Enteric nervous system and inflammatory bowel disease

The enteric nervous system (ENS), often termed the "second brain," plays a pivotal role in regulating gastrointestinal functions and maintaining intestinal homeostasis. This review explores the intricate interactions between the ENS and inflammatory bowel disease (IBD), emphasizing how ENS dysfunction contributes to IBD pathogenesis. Key findings highlight that IBD patients exhibit enteric neuropathies, including heightened neural excitability, synaptic vulnerability, and diminished inhibitory signaling, which exacerbate intestinal inflammation and barrier dysfunction. Bidirectional communication between enteric neurons, glial cells, and immune cells is critical in modulating immune responses and inflammation. Enteric glial cells (EGCs) emerge as central regulators of gut homeostasis, influencing neuronal survival, immune cell activity, and mucosal integrity, while their dysfunction contributes to chronic inflammation and colorectal cancer progression. Experimental colitis revealed that neuro-immune crosstalk, mediated by neurotransmitters and cytokines, exerted both protective and pro-inflammatory effect on colitis. Furthermore, the ENS contributes to colorectal cancer through neurogenesis, perineural invasion, and paracrine interactions with tumor cells. Emerging therapies targeting ENS activity, such as electrical neuromodulation and neuromodulators, showed promising results in alleviating IBD symptoms by restoring neural-immune balance. However, studying the ENS poses challenges such as low abundance of neuronal cell and technical limitations, which necessitate advanced methodologies like spatial transcriptomics. This review underscores the ENS as a therapeutic frontier for IBD and colorectal cancer, urging interdisciplinary approaches to unravel its multifaceted roles in health and disease.