Microbial Metabolites Regulate Host Lipid Metabolism through NR5A-Hedgehog Signaling

Microbes and their hosts share the same environment, and microbial metabolic molecules (metabolites) exert crucial effects on host physiology(1). Environmental factors not only shape the composition of the host’s resident microbes, but also modulate their metabolism(2). However, the exact molecular relationship among the environment, microbial metabolites and host metabolism remains largely unknown. Here, we discovered that environmental methionine tunes bacterial methyl metabolism to regulate host mitochondrial dynamics and lipid metabolism in Caenorhabditis elegans through an endocrine crosstalk involving NR5A nuclear receptor and hedgehog signaling. We discovered that methionine deficiency in bacterial medium decreases the production of bacterial metabolites that are essential for phosphatidylcholine synthesis in C. elegans. Reductions of diundecanoyl and dilauroyl phosphatidylcholines attenuate NR5A nuclear receptor/NHR-25-mediated transcriptional suppression on the Hedgehog-like protein/GRL-21. The induction of GRL-21 consequently inhibits the Patched receptor/PTR-24 cell non-autonomously, resulting in mitochondrial fragmentation and lipid accumulation. Together, our work reveals an environment-microbe-host metabolic axis regulating host mitochondrial dynamics and lipid metabolism, and discovers NR5A-Hedgehog intercellular signaling that controls these metabolic responses with critical consequences for host health and survival.