Browsing by Author "Roth, Timothy Douglas"

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    Microbial dysbiosis alters serotonin signalling in a post-inflammatory murine model of visceral pain
    (2024-07-10) Roth, Timothy Douglas; Sharkey, Keith; Nasser, Yasmin; Altier, Christophe
    Inflammatory bowel disease (IBD) is a chronic disorder characterized by inflammation of the gastrointestinal tract, affecting a growing number of individuals worldwide. Despite achieving endoscopic remission, many IBD patients continue to experience visceral pain, suggesting underlying mechanisms beyond inflammation. One hypothesis implicates alterations in gut microbiota post-inflammation, leading to dysregulated serotonin (5-HT) signalling within the gut and heightened pain sensitivity. This thesis investigated this hypothesis using a mouse model of IBD in remission associated with visceral pain to explore changes in enterochromaffin cell populations, gene expression related to 5-HT synthesis, transport, and degradation, as well as 5-HT concentration and its metabolites. Additionally, fecal microbiota transplant (FMT) experiments were performed using stool from DSS-treated mice, alongside comparative analyses with germ-free (GF) mice, to delineate the impact of the microbiota on post-inflammatory pain in IBD and establish a baseline for gut microbiota effects on 5-HT signalling. High-performance liquid chromatography (HPLC) was utilized to assess 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) tissue concentrations, and enzyme-linked immunosorbent assay (ELISA) was employed to determine 5-HT release dynamics in the gut. Our findings revealed region-specific differences in 5-HT release in the terminal ileum, proximal colon, and distal colon, suggesting localized alterations in 5-HT signalling post-inflammation. Additionally, GF mice displayed distinct patterns of altered gene expression and 5-HT/5-HIAA concentration compared to conventionally colonized counterparts, underscoring the pivotal role of gut microbiota in modulating 5-HT metabolism and signalling. FMT experiments allowed us to assess the impact of dysbiotic microbiota on post-inflammatory pain. Surprisingly, we found no significant differences in gene expression between control and DSS-treated FMT groups, suggesting resilience of the host to changes in microbiota composition. However, we observed differences in 5-HT release dynamics between FMT groups, indicating potential microbiota-driven alterations in neuronal signalling pathways. Overall, we found alterations in 5-HT signalling in the recovery model of DSS-induced colitis. These findings enhance our understanding of the pathophysiology of IBD-related pain, highlighting the complex interplay between gut microbiota and 5-HT signalling after a period of intestinal inflammation.