The Gut Microbiota–Sex–Immunity Axis in Non-Communicable Diseases

Non-communicable diseases (NCDs), including cancer and autoimmune, metabolic, cardiovascular,\r\nand neurodegenerative diseases, represent the leading cause of death globally\r\nand a growing healthcare burden. The gut microbiota (GM) has been recognized as a\r\nkey biological component of host health that contributes to the maintenance of immune\r\nregulation, metabolic homeostasis, and epithelial barrier function. Several studies are now\r\ndemonstrating that biological sex has an influence on both GM composition and function,\r\nwhich might explain sex differences in disease predisposition, course, and treatment response.\r\nEvidence from both clinical and experimental studies indicates that sex hormones,\r\ngenetics, and lifestyle-related exposures interact with GM to influence the development\r\nand progression of most common NCDs. Some research suggests that estrogens promote\r\ndiversity in GM with anti-inflammatory immune responses, while androgens and maleabundant\r\ntaxa are associated with pro-inflammatory conditions. However, the evidence in\r\nhumans is largely confounded by other variables (such as age, genetics, and lifestyle) and\r\nshould be interpreted with caution. Unique GM metabolites, such as short-chain fatty acids\r\nand secondary bile acids, can have distinct, sex-specific effects on inflammation, metabolic\r\nregulation, and even antitumor immunity. While the existence of a sex–gut microbiota axis\r\nis gaining increased support, most studies in humans are cross-sectional epidemiological\r\nstudies with limited mechanistic evidence and little consideration for sex as a biological\r\nvariable. Future works should prioritize longitudinal, sex-stratified studies and utilize\r\nmulti-omics integrated approaches to identify causal pathways. Ultimately, integrating\r\nsex differences into GM-based approaches could provide new avenues for personalized\r\nstrategies for the prevention and treatment of NCDs.