A231 THE MICROBIOTA-NOCICEPTORS-MICROGLIA AXIS CONTROLS THE DEVELOPMENT AND MAINTENANCE OF CHRONIC VISCERAL HYPERSENSITIVITY. (4th March 2021)

• Record Type: Journal Article
• Authors: Abdullah, N; Altier, C
• Is Part Of: Journal of the Canadian Association of Gastroenterology. Volume 4(2021)Supplement 1
• Page Start: 279
• Page End: 280
• Publication Date: 2021-03-04
• Subjects: Gastroenterology -- Periodicals; 616.33005
• DOI: 10.1093/jcag/gwab002.229
• Languages: English
• ISSNs: 2515-2084

Abstract

Abstract: Background: Pain is the most common cause of disability in inflammatory bowel disease (IBD). Current medical interventions control the debilitating clinical symptoms by reducing gastrointestinal (GI) inflammation. Despite successful treatment of active disease, abdominal pain persists during remission, suggesting a high level of plasticity in pain-sensing circuits (hyperalgesic priming) caused by inflammation. What drives this remodelling has remained elusive. We have identified microglia as active players of hyperalgesic priming in IBD. Furthermore, it was recently shown that commensal bacteria control the maturation of microglia in the CNS, suggesting that dysbiosis could influence visceral sensitivity through regulating colonic nociceptors-microglia interaction. Here we test the hypothesis that microbiome-nociceptors-microglia interactions control visceral sensitivity and pain in IBD. Aims: We investigated the role of the microbiota in the developmental regulation of colonic nociceptors that express the pain receptor TRPV1. We will identify the microbial factors that control neuron-microglia interactions during bacterial colonization and post-inflammatory dysbiosis. Methods: We have developed a germ-free TRPV1-GFP reporter mouse to be used for a combination of behavioural tests and phenotypic characterization of TRPV1+ nociceptors. RNA-sequencing of FACS isolated TRPV1+ neurons of germ-free mice will be used to identify genes that are under the control of the microbiota. We will restore discrepancies observed in germ-free mice by recolonization to assess the impact of the microbiota. Furthermore, we will investigate the regulation of Ahr in TRPV1+ neurons by the microbiota and the effect of its ligands on microglial activation and post-inflammatory visceral pain. Results: Measuring somatic pain sensation in naive germ-free and SPF mice, we showed a 15% reduction in thermal pain threshold, as measured by the Hargreaves test, and a 50% reduction in mechanical pain threshold, as measured by the Von Frey test, in germ-free mice. When looking at the dorsal root ganglia of germ-free and SPF mice, we saw a 15% increase in the percentage of neurons that were TRPV1-GFP positive in germ-free mice. Conclusions: Our results thus far highlight the importance of the microbiota in regulating the lineage of nociceptive neurons and the threshold of mechanical and thermal pain responses. These findings suggest a major contribution of the microbiota in shaping the neuro-immune axis, with major implications for visceral sensitization in the context of dysbiosis. My project will be looking further into the phenotype of nociceptors in germ-free mice and the effect of microbial-derived Ahr agonists on the maturation and function of colonic TRPV1+ nociceptors. My work will advance our understanding of mechanisms by which commensal bacteria regulate GI pain. Funding Agencies: CIHR