Cell. 2023 Jun 22;186(13):2823-2838.e20. doi: 10.1016/j.cell.2023.05.001. Epub 2023 May 25.

Kai Markus Schneider ¹, Niklas Blank ², Yelina Alvarez ¹, Katharina Thum ¹, Patrick Lundgren ¹, Lev Litichevskiy ¹, Madeleine Sleeman ¹, Klaas Bahnsen ¹, Jihee Kim ¹, Simon Kardo ¹, Shaan Patel ¹, Lenka Dohnalová ¹, Giulia T Uhr ¹, Hélène C Descamps ¹, Susanna Kircher ¹, Alana M McSween ¹, Ashkan Rezazadeh Ardabili ³, Kelsey M Nemec ⁴, Monica T Jimenez ⁵, Lila G Glotfelty ¹, Joshua D Eisenberg ⁶, Emma E Furth ⁷, Jorge Henao-Mejia ⁸, F Chris Bennett ⁹, Marie J Pierik ³, Mariëlle Romberg-Camps ¹⁰, Zlatan Mujagic ³, Marco Prinz ¹¹, Carolin V Schneider ¹², E John Wherry ¹³, Meenakshi Bewtra ¹⁴, Robert O Heuckeroth ⁶, Maayan Levy ¹⁵, Christoph A Thaiss ¹⁶

Author information

¹Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

²Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.

³Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands; School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands.

⁴Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

⁵Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

⁶Department of Pediatrics, Children's Hospital of Philadelphia Research Institute, and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

⁷Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

⁸Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Pennsylvania, University of Pennsylvania, Philadelphia, PA 19104, USA.

⁹Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

¹⁰Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Centre, Sittard-Geleen, the Netherlands.

¹¹Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany; Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

¹²Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

¹³Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

¹⁴Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

¹⁵Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: maayanle@pennmedicine.upenn.edu.

¹⁶Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: thaiss@pennmedicine.upenn.edu.

Abstract

Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-β2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.