Gut-ocular surface axis in dry eye disease: phenotype-specific mechanisms, evidence, and microbiome-targeted...

Dry eye disease is a multifactorial, heterogeneous ocular surface disorder characterized primarily by an imbalance in tear film homeostasis. The traditional classification into "aqueous deficiency" and "evaporative" types fails to fully account for the differences in its inflammatory biology, clinical manifestations, and treatment responses. In recent years, the gut microbiota has been implicated in influencing ocular surface homeostasis through immune-inflammatory, metabolic-barrier, and neuroimmune pathways; however, the magnitude of its effects and their biological significance may vary depending on the specific phenotype of dry eye disease (DED). This article reviews the current evidence regarding the gut-ocular surface axis in dry eye disease from a phenotype-specific perspective, categorizing it into direct clinical evidence, animal and mechanistic evidence, indirect and inferential evidence, and hypothesis-generating evidence based on the source and directness of the evidence. The existing evidence is primarily focused on Sjögren syndrome-associated and other immune-mediated forms of dry eye disease. Clinical microbiome studies, germ-free animal models, antibiotic-induced dysbiosis models, and patient-derived microbiota transplantation experiments all suggest that gut microbiota dysbiosis may contribute to systemic immune remodeling and lacrimal-ocular surface inflammatory responses. In contrast, for dry eye syndromes dominated by meibomian gland dysfunction or evaporative dry eye, as well as non-Sjögren aqueous-deficient dry eye, current evidence is primarily supported indirectly by studies on metabolic susceptibility, local microbiome, and animal mechanisms; whereas postoperative, environment-related, and symptom-sign incongruence types of dry eye are more often characterized by early clues or research hypotheses related to host inflammatory thresholds, ocular surface repair capacity, and neuroimmune regulation. Although microbiome-targeted interventions (including probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation) have demonstrated some translational potential, they remain limited by small sample sizes, high heterogeneity in study designs, short follow-up periods, and a lack of validation through phenotypic stratification. Future research should shift from general descriptions of microbial differences to stratified cohorts, causal validation, functional multi-omics analysis, and mechanism-driven intervention trials to clarify the true role of the gut microbiota in different DED phenotypes and to advance the development of precision adjunctive treatment strategies.