An Intestinal Organ Culture System Uncovers a Role for the Nervous System in Microbe-Immune Crosstalk

Nissan Yissachar, Yan Zhou, Lloyd Ung, Nicole Y. Lai, James F. Mohan, Allen Ehrlicher, David A. Weitz, Dennis L. Kasper, Isaac M. Chiu, Diane Mathis, Christophe Benoist

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

Abstract

Investigation of host-environment interactions in the gut would benefit from a culture system that maintained tissue architecture yet allowed tight experimental control. We devised a microfabricated organ culture system that viably preserves the normal multicellular composition of the mouse intestine, with luminal flow to control perturbations (e.g., microbes, drugs). It enables studying short-term responses of diverse gut components (immune, neuronal, etc.). We focused on the early response to bacteria that induce either Th17 or RORg+ T-regulatory (Treg) cells in vivo. Transcriptional responses partially reproduced in vivo signatures, but these microbes elicited diametrically opposite changes in expression of a neuronal-specific gene set, notably nociceptive neuropeptides. We demonstrated activation of sensory neurons by microbes, correlating with RORg+ Treg induction. Colonic RORg+ Treg frequencies increased in mice lacking TAC1 neuropeptide precursor and decreased in capsaicin-diet fed mice. Thus, differential engagement of the enteric nervous system may partake in bifurcating pro- or anti-inflammatory responses to microbes.

Original languageEnglish
Pages (from-to)1135-1148.e12
JournalCell
Volume168
Issue number6
DOIs
StatePublished - 9 Mar 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

  • enteric nervous system
  • gut microbiota
  • neuropeptides
  • regulatory T cells
  • substance P

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