title: An Intestinal Organ Culture System Uncovers a Role for the Nervous System in Microbe-Immune Crosstalk.
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.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nissan
authors.initials: N
authors.lastname: Yissachar
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Physics, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Ung
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nicole Y
authors.initials: NY
authors.lastname: Lai
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Mohan
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Physics, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Ehrlicher
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Physics, Harvard University, Cambridge, MA 02138, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Weitz
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kasper
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: isaac_chiu@hms.harvard.edu.
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Chiu
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: cbdm@hms.harvard.edu.
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: cbdm@hms.harvard.edu.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D003013:Clostridium / Q000145:classification / Q000254:growth & development* / Q000502:physiology; D007422:Intestines / Q000166:cytology / Q000254:growth & development* / Q000382:microbiology*; D051379:Mice; D009924:Organ Culture Techniques; D013559:Symbiosis
keywords: enteric nervous system; gut microbiota; neuropeptides; regulatory T cells; substance P