The gut microbiome in autoimmune disease: mechanisms, interactions, and therapeutic potential

Autoimmune diseases arise from loss of immunological tolerance through interactions among genetic susceptibility, environmental exposures, immune-regulatory defects, and microbial factors. The intestinal microbiome contributes to immune maturation, epithelial-barrier integrity, microbial-metabolite production, and regulation of the Treg/Th17 balance. However, the clinical significance of disease-associated dysbiosis remains uncertain because most human studies are cross-sectional, incompletely control major host variables, and identify microbial signatures that are not consistently reproduced across populations. Evidence from germ-free, gnotobiotic, microbiota-transfer, and other mechanistic models shows that microorganisms and their products can alter barrier integrity, antigen exposure, inflammatory signaling, and autoimmune phenotypes, whereas human studies mainly support associations rather than causality. Functional disturbances involving microbial metabolism and host immune signaling appear more reproducible than universal disease-associated taxa. Host genetics, diet, medications, age, geography, and disease activity further shape microbiome profiles and complicate interpretation. Microbiome-modulation strategies include dietary interventions, probiotics, synbiotics, fecal microbiota transplantation, postbiotics, defined microbial products, and engineered live biotherapeutics. Early human studies report changes in selected microbial, inflammatory, or clinical measures, but current evidence does not establish prevention or durable disease modification and does not support replacing approved treatments. This review critically integrates human and experimental evidence while distinguishing association, mechanism, and causality. Future translation requires longitudinal cohorts, standardized sampling and analysis, externally validated biomarkers, and adequately powered product-specific clinical trials with clinically meaningful endpoints.