Systemic immunoregulatory consequences of bacterial translocation during health and disease

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Autoimmune hepatitis (AIH) is a chronic, progressive, auto-inflammatory liver disorder that often becomes refractory to immunosuppressants-the sole therapeutic option for AIH patients. Hepatic inflammation, which sets the stage for overt AIH, is considered the main driver of hepatic tissue damage and fibrosis. While reversible, in the absence of treatment AIH progresses to cirrhosis and end stage liver disease, requiring liver transplantation in around 10% of cases. Its exact trigger and the underlying mechanisms by which AIH develops are poorly understood, although genetic and environmental factors play an important role. The local liver microbiome has been identified as one critical environmental factor that modulates hepatic pathology. The expansion of commensal bacteria such as Lactobacilli spp. within the liver is associated with an increased severity of experimental liver pathology, and Lactobacilli spp. are enriched in livers of AIH patients. Our lab recently published that Lactobacillus reuteri (L. reuteri) translocates to internal tissues and thereby drives systemic inflammation in mice that lack the epigenetic regulator Tet methylcytosine dioxygenase 2 (Tet2) in hematopoietic cells (Tet2VAV mice). We recently found that such mice have AIH and are a model system to study this disease, supported by epidemiological evidence that TET2 deficient individuals display cardinal features of liver disease. The pathogenetic mechanisms underlying AIH, and in particular how the liver microbiome may drive it, are unclear. Interferon- γ (IFN-γ) producing TCR CD8 T cells (Tc1 cells) have been identified to play an essential role in AIH. Missing is an understanding of the key signals from the liver microbiota and how they are linked to the induction of such pathogenic cells. Intriguingly, L. reuteri efficiently catabolizes dietary tryptophan (Trp) to the aryl hydrocarbon receptor (AhR) agonist indole-3-carbinol (I3C). In a lupus model, AhR ligands derived from E. gallinarum promoted Th17-driven autoimmunity. Here, based on our new data and this context from the literature, we propose a model and testable hypothesis explaining how L. reuteri promotes AIH. We will test our central hypothesis that L. reuteri promotes hepatic Tc1 cell immunity by releasing I3C and/or by fueling L. reuteri- specific Tc1 cells in two independent models of AIH (Tet2VAV mice and Concanavalin A-mediated hepatitis). Furthermore, we posit that therapeutic approaches that suppress AhR signaling protect from L. reuteri-triggered Tc1 cell mediated AIH-like pathology. We will investigate this hypothesis in three specific aims. In Aim 1 we will determine whether L. reuteri derived I3C acts directly on CD8 T cells via AhR, which promotes Tc1 cell effector function that drives AIH-like pathology. In Aim 2 we will define whether L. reuteri-specific CD8 T cells drive AIH- like disease. In Aim 3 we will define therapeutic approaches targeting AhR signaling within CD8 T cells (dietary Trp, AhR blockade) in protecting from AIH-like pathology. These aims will lead to a better understanding of the pathophysiology of AIH and assess rationale therapeutic interventions for patients with AIH.