Taken together with the MGWAS studies, these data suggest PF 2341066 that altered (less SCFA-producing) gut microbiota composition may affect the host metabolism via impaired intestinal barrier function resulting in low-grade endotoxaemia. Earlier human studies had already reported that obese subjects have altered faecal SCFA levels which were linked to impaired epithelial intestinal barrier function [32]. Thus, the previous reported MGWAS association

of T2DM with impaired butyrate production is of interest, as oral supplementation with butyrate can reverse insulin resistance in dietary-obese mice [33] and increase energy expenditure [34], and we are currently performing such a study in human subjects with metabolic syndrome at our institution. Moreover, as germ-free mice produce almost no SCFA [35], this suggests a direct pathophysiological mechanism between intestinal microbiota histone deacetylase activity composition, bacterial SCFA in the intestine and development of insulin resistance. It has long been recognized that intestinal bacteria release short chain fatty acids, peroxidases, proteases and bacteriocins to prevent pathogens from settling in the intestine [36]. The main substrate available to the

intestinal bacteria for this process is indigestible dietary carbohydrates, specifically dietary starches and fibres which are broken down into SCFAs (including acetate, propionate and butyrate) [32]. These SCFAs may serve as an energy source for intestinal epithelium and liver, given their transport predominantly via the portal vein after intestinal absorption (see Fig. 1). Other observations suggest that the signalling properties of the altered SCFAs may be more responsible for the metabolic effects of the obesity-associated microbiota than their caloric content. For example, SCFAs signal through several G-protein (GPR)-coupled receptors, including GPR-41 and GPR-43 [37]. Moreover, mice lacking GPR41 (the SCFA receptor most active in intestinal epithelial cells) have lower recovery of dietary SCFAs [38],

suggestive of a reciprocal mechanism between during intestinal epithelial cell function, intestinal microbiota composition and their produced SCFAs. In line with this, these authors showed that the SCFA propionate was used for gluconeogenesis and lipogenesis, whereas the SCFA butyrate had a distinct effect on reduced inflammatory status via inhibition of nuclear factor (NF)-kappa-B transcription. Although it has been acknowledged that SCFAs have a direct immunomodulatory effect via improving intestinal permeability [33], another possible mechanism could be indirect by acting as a histone deacetylase (HDAC) inhibitor, affecting proliferation, differentiation and methylation of gene expression [39] (see also Fig. 1). Bile acids have been highlighted as crucial metabolic integrators and signalling molecules involved in the regulation of metabolic pathways, including glucose, lipid and energy metabolism [40].