UCSF

Despite centuries of research, the etiology of Ulcerative Colitis (UC; a chronic form of colonic inflammation) remains a mystery. As such, diagnosis is difficult, relying on clinical manifestations and resulting in an incredibly heterogeneous patient population. Furthermore, no cure (save colectomy) is available for UC, leading to a lifetime of therapies (many having variable efficacy; a consequence of UC patient heterogeneity). As UC prevalence rises, substantial need for enhanced therapies exists.

The gastrointestinal microbiome represents a promising avenue for improved treatment practices for UC. Being a diverse microbial community with substantial metabolic activity, opportunity exists for commensal microbes to influence host health, specifically the immune system. Indeed, several common colonizers of the mammalian gut regulate specific aspects of host immunity relevant to UC (such as Th17 and regulatory T-cell abundance, lymphocyte recruitment, and epithelial barrier function) through production of immunomodulatory metabolites. While UC was originally described as non-infectious diarrhea, studies demonstrating the potential efficacy of microbe-based treatments (i.e., probiotics) and the impact of microbes on animal models of UC suggest the microbiome contributes in a non-classical form of pathogenesis. Building on this, independent researchers found the gastrointestinal microbiome of UC patients to be less diverse and more compositionally variable compared to healthy people. Though these findings implicate the gastrointestinal microbiome in UC, questions remain regarding the therapeutic potential of gut microbes to improve patient outcomes.

This thesis addresses the clinical utility of the gastrointestinal microbiome in improving UC treatment. The therapeutic potential of microbiome manipulation was demonstrated using a murine model of UC and indicated gastrointestinal niches upstream of the colon harbor microbial activity associated with both disease induction and remission, suggesting patients might benefit from remodeling of microbial communities throughout the intestines. Additionally, a human study was conducted to demonstrate the utility of the microbiome with respect to improved stratification of UC patients. This work indicated discrete microbial states exist within the UC population, associate with symptom severity, and, via unique metabolic programming, differentially regulate T-cell activity. Together, this work highlights the microbiome as a resource for the development of both novel therapies and personalized treatment regimens for UC.