Microbiome-orchestrated cross-organ immunity in autoimmunity: from metabolites to therapeutic targets

Autoimmune diseases are systemic disorders in which barrier-site immune activation, especially in the gut, can reshape inflammatory programs in distant organs. This review advances a metabolite-centered, cross-organ framework for understanding how gut microbial ecology influences autoimmunity beyond individual gut-organ axes. We synthesize evidence that short-chain fatty acids, bile acid derivatives, tryptophan catabolites, polyamines and related microbial products act as mobile biochemical checkpoints linking intestinal barrier integrity, pattern-recognition signaling, immune-cell metabolism and tissue-specific inflammation in joints, kidneys, skin, lungs and the central nervous system. Across these axes, shared mechanisms include barrier failure, altered microbial metabolite pools, dysregulated MAMP sensing, trafficking or systemic conditioning of lymphoid and myeloid cells, and local stromal imprinting in target organs. We also discuss sex-dependent microbiome-immune interactions, including the microgenderome concept, as a framework for explaining why microbiome composition, hormone metabolism and immune responses may shape autoimmune risk and treatment response differently in females and males. Finally, we evaluate multi-omics, single-cell and spatial profiling, organ-on-chip platforms and causal computational tools, and we outline translational strategies ranging from diet, probiotics, fecal microbiota transplantation and engineered consortia to pharmacologic targeting of metabolite receptors. By treating microbial metabolites as actionable cross-organ immune checkpoints, this review highlights opportunities and limitations for biomarker-guided, metabolite-focused precision therapy in autoimmunity.