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Irritable Bowel Syndrome (IBS) is the most common gastrointestinal disorder which affects approximately 4% of the population worldwide, according to the Rome IV criteria. It is characterized by abdominal pain and altered bowel movements in the absence of relevant structural abnormalities. The diagnosis of IBS is based on symptom profiles as no biomarkers exist to guide diagnosis or treatment stratification. Accumulating data suggests that altered gut microbiota and chronic low-grade inflammation play important roles in genesis of IBS. However, the mechanisms are unclear. My thesis first addresses the hypothesis that changes in fecal β-defensin secretion reflect compositional changes in the intestinal microbiota. This was driven by the understanding that compositional changes in the microbiota (“dysbiosis”) may play a role in the expression of IBS, and that a marker of these will identify those patients who might benefit from microbiota-directed therapies. I used a murine model in which I disrupted the microbiota using interventions relevant to the natural history of IBS i.e., antibiotics, stress, or dietary changes. I showed that experimentally induced compositional changes in the microbiota, with the exception of stress, altered the secretion of fecal β-defensin. My study indicates that monitoring fecal β-defensin over time identifies compositional changes in microbiota. I next investigated mechanisms and treatment options for a recently recognized variant of post-infectious IBS (PI-IBS) developed following antibiotic treatment in patients recovering from Clostridioides difficile infection (CDI). I refer to this variant as post-CDI gut dysfunction. I used a humanized mouse model in which germ-free mice were colonized with fecal microbiota from patients with post-CDI gut dysfunction, or age and sex matched healthy controls. I found that mice colonized with microbiota from a patient with severe slow transit constipation post-CDI reproduced the donor phenotype. Mice developed slow colonic transit due to macrophage mediated damage to the interstitial cells of Cajal (ICC) that maintain normal motility. These changes were reversed after fecal microbiota transplantation (FMT) from healthy donor mice thus confirming that the post-CDI gut dysfunction is microbiota driven. Similar results were obtained in a patient with slow transit constipation without a history of infection. My findings prompted me to next evaluate the therapeutic potential of microbiota-directed dietary therapies. I chose psyllium, the flavonoid quercetin, and pectin based on their demonstrated ability to alter microbiota composition. Psyllium and pectin each normalized colonic transit, and this was accompanied by an alteration in macrophages morphology, restoration of the disrupted ICC network and an increase in short chain fatty acids production. My results demonstrate the importance of a dysbiotic microbiota in this post infectious- IBS (PI-IBS) variant and, identify two potentially useful dietary based therapeutic approaches to improve gut dysfunction in these and similar patients. If findings from my thesis are confirmed in humans, it could offer novel approaches for identifying those IBS patients who might benefit from microbiota-directed therapeutics. / Thesis / Candidate in Philosophy

Inflammatory bowel disease (IBD) is a serious, complex disease that is challenging to treat effectively and affects over 5 million people globally. Current treatment goals for both subtypes of IBD, Ulcerative Colitis (UC) and Crohn Disease (CD), focus on attaining and maintaining remission through anti-inflammatory agents, immunomodulators, or biologics. In spite of these treatments, more than 25% of patients require devastating surgical removal of part of their colon due to severe inflammation. Recent advances in our understanding of serotonergic effects beyond the central nervous system (CNS) provide encouragement for IBD treatment. The newest member of serotonin receptor family, the 5-HT7 subtype, is involved in the release of pro-inflammatory cytokines following stimulation by serotonin in the gastrointestinal tract (GIT). Khan et al have shown that inflammation associated with the DSS and DNBS mouse models of IBD is significantly attenuated in knock-out mice lacking the 5-HT7 receptor or mice treated with 5-HT7 selective antagonists. Previously reported 5-HT7 receptor antagonists (e.g., SB-269970) readily crosses the blood brain barrier (BBB) and are therefore not good choices for IBD treatments. Our group has identified a novel series of arylpiperazinyl lactones with high affinity and excellent selectivity for the 5-HT7. The aim of this project is to design, synthesize, and characterize new gamma-butyrolactone-based 5-HT7 ligands with high affinity, good selectively, acceptable drug-like properties, with limited access to the CNS. A total of 18 compounds were successfully synthesized and evaluated as potential new lead compounds for the treatment of IBD. / Pharmaceutical Sciences