Nutrients activate distinct patterns of small-intestinal enteric neurons

Candice Fung, Tom Venneman, Amy M. Holland, Tobie Martens, Milvia I. Alata, Marlene M. Hao, Ceyhun Alar, Yuuki Obata, Jan Tack, Alejandro Sifrim, Vassilis Pachnis, Werend Boesmans and Pieter Vanden Berghe ()
Additional contact information
Candice Fung: KU Leuven
Tom Venneman: KU Leuven
Amy M. Holland: GROW – Research Institute for Oncology and Reproduction
Tobie Martens: KU Leuven
Milvia I. Alata: KU Leuven
Marlene M. Hao: KU Leuven
Ceyhun Alar: KU Leuven Institute for Single Cell Omics (LISCO)
Yuuki Obata: Francis Crick Institute
Jan Tack: KU Leuven
Alejandro Sifrim: KU Leuven Institute for Single Cell Omics (LISCO)
Vassilis Pachnis: Francis Crick Institute
Werend Boesmans: GROW – Research Institute for Oncology and Reproduction
Pieter Vanden Berghe: KU Leuven

Nature, 2025, vol. 644, issue 8078, 1069-1077

Abstract: Abstract The ability to detect and respond appropriately to ingested nutrients is essential for an organism’s survival and to ensure its metabolic demands are met. Nutrient signals from the gut lumen trigger local intestinal reflexes in the enteric nervous system (ENS) to facilitate digestion and absorption1–4, but the precise cellular pathways that are involved in the initial neuronal sensory process remain unclear. The extent to which the ENS is capable of discerning different luminal chemicals is also unknown. Here we use calcium imaging to identify specific enteric pathways that are activated in response to luminal nutrients applied to mouse jejunum. Notably, we show that different nutrients activate neurochemically defined ensembles of myenteric and submucosal neurons. Furthermore, we find that enteric neurons are not directly sensitive to nutrients but detect different luminal chemicals through the epithelium, mainly via a serotonin signalling pathway. Finally, our data reveal a spatial distribution of luminal information along the radial axis of the intestine, whereby some signals that originate from the villus epithelium are transmitted first to the myenteric plexus, and then back to the submucosal plexus, which is closer to the lumen.

Date: 2025
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DOI: 10.1038/s41586-025-09228-z

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