Elucidating the pathological translocation mechanism(s) of a commensal bacterium in autoimmune liver disease

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Project summary The resident gut microbiota and the host immune system have co-evolved for millennia. However, modern societal conditions have disturbed this co-evolution and this has coincided with a steep rise in immune-mediated diseases. Bacterial translocation across the intestinal barrier and into extraintestinal organs such as the liver can have major pathological consequences. Translocation of the commensal bacterium, Enterococcus gallinarum, can trigger autoreactivity and chronic inflammation, contributing to autoimmune liver diseases such as autoimmune hepatitis and primary sclerosing cholangitis. However, it is unknown how E. gallinarum in particular is able to translocate across the epithelium and persist in normally sterile tissues such as the liver. Understanding the exact mechanism(s) that enable E. gallinarum to cross the intestinal barrier could lead to the development of novel therapeutic strategies to mitigate the initiation or progression of autoimmune liver disease. My preliminary results suggest that E. gallinarum rapidly acquires the ability to translocate within the intestine after monocolonization of germ-free mice. I hypothesize that spontaneous translocation of E. gallinarum to the liver occurs when it acquires the ability to circumvent the host immune response in a gut microbiota background. Here, I propose to: 1) test the hypothesis that E. gallinarum attains the capability to translocate by evading immune surveillance; and, 2) determine whether specific gut commensals can hinder E. gallinarum translocation via immunological priming. In the first aim, I will elucidate how E. gallinarum is able to evade host immune response using a newly developed technology to profile differential binding of E. gallinarum isolates to host extracellular proteins. In the second aim, I will perform in vivo colonization of E. gallinarum in the context of five unique healthy human gut microbiotas, and determine the variability in resident gut microbiota-mediated host immunological defense against E. gallinarum translocation. These studies will provide insight into the fundamental mechanisms by which commensal bacteria translocate across the intestinal barrier and induce liver autoimmunity. Thus, they may illuminate potential targets for novel therapeutic strategies for the treatment of chronic autoimmune liver diseases that have major social, emotional, and financial costs and for which there are currently no cures.