Restorative Effects of Short-Chain Fatty Acids on Corneal Homeostasis Disrupted by Antibiotic-Induced Gut Dysbiosis

The gut microbiota plays a crucial regulatory role in various physiological processes, yet its impact on corneal homeostasis remains insufficiently understood. Here, we investigate the effects of antibiotic-induced gut dysbiosis (AIGD) and germ-free (GF) conditions on circadian gene expression, barrier integrity, nerve density, and immune cell activity in the corneas of mice. Through RNA sequencing, we found that both AIGD and GF conditions significantly disrupted the overall transcriptomic profile and circadian transcriptomic oscillations in the cornea. These molecular disturbances were accompanied by a reduction in corneal epithelial thickness, nerve density, corneal sensitivity, and compromised barrier function. Notably, supplementation with short-chain fatty acids (SCFAs) significantly restored corneal integrity in AIGD mice. Further single-cell sequencing revealed that SCFA receptors GPR109A (Hcar2), olfactory receptor 78 (Olfr78), and GPR43 (Ffar2) are expressed in corneal epithelial basal cells, embryonically derived macrophages, perivascular cells, and γδ - T cells, respectively. In conclusion, this study demonstrates that the gut microbiota plays a critical role in corneal physiology by regulating circadian gene expression and maintaining barrier function. These findings enhance our understanding of the gut-eye axis, highlighting the cornea as a target for microbiota-derived metabolic signals and underscoring the potential therapeutic value of SCFAs in treating corneal dysfunction.