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