Altered Sigmoid Mucosal Innervation and Mast Cell Proximity to Sensory Nerve Fibers Are Associated With Symptom Severity in Patients With Irritable Bowel Syndrome

Background Peripheral neuronal pathways contribute to the pathophysiology of irritable bowel syndrome (IBS). Aims To use high‐resolution three‐dimensional (3D) imaging and computerized quantification to compare the density and proximity of distinct nerve fibers (NFs) to mast cells (MCs) in sigmoid mucosal biopsies from patients with constipation‐predominant IBS (IBS‐C), diarrhea‐predominant IBS (IBS‐D), and healthy controls (HCs). Methods Sigmoid biopsies from 23 IBS patients (10 IBS‐C [6 females]; 13 IBS‐D [7 females]) and 12 HCs (6 females) were processed, NFs and MCs were immunostained and 3D images were analyzed using Imaris software to quantify NF density and proximity to MCs. Data were correlated with the IBS Severity Scoring System (IBS‐SSS) and abdominal pain ratings. Results Compared to HCs, IBS patients had reduced densities of human peripheral choline acetyltransferase (hpChAT, p = 0.01) and calbindin (Calb, p = 0.08) NFs by 39% and 17%, respectively, with the most prominent reductions of 50% ( p = 0.004) and 26% ( p = 0.03) in IBS‐C. Vasoactive intestinal peptide (VIP) NF density was significantly higher in IBS‐D compared to IBS‐C ( p = 0.01). Other NF densities and MC count did not significantly differ between IBS and HCs. IBS‐SSS and abdominal pain scores were positively correlated with the proximity of MCs to SP ( p = 0.038) and Calb ( p = 0.047) NFs and negatively with the density of VIP ( p = 0.039) and NPY ( p = 0.005) NFs. Conclusions & Inferences In IBS, there are reduced densities of colonic enteric cholinergic and intrinsic primary afferent NFs. Correlations between abdominal pain severity and MC‐NF interactions in IBS patients suggest that altered neuroimmune signaling may contribute to IBS pathophysiology and represent a potential therapeutic target.