SUMMARY
The gastrointestinal (GI) tract is extensively innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia, which together regulate gut physiology. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Herein, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites, as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+ or TH+ neurons increases fecal output, while only ChAT+ activation results in increased colonic migrating motor complexes and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally-activated ENS neurons differentially regulate the gut microbiome and GI physiology in mice, without involvement of signals from the brain.
Competing Interest Statement
B.B.Y. declares financial interests in Nuanced Health, which is not related to the present study. S.K.M. declares financial interests in Axial Therapeutics and Nuanced Health, which is not related to the present study. P.C.D. is an advisor and holds equity in Cybele and Sirenas and a Scientific co-founder, advisor and holds equity to Ometa, Enveda, and Arome with prior approval by UC-San Diego. He also consulted for DSM animal health in 2023. R.K. is a scientific advisory board member, and consultant for BiomeSense, Inc., has equity and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant and scientific advisory board member for DayTwo, and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc., and has equity. He is a cofounder of Micronoma, and has equity and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.
Footnotes
Revision to update to correct license, funding, declarations, and clarify points in the methods.