Editorial: understanding IBS pathophysiology through “converging channels” of research

Although irritable bowel syndrome (IBS) is well recognised clinically by its prototypical abdominal pain and altered bowel habits, it remains incompletely understood from a pathophysiologic perspective. Visceral hypersensitivity was one of the earliest mechanistic factors to be associated with IBS symptoms. In 1972, Ritchie et al described the induction of abdominal pain using sigmoid colon balloon inflations as a means of distinguishing “irritable colon” patients from normal controls.1,2 At the same time, this study highlighted mechanistic heterogeneity inherent in IBS, as nearly one half of IBS subjects did not experience balloon distentionrelated visceral sensitivity. In the decades that followed, numerous other putative mechanisms have been elucidated, revealing IBS to be a complex, multifactorial condition. Such pathophysiologic factors have included alterations in mucosal barrier function, gut microbiota, immune activation and interactions of the enteric and central nervous systems (i.e., the “gutbrain axis”).3 Furthermore, a heritable component to IBS pathogenesis has been demonstrated in large, genomewide association studies, including functional variants involving ion channels, serotonin transport and disaccharidases.46 IBS patients often endorse food triggers of symptoms, and fatty meals have been shown to induce IBS symptoms and visceral hypersensitivity.7 Yet, despite such advances in our understanding of IBS pathogenesis, all of these mechanistic observations are probably only relevant to a portion of IBS patients. Most studies simplistically focus on a single pathophysiologic factor or pathway, without accounting for other relevant observations or interaction of factors, as suggested by the biopsychosocial framework.8 Grover et al have taken a deeper dive into IBS pathophysiology, seeking to build a more sophisticated understanding of highfat meal effects in IBS.9 Several parallel lines of investigation were pursued in IBS subjects and healthy controls, including clinical measures (lipid infusionrelated abdominal symptoms and rectal sensitivity), physiologic assessments of mucosal integrity (saccharide excretion assays and probebased confocal laser endomicroscopy [pCLE]) and transcriptomics (differential candidate gene expression in small bowel biopsies). As anticipated, IBS patients exhibited greater rectal sensitivity, and intraluminal lipid infusioninduced abdominal symptoms. The postlipid pCLE scores and intestinal permeability assays yielded negative results, without discernible differences between groups. The transcriptomic data were intriguing, finding upregulation of transient receptor potential vanilloid receptor 3 (TRPV3) in both IBS with constipation and IBS with diarrhoea (IBSD), and increased expression of TRPV1 and TRPM4 in IBSD. Perhaps most importantly, across all study subjects, duodenal TRPV1 and TRPV3 expression significantly correlated with postlipid abdominal pain severity and rectal sensation. These translational data thus expand upon recognised role of TRP channel functioning in visceral afferent signalling to include a possible chemoor mechanosensory role in postmeal IBS symptom experiences.9,10 On balance, the findings of this small study should be regarded as preliminary, and require further evaluation. Nevertheless, this investigation nicely highlights the potential of research expansion beyond a restricted focus on single mechanisms, to strategies that simultaneously examine IBS pathogenesis at multiple levels (e.g., clinical, environmental, physiologic and genetic). This pathophysiologic “convergence of channels” holds great promise to further our understanding of the mechanistic underpinnings of IBS.