Abstract

Intermittent fasting (IF) has emerged as a promising immunometabolic intervention, yet its therapeutic value in Sjögren's syndrome (SS)–related dry eye remains unclear. In this study, IF robustly improved tear secretion and corneal integrity in SS mice and markedly reshaped the gut ecosystem. Integrated 16S rRNA sequencing and fecal metabolomics identified Akkermansia muciniphila and bile acids as key responders to IF, and oral supplementation with either Akkermansia or ursodeoxycholic acid effectively recapitulated IF's therapeutic benefits. Single-cell and bulk transcriptomic profiling, together with flow cytometry, revealed extensive remodeling of the lacrimal gland immune microenvironment, characterized by reduced pro-inflammatory Th17 infiltration and the emergence of anti-inflammatory CD8 + effector populations. These findings demonstrate that IF alleviates SS-related dry eye through coordinated regulation of gut microbiota, gut metabolism, and local autoimmune responses. By establishing a healthier gut milieu and rebalancing lacrimal gland immunity, IF represents a safe, system-level strategy with translational potential for long-term management of SS-associated dry eye.