Potential role of the ocular surface microbiome in dry eye: microbial interactions and symptom alleviation

Dry eye is a prevalent ocular disorder characterized by tear film instability, inflammation, and ocular discomfort. Although the ocular surface (OS) microbiome contributes to immune regulation and pathogen defense, its role in dry eye pathophysiology remains unclear. Therefore, the present study aimed to characterize alterations in the OS microbiome of patients with dry eye undergoing cyclosporin A or NewHyalUni treatment and to identify their potential roles related to clinical improvement. Patients with dry eye were treated with either cyclosporin A and NewHyalUni drop combination or NewHyalUni alone. OS samples were collected before and after treatment, and the microbiome was analyzed by whole metagenome sequencing. Potential contaminants were removed before downstream analysis to account for the low-biomass nature of OS samples. Clinical evaluations included symptom scores and the assessment of meibomian gland dysfunction (MGD). No significant differences in the overall microbial composition were observed between the treatment groups. Nevertheless, both groups demonstrated symptomatic improvement. OS microbiome alterations were strongly correlated with improvements in MGD scores. Moreover, microbial interactions were found to shift following treatment. Key species (<i>Staphylococcus epidermidis</i>, <i>Staphylococcus pseudintermedius</i>, <i>Streptomyces lividans,</i> and <i>Edwardsiella tarda</i>) were identified as potential mediators of MGD score improvement by modulating microbiome functions and suppressing inflammation-associated species. Although distinct treatment regimens did not lead to divergent microbiome profiles, symptomatic improvement was associated with alterations in a specific microbiome. These findings highlight the OS microbiome's potential role in dry eye and support the development of microbiome-based therapeutic strategies.IMPORTANCEDry eye is a common ocular disorder with complex pathophysiology that extends beyond tear deficiency and inflammation. Despite growing evidence of host-microbiome interactions at mucosal surfaces, the contribution of the ocular surface (OS) microbiome to dry eye remains poorly understood. Our findings in this study reveal that shifts in specific taxa and ecological interactions correlate with improvements in meibomian gland function and dry eye symptoms, even in the absence of major changes in overall microbiota. By identifying microbial signatures potentially linked to clinical improvement, we provide systems-level insight into the role of low-biomass microbiomes in ocular health. This work expands the current understanding of microbiome-host dynamics in non-gut environments and supports future development of microbiome-informed therapeutic strategies.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT06936462.