Gut mucosal barrier: the frontline of bidirectional regulation of the gut-X axis

While maintaining absorption and physiological exchange, the gut mucosal barrier prevents microorganisms and their products from freely entering tissues and blood vessels. Therefore, its functional state can affect signals transmitted to distal organs. This review defines the gut-X axis as bidirectional communication between the intestine and extraintestinal systems, and points the intestinal barrier as a selective gatekeeper that regulates thresholds and amplifies gut-derived information flow. We summarize barrier organization, the renewal and repair mechanism to maintain the epithelial integrity under persistent exposure. We then integrate factors shaping barrier steady state, including diet, microbial metabolites, host factors and drugs. Next, we explained how barrier-regulated signal outputs disseminate through immune inflammatory mediators, neural pathways and endocrine metabolic signals, and analyzed how reverse regulation by the brain, liver, lungs and systemic metabolic state reshapes barrier responses. In neuropsychiatric, hepatic, pulmonary, and endocrine metabolic diseases, we focus on the positive feedback cycle, heterogeneity, and the ambiguity in causal direction, and evaluate treatment strategies, covering dietary intervention, microbiota-directed therapies including fecal microbiota transplantation (FMT), and pharmacologic or immunologic methods. Progress will rely on standardized intestinal barrier indicators longitudinal research design to clarify temporal relationship, and hierarchical intervention tests to verify barrier-centered causal hypotheses.