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

Products of Intestinal Bacteria in T2DM Pathophysiology

Butyrate and acetate and propionate are short-chain fatty acids (SCFAs) fermented by the intestinal bacteria from dietary fiber that play an important role in energy metabolism (Fig. 2).[29] These SCFAs are absorbed in the intestine, where particularly butyrate provides energy for the colonic epithelial cells, whereas the remaining SCFAs enter the (portal) venous system. Data from animal studies have suggested that propionate affects hepatic lipogenesis and gluconeogenesis, whereas peripherally acetate functions as substrate for cholesterol synthesis.[17] The colonic mucosa primarily relies on the luminal presence of butyrate as energy source, and a lack of these SCFAs has been proposed to play an important part in the pathogenesis of intestinal disease and inflammatory bowel diseases.[30] More specific, low concentrations of SCFAs have been found in ulcerative colitis patients[31] and treatment with SCFA enemas, especially butyrate, has been shown to reduce inflammation in this patient group.[32] Interestingly, oral administration of sodium butyrate was found to be safe and well tolerated in humans with Crohn disease and ulcerative colitis;[33,34] these studies showed a systemic anti-inflammatory effect and improved clinical improvement. In mice, oral butyrate has been demonstrated to improve insulin sensitivity and increase energy expenditure by enhancing mitochondrial function.[35] Whether these beneficial effects apply to humans as well is currently being studied in our department. The underlying mechanisms of the potential positive influence of butyrate on metabolism are not clear. However, there is data on inhibiting effects of butyrate on histone deacetylases in mammalian cultured cells, which regulate gene expression by deacetylating histone proteins and transcription factors.[36] This may contribute to increased expression of PGC-1a, a transcription coactivator associated with increased fatty acid oxidation and mitochondrial activity.[35] Butyrate, being an SCFA, is oxidized in the mitochondria of colonocytes into acetyl-CoA and via the tricarboxylic acid cycle contributes to ATP production. Important catalyzing enzymes in this process have been shown to be downregulated in GF mice, resulting in a significantly decreased level of ATP in GF colonocytes. This indicates a potential stimulating role of the intestinal microbiota, particularly butyrate-producing microbes, in the expression of these enzymes and consequently mitochondrial function and energy metabolism.[37] Another way in which SCFAs might influence the host's energy balance is by acting as specific signaling products. SCFAs bind to G protein–coupled receptors, namely GPR41 and GPR43, which are expressed in enteroendocrine cells in the intestinal epithelium.[3,38] This leads to secretion of certain peptide hormones, like PYY, which are basolaterally released into the systemic circulation, enabling a form of communication between gut milieu and host. Conventional Gpr41−/− mice and GF Gpr41−/− mice colonized with members of the human gut microbiota stayed significantly leaner than their wild-type counterparts, whereas no differences were seen between wild type and GF Gpr41−/− mice. The latter indicates a regulating role of GPR41 in energy homeostasis in relation to the intestinal microbiota and their metabolic products. Furthermore, Gpr41−/− deficiency was associated with a decrease in the gut-derived hormone PYY, resulting in a decreased extraction of energy from the diet associated with an increase in intestinal transit time.[39]

Figure 2.

Role of gut microbiota–produced SCFAs in human glucose metabolism in obese subjects. Fermentation of dietary fibers by intestinal bacteria generates SCFAs, including butyrate, that have both metabolic and epigenetic effects. Obese insulin-resistant subjects are characterized by altered SCFA production compared with lean subjects. We hypothesize that in these subjects, this adversely affects satiety, hepatic glucose, and lipid production as well as inflammatory tone.

Another function of butyrate, which may contribute to its possible beneficial role in the host's metabolism, is maintaining intestinal integrity. This contributes to the prevention of endotoxemia, a process resulting from translocation of endotoxic compounds (lipopolysaccharides [LPS]), of gram-negative intestinal bacteria. In the last decade, it has become evident that insulin resistance and T2DM are characterized by low-grade inflammation.[40] In this respect, LPS trigger a low-grade inflammatory response, and the process of endotoxemia can therefore result in the development of insulin resistance and other metabolic disorders.[41,42] Butyrate also seems to play a part in the recent discovery of the intestine's ability to produce glucose itself. Glucose released by intestinal gluconeogenesis (IGN) is detected by a portal vein glucose sensor that signals to the brain through the peripheral nervous system, thus positively influencing glucose metabolism and intake of food.[43] De Vadder et al.[44] confirmed in rats the beneficial effects of SCFAs and IGN on glucose metabolism and subsequently showed that butyrate is involved by activating gene expression of IGN in mice. However, these findings still need validation in humans, and we are currently executing a study in which we have treated subjects with metabolic syndrome for 4 weeks with oral butyrate to study its effects on insulin sensitivity and microbiota composition.

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