Neuronal programming by microbiota regulates intestinal physiology

Yuuki Obata (), Álvaro Castaño, Stefan Boeing, Ana Carina Bon-Frauches, Candice Fung, Todd Fallesen, Mercedes Gomez Agüero, Bahtiyar Yilmaz, Rita Lopes, Almaz Huseynova, Stuart Horswell, Muralidhara Rao Maradana, Werend Boesmans, Pieter Vanden Berghe, Andrew J. Murray, Brigitta Stockinger, Andrew J. Macpherson and Vassilis Pachnis ()
Additional contact information
Yuuki Obata: The Francis Crick Institute
Álvaro Castaño: The Francis Crick Institute
Stefan Boeing: The Francis Crick Institute
Ana Carina Bon-Frauches: The Francis Crick Institute
Candice Fung: University of Leuven
Todd Fallesen: The Francis Crick Institute
Mercedes Gomez Agüero: Maurice Muller Laboratories (DKF), Universitätsklinik fur Viszerale Chirurgie und Medizin Inselspital, University of Bern
Bahtiyar Yilmaz: Maurice Muller Laboratories (DKF), Universitätsklinik fur Viszerale Chirurgie und Medizin Inselspital, University of Bern
Rita Lopes: The Francis Crick Institute
Almaz Huseynova: The Francis Crick Institute
Stuart Horswell: The Francis Crick Institute
Muralidhara Rao Maradana: The Francis Crick Institute
Werend Boesmans: Hasselt University
Pieter Vanden Berghe: University of Leuven
Andrew J. Murray: University College London
Brigitta Stockinger: The Francis Crick Institute
Andrew J. Macpherson: Maurice Muller Laboratories (DKF), Universitätsklinik fur Viszerale Chirurgie und Medizin Inselspital, University of Bern
Vassilis Pachnis: The Francis Crick Institute

Nature, 2020, vol. 578, issue 7794, 284-289

Abstract: Abstract Neural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in gastrointestinal disorders1. Luminal factors, such as diet and microbiota, regulate neurogenic programs of gut motility2–5, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor aryl hydrocarbon receptor (AHR) functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enables these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restores intestinal motility. Together, our experiments identify AHR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits to maintain gut homeostasis and health.

Date: 2020
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DOI: 10.1038/s41586-020-1975-8

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