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Cell. 2017 Mar 9;168(6):1135-1148.e12. doi: 10.1016/j.cell.2017.02.009. Epub 2017 Mar 2.

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

Author information

1
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
2
School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Physics, Harvard University, Cambridge, MA 02138, USA.
3
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: isaac_chiu@hms.harvard.edu.
4
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: cbdm@hms.harvard.edu.

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.

KEYWORDS:

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

PMID:
28262351
PMCID:
PMC5396461
DOI:
10.1016/j.cell.2017.02.009
[Indexed for MEDLINE]
Free PMC Article

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