The Mechanistic Role of Gut Microbes and Gluten in Alopecia Areata - Project Summary Alopecia Areata (AA) is a chronic autoimmune disease of the hair follicle (HF) that results in hair loss. While the exact cause of AA is unknown, genetic predisposition and environmental triggers might play important roles in the disease. Recent studies suggest that dietary gluten, a known trigger in celiac disease (CD), may exacerbate autoimmune responses in AA, particularly in individuals with gluten sensitivity or CD. However, the precise role of gluten in the onset and progression of AA remains unknown. This project aims to fill this critical knowledge gap by investigating how dietary gluten, through its impact on the gut microbiome, influences autoimmune responses in AA. This research aligns with the mission of the NIAMS by contributing to a better understanding of immune-mediated diseases and informing the development of more effective and safer therapeutic strategies. The long-term goal of this study is to improve the management of AA by investigating how gluten consumption and the gut microbiome contribute to disease progression. The research aims to uncover the relationship between dietary gluten, gut dysbiosis, and immune system activation, potentially leading to novel, personalized interventions such as dietary modifications and microbiome-targeted therapies. The study focuses on two key objectives: Aim 1: Investigate how gluten-induced gut dysbiosis affects gut permeability and promotes immune activation, which drives AA. Aim 2: Explore how gluten metabolism by specific gut bacteria, such as Ligilactobacillus murinus (L. murinus), generates immunogenic peptides that activate CD8+ T cells, contributing to AA progression. This research will use well-established mouse models of AA to investigate gluten’s impact on gut health and immune function. The experimental approach includes: (1). Gut microbiome analysis: We will use 16S rRNA sequencing and shotgun metagenomics to profile gut microbiota changes in AA mouse models due to gluten consumption. (2). Gut permeability and immune activation: We will assess changes in gut permeability using FITC-dextran assays and examine pro-inflammatory cytokines and CD8+ T cell activation to link gut dysbiosis with immune responses in AA. (3). Bacterial gluten metabolism: We will investigate how L. murinus metabolizes gluten into immunogenic peptides, influencing AA progression. This research will address a critical gap by exploring the link between dietary gluten and autoimmune disease. If successful, it could lead to personalized dietary interventions and microbiome-based therapies, offering effective alternatives to immunosuppressive treatments and transforming the management of AA and other autoimmune conditions.
