Inflammation rewires the enteric nervous system through neurogenic monocyte recruitment

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Abstract
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.
Funding Information
  • Penn State College of Medicine
  • Pennsylvania Department of Health
  • Kenneth Rainin Foundation
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (R21AI126351-01)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107603)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080684)
  • National Institute on Aging (R01AG066768)
  • National Institute on Aging (R21AG072107)
  • National Institute of Neurological Disorders and Stroke (R01NS112492)
  • Harvard Digestive Disease Center
  • Icahn School of Medicine at Mount Sinai
  • National Center for Advancing Translational Sciences (UL1TR004419)
  • Leona M. and Harry B. Helmsley Charitable Trust

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