Abstract Background and aims The management of chronic visceral pain is still unsatisfying. Changes in gut microbiota-host interaction likely contribute to visceral hypersensitivity establishment after flares of inflammatory bowel diseases, including ulcerative colitis (UC), and persists during remission. Indeed, preclinical studies demonstrated that visceral sensitivity is closely related to gut microbiota activity which, through the regulation of colon epithelium function and immune response, participates in enteric neuroplasticity. Based on this evidence, our project aims to identify new druggable targets starting from the mechanistic investigation of dysbiosis-related alterations of epithelium to neuron signalling in patients with quiescent UC and experiencing chronic abdominal pain. Methods Organoid-derived monolayers will be exposed to patient-derived faecal samples to reproduce dysbiosis-related insults to the epithelium in vitro. Samples from patients with quiescent UC without pain and patients with pain in the absence of organic gastrointestinal diseases, like those affected by irritable bowel syndrome (IBS), will be used as controls. The direct effect of epithelial injury on sensitivity will be investigated on dorsal root ganglia (DRG) organoids generated by human iPSCs, through advanced omics, histological and electrophysiological analysis. Functional alterations carried by the transfer of faecal supernatants from different patient groups will be further investigated in vivo. The acquired data will be integrated and used to identify new potential therapeutic targets and to set up a human in vitro model of disease for both the diagnosis and the drug screening. Anticipated impact Current microbiota-targeted therapies have limited success in reducing chronic visceral pain in patients with UC in remission, underlying the need to explore the entire microbiota–epithelium–neuronal axis as a therapeutic target: the prospect to restore gut homeostasis, by synergistically acting on microbiota and host, may lead to a paradigm shift in the management of pain in patients with UC.
Innocenti et al. (Thu,) studied this question.