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Principal Investigator: Marlies Meisel
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $422,344
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <1H-indole-3-methanol><2,3,7,8-Tetrachlorodibenzo-p-dioxin Receptors><3-hydroxymethylindole><AH Receptors><Affect><Agonist><Antibiotic Therapy><Antibiotic Treatment><Antigens><Aryl Hydrocarbon Receptor><Autoimmune Hepatitis><Autoimmune Status><Autoimmunity><Automobile Driving><Bacterial Translocation><Biologic Models><Biological Models><Body Tissues><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Body><Cell Communication and Signaling><Cell Protection><Cell Signaling><Cells><Chronic><Cirrhosis><Clonal Expansion><Clone Cells><Concanavalin A><Cytoprotection><Data><Dependence><Diet><Dioxin Receptors><Dioxygenases><Disease><Disorder><Dysfunction><Environmental Factor><Environmental Risk Factor><Epidemiology><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Fibrosis><Functional disorder><Gene Transcription><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic Transcription><Genetic propensity><Germ-Free><Health><Hematopoietic><Hepatic><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatic Tissue><Hepatic Transplantation><Hepatitis><Hepatocyte><Human><I3C><I3C cpd><IFN><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Interferon><Immunes><Immunity><Immunomodulation><Immunosuppressants><Immunosuppressive Agents><Immunosuppressive drug><Immunosuppressive treatment><Individual><Indole-3-Carbinol><Inherited Predisposition><Inherited Susceptibility><Injury to Liver><Interferon Gamma><Interferon Type II><Interferons><Intracellular Communication and Signaling><Knowledge><L reuteri><L-Tryptophan><L. reuteri><Lactobacillus><Lactobacillus reuteri><Levotryptophan><Link><Literature><Liver><Liver Cells><Liver Fibrosis><Liver Grafting><Liver Transplant><Liver diseases><Lupus><Mediating><Mice><Mice Mammals><Mission><Model System><Modeling><Modern Man><Murine><Mus><NIDDK><National Institute of Diabetes and Digestive and Kidney Diseases><Nuclear Translocator><Pathogenicity><Pathology><Patients><Physiopathology><Play><Polyaromatic Hydrocarbon Receptors><Production><Publishing><RNA Expression><Receptor Inhibition><Receptor Signaling><Refractory><Role><Severities><Signal Transduction><Signal Transduction Systems><Signaling><T cell differentiation><T8 Cells><T8 Lymphocytes><TC1 Cell><TCDD Receptors><Teff cell><Testing><Tet><Tetanus Helper Peptide><Therapeutic><Therapeutic Intervention><Tissues><Transcription><Tryptophan><Wild Type Mouse><Work><ahr ligand><aryl hydrocarbon receptor ligand><autoinflammatory><bacterial disease treatment><bacterial infectious disease treatment><biological signal transduction><cirrhotic><commensal bacteria><commensal bacterial species><cytoprotective><determine efficacy><dietary><diets><driving><effector T cell><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><end stage liver disease><end stage liver failure><environmental risk><epidemiologic><epidemiological><epigenetically><evaluate efficacy><examine efficacy><fibrotic liver><gene signatures><genetic etiology><genetic mechanism of disease><genetic signature><genetic vulnerability><genetically predisposed><hemopoietic><hepatic body system><hepatic damage><hepatic disease><hepatic fibrosis><hepatic inflammation><hepatic injury><hepatic organ system><hepatopathy><human disease><immune modulation><immune regulation><immune suppressive agent><immune suppressor><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive substance><immunosuppressor><improved><indole-3-methanol><inflamed liver><inhibitor><intervention therapy><lFN-Gamma><liver damage><liver disorder><liver inflammation><liver injury><liver transplantation><microbial consortia><microbial flora><microbiome><microbiota><microflora><multispecies consortia><pathophysiology><pre-clinical><preclinical><programs><public health relevance><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><systemic inflammation><systemic inflammatory response><wildtype mouse>