Microbe-derived indole tunes organ-function and links microbe metabolites to biological ageing

Abstract

AbstractTo investigate the underlying molecular mechanisms on how the gut microbe metabolite, indoles, regulate host organ growth and function, germ-free male mice were mono-colonized with indole-producing wildtypeEscherichia colior tryptophanase-encodingtnaAknockout mutant indole-non-producingE. coli. The indole mutantE. colirecipient mice exhibited significant multiorgan decline and growth retardation combined with catabolism and energy deficiency despite increased food intake compared to control mice. In addition, indole mutant mice displayed malfunctional intestine, enlarged caecum, reduced numbers of colonic enterochromaffin cells and reduced circulating serotonin levels, resulting in reduced gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice also displayed decreased expression ofKcnj12gene, suggesting reduced excitability of enteric neurons thus adding to intestinal dysfunctional phenotype. In conclusion, indoles are necessary to maintain adult metabolic homeostasis across multiple organs in vivo. Impairment of indole levels results in multiorgan functional decline suggesting a mechanism whereby gut microbe metabolites may regulate biological ageing and thus increase the risk for disease.Graphical summary