Abstract 4080: The neural bridge: Stress-remodeled enteric nervous system (ENS) in the colitis-cancer transition

Abstract Chronic stress, driven by environmental and psychosocial factors, disrupts systemic homeostasis and adversely affects cognitive function, behavior, and the cardiovascular, gastrointestinal (GI), and immune systems. It is closely associated with GI disorders and can exacerbate inflammatory bowel disease (IBD), a known precursor to colorectal cancer (CRC). Effective repair of the colonic epithelium is essential for favorable long-term outcomes in IBD patients, who frequently experience chronic GI injury. Moreover, disruption of gut homeostasis is linked to conditions such as obesity, diabetes, and colitis, all of which may contribute to tumorigenesis. Although multiple mechanisms are implicated in gut homeostasis, a key regulator is the enteric nervous system (ENS), an extensive network of neurons and enteric glial cells (EGCs) that innervates the GI tract. EGCs act as signaling hubs, modulating intestinal motility, immune responses, and epithelial barrier function by releasing factors that influence neighboring cells in response to environmental changes. In Crohn’s disease, for example, a reduced glial network is correlated with impaired mucosal healing. Therefore, understanding the mechanisms that facilitate gut homeostasis of significant therapeutic importance, as defective mucosal repair can lead to fibrosis and increased risk of GI adenocarcinoma. To address the role of stress in colitis, a pre-cancer disease, we used a physical restraint model from our previous work, which induces a leaky gut phenotype in mice. In a dextran sodium sulfate (DSS)-induced colitis model, we further found that stress significantly delayed colitis healing, with the accumulation of p16+ senescent enteric glial cells (senEGCs). The senEGCs, which no longer proliferate but remain metabolically active, secrete a diverse array of cytokines, growth factors, and proteases, collectively known as the senescence-associated secretory phenotype (SASP), resulting in inhibiting intestinal organoid outgrowth. Remarkably, either pharmacological intervention with senolytics drug (dasatinib and quercetin) or genetic ablation of senescent cells in INK-ATTAC mice fully reverses stress-impaired colitis recovery. Colitis-associated cancer (CAC), a CRC subtype linked to IBD, carries a high mortality rate: within 30 years of disease onset, over 20% of IBD patients develop CAC, and more than half of these cases result in death. Inflammation also plays a role in the development of sporadic CRCs. In two established CAC models, we found restraint stress increased colorectal tumor number by two-fold relative to controls and enhanced tumor innervation. Given that perineural invasion is a strong and independent prognostic indicator in CRC, our findings provide new insights into the systemic influence of stress on CRC development and open avenues for novel therapeutic strategies to improve CRC treatment outcomes. Citation Format: Xiaoxiao Zhou, Chen Chen, Henry Choi, Jihan Liu, Steven Chi, Ngoc Tran, Matthew Ciorba, Sheila A. Stewart, Xue-Yan He. The neural bridge: Stress-remodeled enteric nervous system (ENS) in the colitis-cancer transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4080.