The Gut–Immune Axis in Type 1 Diabetes: Microbial Dysbiosis and Autoimmune β-Cell Destruction

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune condition primarily caused by the immune-mediated destruction of pancreatic β-cells, leading to absolute insulin deficiency. While genetic predisposition, particularly within the HLA region, plays a major role in T1D susceptibility, recent research highlights the significance of environmental factors especially gut microbiota in disease onset and progression. The gastrointestinal (GI) tract harbors a diverse microbial ecosystem that influences immune regulation, metabolic processes, and epithelial integrity. Alterations in gut microbiota, or dysbiosis, have been associated with increased intestinal permeability and systemic immune activation, contributing to insulitis and β-cell autoimmunity. Emerging studies, including findings from The Environmental Determinants of Diabetes in the Young (TEDDY) cohort, reveal distinct microbial signatures in children at risk for T1D, often years before clinical diagnosis. These changes are influenced by factors such as diet, antibiotic exposure, infections, and mode of birth. Moreover, interventions like prebiotics, probiotics, and dietary modulation have shown potential in restoring microbial balance and delaying autoimmune onset. Despite growing evidence linking gut health to T1D, challenges remain in distinguishing causal relationships from mere associations. Current and future research is focused on elucidating microbial mechanisms, identifying protective and pathogenic taxa, and designing early-life preventive strategies. This review underscores the complex interplay between gut microbiota and host immunity and suggests that gut-targeted interventions may serve as promising avenues for T1D prevention and management. Altered bacterial populations can weaken gut barrier integrity, allowing microbial and dietary antigens to cross into the bloodstream. This increased gut permeability promotes immune activation: innate immune cells (e.g., macrophages) respond to microbial components and release inflammatory signals, while adaptive immune cells (T cells) become dysregulated. Molecular mimicry (similarity between microbial proteins and pancreatic β-cell antigens) may further drive autoimmunity. Moreover, a depletion of short-chain fatty acid (SCFA) producing bacteria diminishes the induction of regulatory T cells (Tregs), reducing immune tolerance. Together, these mechanisms contribute to the activation and expansion of autoreactive T cells that target pancreatic β cells, leading to their destruction.