Insights Into the Role of the Microbiome in Obesity and Type 2 Diabetes

Annick V. Hartstra; Kristien E.C. Bouter; Fredrik Bäckhed; Max Nieuwdorp

Disclosures

Diabetes Care. 2015;38(1):159-165. 

In This Article

Innovative Strategies for Novel Therapeutics in T2DM

Interestingly, in animal models, butyrate has also been shown to both affect intestinal serotonin levels[45] and increase serotonin transporters (SERTs) in the hypothalamus.[46] Furthermore, butyrate directly affects sympathetic tone and intestinal transit times[47] as well as physical activity.[48] In line, it is known that serotonin itself can regulate intestinal permeability[49] besides being an important signaling neurotransmitter in the gut and brain involved in regulation of body weight and food intake by enhancing satiety.[50] A reduction in cerebral SERTs, essential regulators of serotonergic transmission, is associated with obesity.[51] In a human study, when healthy lean subjects received a hypercaloric snacking diet for 6 weeks, a significant 30% decrease of hypothalamic SERT binding was seen.[52]

In this respect, it is interesting to note that studies have suggested a regulating influence of intestinal bacteria on serotonin.[53,54] For example, bariatric surgery (Roux-en-Y gastric bypass [RYGB]) has been shown to significantly affect serotonin metabolism in both animals[51,55] and humans.[56] Moreover, RYGB is regarded as a last resort but very successful treatment for morbidly obese patients, because next to inducing weight loss up to 50% of the original weight, it also decreases the risk of T2DM and cardiovascular pathology.[57,58] RYGB has even been shown to resolve insulin resistance faster than the actual weight loss, underscoring a potential weight-independent effect on metabolism.[41,58] As RYGB can alter the composition of the gut microbiota in both mice[59] and humans,[60,61] this might be one of the contributing factors. When diabetic mice were colonized with feces of post-RYGB mice, they lost weight and showed improvement in glucose and lipid metabolism with specific changes in butyrate-producing bacteria.[59] These findings suggest that the change in butyrate-producing microbiota after RYGB may play an important role in satiety as well as regulation of glucose and lipid metabolism.

It is thus becoming increasingly evident that the composition of gut microbiota plays a role in the regulation of glucose and lipid metabolism. Specifically, there seems to be an association between butyrate-producing bacteria and beneficial effects on metabolism in both mice and humans.[24,35] Furthermore, an alteration in the composition of the gut microbiota may be involved in the development of obesity and T2DM. Further studies are however needed to establish the causality of this and as to whether increasing intestinal SCFAs, including butyrate, has the same metabolic influence as SCFA-producing bacteria on human metabolism, including insulin sensitivity and inflammatory tone. Thus, in order to validate the hypothesis of butyrate-producing bacteria as role players and their products as signaling molecules in human glucose and lipid metabolism, double-blinded randomized controlled trials using either SCFA supplementation (given either orally or rectally) or FMT derived from different donors (e.g., on different diets) are needed. Priorities for further studies also include therapeutic intervention trials with specific types of single bacterial strains in order to elucidate particular beneficial patterns in gut microbiota composition.

Other areas of therapeutic interest in this respect are nondigestible but fermentable fibers, such as inulin, fructo-oligosaccharides, galacto-oligosaccharides, and lactulose. Food artificially enriched with these fibers has been termed a prebiotic when it is able to shift the composition of gut microbiota by stimulating the growth or activity of beneficial species.[23] In this respect, carbohydrate-fermenting bacteria such as Bifidobacteria and Lactobacilli increase upon prebiotic treatment in different age-groups.[62] The effects of prebiotics have been ascribed to an immune-mediated mechanism. As previously mentioned, high-fat dietary feeding is associated with endotoxemia, which in turn is linked to a reduced abundance of Bifidobacteria with a concomitant increase in gram-negative (LPS-containing) bacteria. In line, when prebiotic-containing oligofructose (OFS) were fed to mice on a high-fat diet, this restored levels of their Bifidobacteria and consequently reduced endotoxemia and improved glucose tolerance.[63]

Another line of therapeutic approach is probiotics, which encompass food supplements enriched with strains of live bacteria, including species of Bifidobacteria and Lactobacilli, that are able to alter the gut microbiota beneficially for the host.[28,64] In mice, antidiabetic effects have been shown following administration of probiotics containing certain Lactobacillus strains[65] with a concomitant reduction in endotoxemia.[66] Due to the placebo effect of these products, proper double-blinded randomized controlled trials with accepted hard end points are needed in humans to address the potentially beneficial metabolic effects of probiotic strains in relation to the composition of the intestinal microbiota.

Although public health has benefited substantially from the discovery of antibiotics, its rapid increase in use is starting to raise health concerns. Next to the obvious issue of antibiotic resistance, its worldwide use might potentially be associated with the obesity epidemic.[67] Although oral antibiotic treatment effectively eradicates pathogenic bacteria, the beneficial intestinal microbial community is also affected with possible dire metabolic consequences. Long-term intravenous vancomycin (aimed at gram-positive bacteria) in adult patients was linked to an increased risk of developing obesity,[68] whereas amoxicillin (aimed at gram-negative and anaerobic bacteria) had only minor effects. In line, short-term oral administration of vancomycin (but not amoxicillin) significantly impaired peripheral insulin sensitivity via altered bile acid dehydroxylation in males with metabolic syndrome, which was associated with a changed gut microbiota composition.[69] Moreover, even short-term courses of oral antibiotics were shown to have profound (irreversible) effects on intestinal microbial diversity and composition.[70] The recent data linking use of antibiotics in early infancy to distinct long-term effects on intestinal microbiota diversity and the risk of childhood overweight[71] are even more alarming but not surprising. In the last 50 years, the use of subtherapeutic antibiotic therapy in farm animals has become widely used as it increases growth and therefore food production. In mice, treatment with subtherapeutic doses of antibiotics alters the composition of the intestinal microbiota and therefore affects metabolic pathways, particularly concerning SCFA metabolism.[72] These findings emphasize the causal relationship between metabolism and the gut microbiome, and a more cautionary use of antibiotics seems to be more justified than ever.

However, the simplest solution to restoring pathological disturbances in the composition of the gut microbiota may be a change in dietary habits. Diet has been shown to strongly affect the composition of the microbiome.[73] When obese humans were put either on a fat-restricted or carbohydrate-restricted low-calorie diet, an increase in the abundance of Bacteroidetes and a decrease in Firmicutes was reported.[12] In another study, diet-induced weight loss versus weight-stabilization interventions in obese humans increased intestinal microbial gene richness and was associated with a reduced systemic inflammation.[74] These data corroborate with another controlled diet intervention study in 98 human subjects showing that certain dominant gut microbial communities, or "enterotypes," correlated with specific kinds of diets.[73] For example, Bacteroides was associated with a protein-rich diet, whereas Prevotella correlated with a fiber-rich diet; moreover, gut microbiota composition could be altered within 24 h whereas enterotype remained stable during the 10 days of the study. Based on this rapid and dramatic plasticity of intestinal microbiota composition, there is a specific need to determine intestinal microbiota composition in a standardized way (e.g., sequencing several fecal samples per person over a specific time point while taking dietary intake and medication use into account).

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