metagenome analysis allows for inferences of potential collective microbial function. For the studies mentioned, and consistent with the compositional observations, decreased potential for butyrate biosynthesis has been noted in individuals with type 2 diabetes, along with increased potential for membrane transport of sugars and upregulation of a range of genes involved in oxidative stress pathways. In addition, these studies have been able to use combinations of metagenome markers to successfully predict type 2 diabetes status, providing further support for the relationships between the gut microbiome and risk of type 2 diabetes.
The intestinal microbiome can influence intestinal permeability
A permeable intestinal mucosa is necessary to facilitate critical absorptive functions, but maintenance of barrier exclusion is essential in isolating the intestinal microbiota within the intestinal lumen. The interaction between various integral membrane proteins and cytoskeletal components provides a structural framework to maintain integrity of the intestinal mucosa via intercellular tight junctions. The intestinal microbiota has been suggested to contribute to the ongoing remodelling of the mucosal epithelium and the direct roles of particular microbial metabolites, including tryptophan metabolites, in regulating mucosal barrier function are also recognized. In vitro experiments utilizing cultured intestinal epithelial cells have demonstrated that treatment with commensal and probiotic microbial species or a Faecalibacterium prasnitzii–derived protein preparation elicit upregulation and increased phosphorylation of key tight junction proteins and reductions in paracellular permeability. Likewise, colonization of germ- free mice with probiotic species has been shown to result in the upregulation of key tight junction proteins and normalization of intestinal barrier function in animal models of disease. Further, human clinical studies involving manipulation of the intestinal microbiota via probiotic supplementation report outcomes that include increased tight junction protein expression in collected duodenal biopsy samples, decreased faecal excretion of the key tight junction protein zonulin, and reductions in intestinal permeability assessed using a dual- glucose absorption test, all suggesting preserved integrity of the intestinal mucosa mediated by the intestinal microbiota. Conceivably, altered composition of the intestinal microbiota reported in obesity could impact adversely on intestinal permeability and contribute to translocation of the intestinal microbiota to the circulation and subsequent systemic responses that may con tribute to an increased risk for type 2 diabetes.
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