Intestinal colonization of germ-free mice with indole-producing E. coli modulates the central and peripheral endocannabinoidome.

Colonization of germ-free (GF) mice with indole-producing E. coli exacerbates anxiety- and depression-like behaviors. Lack and subsequent reintroduction of gut microbiota in mice alter in opposing ways the brain and intestinal levels of the lipid mediators of the expanded endocannabinoid system, or endocannabinoidome (eCBome), which controls affective behaviors. By using LC/MS-MS-based targeted lipidomics and qPCR, we investigated the effect of GF mouse colonization with E. coli strains capable (wild-type, I+) or not (knock-out, I-) of producing indole, on the brain and intestinal eCBome. Compared to untreated GF mice, and unlike the I- strain, the I+ strain reduced the levels of 2-monoacylglycerols (2-MAGs), and 2-arachidonoylglycerol in particular, in the amygdala, and of 2-MAGs and NAEs in the hippocampus. Moreover, it elevated 2-MAGs in the ileum and reduced NAEs in the cecum. The mRNA expression of some eCBome receptors was also selectively altered by the I+ strain, including Gpr55 (upregulated in the amygdala), Gpr18 (downregulated in the ileum), Cnr2 (upregulated in the colon), and Gpr119 (downregulated in the cecum). LC/MS-MS-based targeted metabolomics detected the indole metabolite indoxyl-3-sulfate in the plasma and liver, but not brain, of I+-colonized mice. Our data pinpoint the eCBome as a potential mediator of the effects of indole.