The integrative role of the microbiome in systemic immuno-inflammatory aberrations

The human immune system maintains a delicate balance between protective immunity and self-tolerance. Disruption of this equilibrium leads to immune-mediated diseases (IMDs), a heterogeneous group of disorders including autoimmune, allergy, and autoinflammatory conditions [examples include familial Mediterranean fever (FMF) and cryopyrin-associated periodic syndromes (CAPS)]. Traditionally viewed as organ-specific pathologies, IMDs are now recognized as systemic disorders driven by chronic, self-sustaining low-grade inflammation. The microbiome, a key regulator of immune development and barrier function, acts as a central driver of this systemic inflammatory circuit. Dysbiosis impairs epithelial integrity, promotes microbial translocation, and triggers aberrant activation of pattern-recognition receptors, inflammasomes, and inflammatory signaling pathways. It skews cytokine networks toward pro-inflammatory phenotypes and disrupts the differentiation and function of critical immune cell populations, establishing a vicious cycle that propagates systemic inflammation and multi-organ comorbidities via gut-skin, gut-joint, and gut-lung axes. This review summarizes the roles of microbiome dysbiosis in IMD pathogenesis, highlights related biomarkers, and evaluates emerging therapeutic strategies targeting the host-microbiota axis. We advocate a systems immunology paradigm that integrates the microbiome as a core therapeutic target to restore immune homeostasis, achieve durable remission, and reduce the systemic comorbidity burden in patients with IMDs.