Gut Microbes Secretions May Trigger Mononuclear Cell Migration and Offer Comorbidity Mechanism Between Inflammatory Bowel Disease and Diabetic Retinopathy.

Background: Researches have found that the gut microbiota stimulate inflammation by releasing proinflammatory chemicals, including bile acids (BAs) and L-kynurenine. In the present study, our purpose is to investigate the potential functional roles of gut microbes and their secretions in the comorbidity mechanism between inflammatory bowel disease (IBD) and diabetic retinopathy (DR). Methods: Specific existing gut microbes among IBD and diabetes mellitus (DM) patients were gained and analyzed to figure out the proinflammatory chemicals secreted by specific existent microbes. The expression data of peripheral blood mononuclear cells (PBMCs) were obtained and underwent differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA) to find out potential effects of microbes secretions on PBMCs. Single-cell analysis was conducted to elucidate the underlying cytological comorbidity mechanisms. Results: The results of the study showed that the secretions of abnormal gut microbes in IBD and DM patients, such as BAs and L-Kynurenine, can stimulate abnormal immune response. PBMCs can be activated, mobilized, and disrupt vascular endothelial barriers upon exposure to proinflammatory substances generated by Veillonella and Clostridium, the dysbiotic gut microbiota in IBD, which exacerbate retinal inflammation and worsening DR pathological conditions. Furthermore, genes related to PBMC migration, such as RSU1, FN1, and CD9, are activated in PBMCs after exposure to pro-inflammatory chemicals from abnormal gut microbes, offering a genetic comorbidity mechanism for IBD and DR. We also unraveled that IBD can promote the proliferation and activation of effector memory T (Tem) cells, which also showed elevation in DR patients, thereby providing a cellular basis for the comorbidity between IBD and DR. Conclusion: The aberrant gut bacteria in IBD patients might secrete proinflammatory substances, such as L-kynurenine and BAs, which may activate mononuclear cells, especially the Tem. The mononuclear cells subsequently migrated into the retina, exacerbating the situation of DR. This finding underscores the potential of comorbidity mechanism for better treatment of DR in the future.