The exposome-autoimmunity axis: environmental xenobiotics, gut dysbiosis, and potential pathways to immunosenescence

The escalating incidence of autoimmune diseases cannot be fully explained by genetics alone. It is increasingly linked to the exposome-the cumulative burden of lifelong environmental exposures. This review examines how pollutants (particulate matter, microplastics, agrochemicals, heavy metals) reshape the gut microbiota-immune axis and disrupt intestinal homeostasis. This triggers profound dysbiosis, characterized by reduced commensal diversity and expanded pathobionts. We highlight three mechanisms driving pollution-induced immune reprogramming: (i) barrier compromise facilitating metabolic endotoxemia; (ii) toxic Aryl Hydrocarbon Receptor (AhR) overactivation skewing the Th17/Treg balance; and (iii) epigenetic modifications like aberrant DNA methylation. Chronic environmental exposure accelerates telomere attrition, inducing premature immunosenescence and inflammaging. This promotes the pathological accumulation of senescent T cells and Age-associated B Cells (ABCs), linking environmental stress to tissue damage and autoantibody generation. However, a major limitation of the current literature is that many in vivo and in vitro models employ supraphysiological concentrations of pollutants that do not reflect actual human exposure scenarios. Without evaluating these specific exposure scenarios against realistic human gut concentrations, it is difficult to determine under which exact conditions the postulated dysbiotic effects occur. Ultimately, mitigating environmental risks and employing microbiota-targeted therapeutics are vital to restore barrier integrity.