Background: Specialised enterochromaffin (EC) cells within the gut provide almost all serotonin (5-HT) in the body, the synthesis of which is regulated by the rate-limiting enzyme, tryptophan hydroxylase 1 (TPH1). EC cells are important luminal sensors, and gut microbiota signal to EC cells via a range of microbial metabolites to increase 5-HT biosynthesis. We have demonstrated that gut-derived 5-HT is a signalling nexus between gut microbiota and host metabolism [1]. We, and others [2,3], observed that gut-derived 5-HT also impacts gut microbiota composition. The impacts of 5-HT driven changes to microbial composition on specific metabolite abundance and host metabolism remain unknown, however. The aims of this study were to establish whether a bi-directional relationship exists between gut microbiota and EC cells and to examine the metabolic impacts of this in mice.
Methods: Gut-derived 5-HT synthesis was inhibited in mice by a daily oral gavage of the TPH inhibitor, LP533401 (30 mg/kg) for 28 days. Faecal samples were collected at Days 0 and 28 and analysed for microbial taxonomic and metabolite composition. Cecum contents from control (C-FMT) and LP533401-treated (drug-treated, D-FMT) mice were then transplanted into donor germ-free (GF) mice via oral gavage and mice colonised for a further 28 days. Effect of donor microbial composition on blood glucose control were determined by intraperitoneal glucose tolerance test, circulating and mucosal 5-HT levels analysed by ELISA, and EC cell density quantified by immunohistochemistry.
Results: Inhibition of gut-derived 5-HT synthesis significantly altered the gut microbiome and microbial metabolite abundance after 28 days compared to controls. In D-FMT mice, this shift in microbial composition was not associated with changes to blood glucose control, weight or duodenal 5-HT content compared to C-FMT mice. However, colonic mucosal 5-HT and EC cell density was significantly lower in D-FMT mice compared to C-FMT controls.