Inflammation rewires the enteric nervous system through neurogenic monocyte recruitment
Proper organization of the enteric nervous system (ENS) is critical for normal gastrointestinal (GI) physiology. Inflammatory bowel disease (IBD) disrupts key GI functions, including bowel motility. However, in many IBD patients, motility disorders persist even during remission, suggesting an irreversible ENS defect secondary to IBD. Here, we show that postinflammatory GI motility dysfunction arises from structural remodeling of the ENS, driven by a combination of neuronal loss and neurogenesis. During mucosal inflammation, enteric neurons upregulate CCL2 expression, facilitating the recruitment of monocytes into the myenteric plexus within the intestinal muscle. Monocyte-derived macrophages infiltrate the myenteric ganglia, contributing to excessive ENS remodeling and postinflammatory motility dysfunction. This neuroimmune axis is counterbalanced by a hypoxia-induced stress response in enteric neurons mediated by HIF1α. Enhancing the neuron-intrinsic hypoxia pathway limits ENS remodeling and preserves motility. In summary, this study presents a mechanistic model of postinflammatory GI motility dysfunction and proposes a therapeutic strategy to maintain ENS integrity and function during inflammation.
Authors
- Sravya Kurapati
- Sushma Nagaraj (ORCID: https://orcid.org/0000-0001-5166-1309)
- Changsik Shin
- Kevin Brown (ORCID: https://orcid.org/0000-0003-2959-2401)
- Subhash Kulkarni (ORCID: https://orcid.org/0000-0002-2298-0623)
- Chinmayee Dash (ORCID: https://orcid.org/0000-0002-2677-603X)
- Balázs Koscsó (ORCID: https://orcid.org/0000-0001-9676-2066)
- Milena Bogunovic (ORCID: https://orcid.org/0000-0002-0247-626X)
- Azree Zaffran Ashraf
- Christina E. Baer (ORCID: https://orcid.org/0000-0002-8909-2583)
- Travis Thomson (ORCID: https://orcid.org/0000-0001-8994-8241)
- Amanda M. Clark (ORCID: https://orcid.org/0000-0003-1590-2560)
- Katherine L. Kruckow (ORCID: https://orcid.org/0000-0003-2730-8163)
- Natalia Shulzhenko (ORCID: https://orcid.org/0000-0003-0077-8456)
- Shanthi Srinivasan (ORCID: https://orcid.org/0000-0002-6275-2369)
- Andrey Morgun (ORCID: https://orcid.org/0000-0002-8924-6108)
- Wenhui Wang
- Krisztina Szabo
- Monalee Saha
- L Guerrero Navarro
- Yu Liu
- Pankaj J. Pasricha
- Lauren A. Peters
- Jun Zhu
Institutions
- Pennsylvania State University (US)
- Oregon State University (US)
- Beth Israel Deaconess Medical Center (US)
- Johns Hopkins University (US)
- Emory University (US)
- University of Massachusetts Chan Medical School (US)
- Johns Hopkins Medicine (US)
- Mayo Clinic in Arizona (US)
- Penn State Milton S. Hershey Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-12-20
- DOI
- https://doi.org/10.1084/jem.20251761
- Primary Topic
- Gastrointestinal motility and disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00