Longitudinal changes in the Gut Microbiota in Non-infectious Uveitis

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

ABSTRACT To date, the immunological mechanisms that underpin non-infectious uveitis (NIU) are not fully understood. The contribution of the gut microbiota and their metabolites to the development of autoimmune diseases is increasingly being recognized. Recent evidence suggests that alterations in the gut microbiota in certain systemic autoimmune diseases are associated with disease flares, and that restoration of altered microbiome composition occurs following treatment of the disease. Like systemic autoimmune diseases, the gut-eye axis has been implicated as an important factor in intraocular inflammation. However, comparatively less is known about the gut microbiota in the development of uveitis, and to date, longitudinal studies are lacking. We hypothesize that distinct alterations in the gut microbiota and metabolome will be observed with changes in disease activity in NIU. Thus, the overall goals of this study are to compare the gut microbiota and metabolome in patients with active posterior segment NIU with healthy controls (HC) and investigate the longitudinal changes in the gut microbiota composition and metabolome in patients with NIU to detect associations with disease activity and determine whether these alterations resolve following treatment. Specifically, the scientific aims of this proposal are the following: 1) Investigate how longitudinal differences in gut microbiota composition and diversity in NIU change with disease activity; 2) investigate longitudinal alternations in the fecal metabolome in NIU; and 3) utilize a machine-learning approach with predictive modelling to identify NIU patients responsive to treatment and those at risk of treatment failure. The successful completion of the proposed aims will lead to an improved understanding of the relationship between the gut microbiota and fecal metabolome in NIU and disease activity and inform precision medicine approaches to NIU. My overarching goal is to become an independent physician-scientist leading a translational research program focused on ocular inflammatory diseases. To facilitate my transition towards independence, I have together with my mentors developed a structured training plan which complement my scientific objectives. I will receive training through a combination of hands-on learning and didactics on the following objectives: 1) developing expertise in gut microbiome studies including study design and bioinformatics skills in the analysis of 16S rRNA and fecal metabolome data; 2) acquiring training in advanced biostatistics, integration of large data sets, and predictive modelling; and 3) cultivating the skills required to effectively direct an independent laboratory. I will benefit from the outstanding environment at the University of Michigan for early career physician-scientists and leverage the deep institutional expertise in microbiome and metabolomics studies to complete the proposed work.