Short‐Chain Fatty Acids: Microbial Metabolites Driving Gut‐Eye Axis Signaling

Abstract

ABSTRACT Short‐chain fatty acids (SCFAs) have emerged as key molecular mediators of gut–eye communication, linking microbial metabolism to ocular physiology and disease. Produced through microbial fermentation of dietary fiber, SCFAs function as systemic signaling molecules that regulate immune homeostasis, metabolic function, vascular integrity, and neuroinflammatory pathways through activation of SCFA‐responsive receptors and epigenetic mechanisms. Growing evidence indicates that SCFAs influence biological processes central to ocular health, including inflammation, oxidative stress, neurodegeneration, and pathological angiogenesis. Experimental, metabolomic, and emerging clinical studies suggest that disruptions in SCFA signaling may contribute to the pathogenesis of retinal and ocular surface diseases; however, the mechanisms governing ocular exposure, target engagement, and therapeutic efficacy remain incompletely understood, highlighting a critical gap between mechanistic insight and clinical translation. In this review, we integrate current evidence into a mechanistic and translational framework that positions SCFAs as central effectors of the gut–eye axis. We further evaluate the therapeutic potential of SCFA modulation and identify key barriers to clinical implementation, including bioavailability, pharmacokinetics, dosing, and long‐term safety, thereby delineating a roadmap for the development of microbiome‐derived precision therapeutics in ophthalmology.