Gut microbiota-intestinal barrier crosstalk: mechanistic advances, disease relevance, and public health implications.

Background: The intestinal barrier is a critical interface between the host and the external environment, and growing evidence indicates that bidirectional crosstalk between the gut microbiota and the intestinal barrier is a key determinant of intestinal and systemic health. Disruption of this interaction has been implicated in the development of multiple chronic non-communicable diseases, including inflammatory, metabolic, neurodegenerative, and immune-mediated conditions. However, previous reviews have often examined gut microbiota or intestinal barrier dysfunction separately, with less emphasis on their bidirectional interaction as an integrated mechanistic and public health framework. Objective: This review aims to synthesize current mechanistic advances in gut microbiota-intestinal barrier crosstalk, evaluate its relevance across major disease domains, and examine its potential implications for chronic disease prevention and public health practice. In particular, this review highlights the gut microbiota-intestinal barrier axis as a unifying framework linking microbial metabolism, mucosal homeostasis, systemic inflammation, and prevention-oriented health strategies. Methods: We conducted a structured review of recent studies published between 2019 and 2025 in PubMed, Scopus, and Web of Science, with emphasis on both foundational and emerging evidence. The review focused on microbiota-derived metabolites, epithelial junction integrity, mucosal immune regulation, disease-associated barrier dysfunction, and microbiota-targeted interventions. Evidence from mechanistic, preclinical, and clinical studies was integrated to identify major advances, translational opportunities, and current limitations in the field. Results: Current evidence indicates that gut microbiota regulate intestinal barrier integrity through metabolites such as short-chain fatty acids (SCFAs), indole derivatives, and bile acids, which influence tight junction expression, mucin production, epithelial repair, and mucosal immune balance. Conversely, barrier dysfunction may promote microbial translocation, endotoxemia, and chronic low-grade inflammation, thereby contributing to diseases such as inflammatory bowel disease, type 2 diabetes, metabolic-associated fatty liver disease, and neurodegenerative or neuropsychiatric disorders. Microbiota-targeted interventions, including prebiotics, probiotics, dietary approaches, and fecal microbiota transplantation, have shown potential to restore barrier-related homeostasis. However, the current evidence remains constrained by heterogeneity in study design, incomplete causal validation, inconsistent clinical outcomes, and limited standardization of intervention strategies, all of which restrict clinical translation and large-scale public health implementation. Conclusion: The gut microbiota-intestinal barrier axis is an important determinant of health and disease and may represent a promising target for future prevention-oriented strategies. By integrating mechanistic evidence with disease relevance, translational limitations, and public health perspectives, this review provides a more coherent framework for understanding microbiota-barrier crosstalk. Future research should prioritize causal validation, standardized methodologies, and equitable implementation pathways to support the development of scalable preventive and therapeutic strategies.