University of Toronto study links immune cells to chronic pain in ulcerative colitis

Researchers at the University of Toronto and collaborators reported that immune cells in the gut can transform pain‑sensing neurons, causing chronic abdominal pain in ulcerative colitis even when inflammation is medically controlled. The findings, published in Nature Medicine on Oct. 25, stem from experiments on mice and analysis of human colon tissue from patients in remission. Lead author Dr. Maya Patel said the study shows a direct link between gut‑resident macrophages and heightened neuronal excitability.

Pain is a major unmet need in inflammatory bowel disease (IBD). More than half of ulcerative colitis patients continue to experience severe abdominal discomfort despite achieving endoscopic remission with biologics or steroids. Current therapies target the immune cascade that drives inflammation but do not address the nervous system’s role in symptom persistence. Clinicians have long suspected that a “pain‑memory” may linger after the gut heals, but the mechanisms have remained unclear. The new work provides a biological explanation for why patients can feel pain even when standard markers show the disease is quiescent.

In mouse models, the team depleted a subset of intestinal macrophages and observed a 70 % drop in neuronal firing rates measured by calcium imaging. Human biopsies revealed that macrophages in remission tissue released high levels of interleukin‑1β and tumor necrosis factor‑α, which bound to receptors on sensory neurons and up‑regulated the ion channel TRPV1, a known mediator of heat and chemical pain. Patients whose samples showed the strongest cytokine signature reported the highest pain scores on the validated IBD‑Pain Index. “We are seeing a clear cytokine‑neuron crosstalk that sensitises the gut’s pain pathways,” Patel explained.

The discovery opens a path for new treatments that target the nervous system rather than just inflammation. Pharmaceutical companies are already testing TRPV1 antagonists and selective cytokine blockers in early‑phase trials for neuropathic pain, and researchers plan to evaluate these agents in ulcerative colitis patients with refractory pain. If successful, the approach could shift clinical practice toward combined anti‑inflammatory and neuromodulatory regimens, offering relief to the many who suffer from pain despite disease remission.