Serotonin (5-HT), produced from enterochromaffin (EC) cells within the gut, has important signalling roles in metabolism by triggering hepatic gluconeogenesis, contributing to peripheral insulin resistance via actions on hepatocytes and adipocytes [1] and increasing fat mass and obesity by suppressing thermogenesis [2,3]. The gut microbiome has similar effects on host metabolism and has recently been shown to augment EC cell 5-HT content [4,5]. We therefore assessed whether the gut microbiome regulates host metabolism via modulation of gut 5-HT. Mice were treated for 28 days with either (1) antibiotics (Abx), (2) the TPH1 inhibitor LP533401 to reduce EC cell 5-HT, or (3) a combination of both treatments. Depletion of intestinal microbiota significantly improved peripheral insulin sensitivity and glucose tolerance, and reduced fasting blood glucose (FBG) levels and white adipose fat mass. LP533401 treatment also increased insulin sensitivity, improved glucose tolerance and decreased FBG, although to a lesser extent than the Abx group. Serum 5-HT and mucosal 5-HT content were reduced to similar levels by either treatment. Importantly, mice treated with both LP533401 and Abx similarly showed no additional improvement in insulin sensitivity, glucose tolerance and decreased FBG compared to Abx alone. These effects are independent of feeding and activity behaviour. MRI analysis of body fat revealed mice from all three treatment groups had reduced volume of subcutaneous adipose tissue compared to controls. LP533401 treated mice showed a shift in Day 28 faecal microbiota composition compared to Day 0 and controls. Our data demonstrates that resident intestinal microbiota are acting, in part, via gut 5-HT to modulate host metabolism, and that this relationship appears to be bi-directional.
[1] Sumara et al (2012) Cell Metab, [2] Crane et al (2015) Nat Med, [3] Suarez-Zamorano et al (2015) Nat Med, [4] Reigstad et al (2015) FASEB J, [5] Yano et al (2015) Cell