Gut microbiota and sirtuins in obesity-related inflammation and bowel dysfunction

Abstract

Obesity is a chronic disease characterized by persistent low-grade inflammation with alterations in gut motility. Motor abnormalities suggest that obesity has effects on the enteric nervous system (ENS), which controls virtually all gut functions. Recent studies have revealed that the gut microbiota can affect obesity and increase inflammatory tone by modulating mucosal barrier function. Furthermore, the observation that inflammatory conditions influence the excitability of enteric neurons may add to the gut dysfunction in obesity. In this article, we discuss recent advances in understanding the role of gut microbiota and inflammation in the pathogenesis of obesity and obesity-related gastrointestinal dysfunction. The potential contribution of sirtuins in protecting or regulating the circuitry of the ENS under inflamed states is also considered.

Figure 1

Immunohistochemical localization of the class III histone deacetylase SIRT1 (Sir2) in the murine enteric nervous system. A. Confocal image of a whole mount preparation of colon stained with a goat antibody to the neuronal marker human neuronal protein (HuD; 1:100; Santa Cruz; sc-5977; green). HuD immunoreactivity is displayed by neurons in a myenteric ganglion. B. Double label confocal image of the same area depicted in A stained with an antibody to HuD and a SIRT1-specific antibody made in rabbit (1:500; Abcam Inc. Cambridge MA; ab 16640). Myenteric neurons display both HuD (green) and nuclear SIRT1 immunoreactivity (red). For whole-mount preparations, segments of colon were cut along the mesenteric border and the resulting sheet of gut was pinned flat, mucosal side up, in a silicone elastomer (Sylgard, Dow Corning, Midland, MI)-coated dish. The tissue was fixed for 3 hours with 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4). After fixation, the preparations were washed in phosphate-buffered saline (PBS) for 1 hour and whole-mount preparations of longitudinal muscle with adherent myenteric plexus (LMMP) were generated as previously described [128]. Non-specific binding was blocked by incubating the preparations with 6% (v/v) normal horse serum, with Triton X-100 (0.5%), in PBS for 60 minutes. The preparations were then exposed for 24 h to primary antibodies at 4°C. After washing with PBS, sites of bound primary antibodies were detected by incubation with donkey anti-rabbit or donkey anti-goat secondary antibodies coupled to DyLight™ 549 (1:400; Jackson ImmunoResearch Labs.West Grove, PA) or DyLight™ 488 (1:400; Jackson ImmunoResearch Labs.) for 3 hours. Confocal images were obtained using an Olympus FluoView FV300 confocal microscope. Scale bar, 30 μm.