Grant: Foundation Grant

<html> <body> <p>The overarching concept of this proposal is that the intestinal microbiota contributes to disease expression in subsets of patients with Irritable Bowel Syndrome (IBS) and patients with depression and anxiety that either co-exists with IBS, or that exist independently as primary mood disorders. It is based on differences in microbiota composition in a subset of IBS patients, and on preliminary data showing (a) differences in the microbiota composition of treatment-na&iuml;ve patients with primary depression or anxiety; (b) that both intestinal dysfunction and behavioral changes can be induced in gnotobiotic mice by colonization with microbiota from patients with IBS and co-morbid anxiety; (c) that probiotic bacteria improve depression and alter brain activity in humans.</p> <p>We will address the following broad questions:<br> </p> <ul> <li>Can we identify microbiota profiles that correlate with symptom expression in patients with IBS, depression or anxiety?</li> <li>Does the microbiota from these patients have functional impact on gut and/or brain?</li> <li>What are the metabolic and immunological pathways that mediate effects of microbiota on host?</li> </ul> <p>We will address these questions by:<br> </p> <ul> <li>Correlating metabolomic, immunologic and microbial profiles with symptom expression in these patients.</li> <li>Examining gut and brain function in gnotobiotic mice colonized with microbiota from patients with IBS or primary mood disorder and controls, and exploring underlying metabolic and immunological mechanisms.</li> </ul> <p>These approaches will (i) investigate molecules or microbiota profiles that identify patient subgroups that may benefit from microbiota-directed therapies and (ii) inform the development of second-generation human-derived probiotics.<br> The Farncombe Institute provides expertise in assessment of intestinal function, behavior and brain chemistry in mice and access to a large registry of IBS patients. Our unique axenic-gnotobiotic unit (AGU) and a center for molecular and culture-based microbiota profiling enable the proposed animal studies. Collaboration with Psychiatry provides well phenotyped patients with anxiety and mood disorders. Existing collaborative expertise in immunology and metabolomics is reflected in our preliminary data.</p> <p>IBS is often diagnosed by the costly exclusion of other diseases and current therapies have limited efficacy. We address these issues by identifying molecules or microbial profiles that will lead to the development of clinically useful biomarkers, enabling stratification of patients who will benefit from microbial therapies. The development of next generation probiotics will occur with established partners in the private sector. Antidepressants provide only modest benefit in patients with mild to moderate depression, suggesting a role for other therapies such as probiotics (shown in our pilot study to be beneficial against depression). The development of biomarkers to stratify patients for microbial directed therapy is therefore relevant.</p> <p>The program identifies five inderdisciplinary themes as training vehicles for students and fellows. Our AGU will generate HQP with a unique experience that will be in demand as other institutions build similar units. McMaster's new Biomedical Discovery and Commercialization Program enables us to recruit trainees interested in private sector careers to work on new biomarker and probiotic discovery. The Institute's endowed &ldquo;junior chair" program facilitates the transition of our best academically oriented trainees into faculty positions.<br> </p> </body> </html>