{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:19:14Z","timestamp":1785424754432,"version":"3.56.0"},"reference-count":59,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jiangsu Province Science and Technology Department","award":["BE2023665"],"award-info":[{"award-number":["BE2023665"]}]},{"award":["BE2023665"],"award-info":[{"award-number":["BE2023665"]}],"id":[{"id":"https:\/\/ror.org\/02mkqta53","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetic retinopathy (DR) reflects retinal microvascular injury and systemic immune-metabolic stress, and most public DR transcriptomic datasets lack paired microbiome\/metabolomic profiles. We used gutMGene v2.0 as a curated microbe\/metabolite\u2013host gene prior and integrated it with peripheral blood transcriptomics from GSE221521. Candidate genes were refined by weighted gene co-expression network analysis (WGCNA), repeated resampling, cross-dataset assessment, mechanism scoring, peripheral blood mononuclear cell (PBMC) single-cell localization and filamin A (FLNA)-centered single-cell gene regulatory network (GRN) virtual knockout. The gutMGene prior contained 238 host genes; 15 DR-associated genes overlapped this prior, and WGCNA retained ten candidate gut microbe and microbial metabolite-related genes (GMMRGs): FLNA, AKT1, IRAK1, BCL10, CDK6, CTSD, JUP, CXCL1, CXCR2 and IL4R. Resampling prioritized FLNA as the most consistent candidate. Cross-dataset assessment localized the strongest signal to type 2 diabetes (T2D) PBMCs, retinal endothelial cells and advanced proliferative diabetic retinopathy with diabetic macular edema (PDR + DME) retinal tissue, with weaker separation in whole blood, broad retinal tissue and six-donor type 1 diabetes (T1D) PBMCs. FLNA virtual knockout predicted cell-context-dependent perturbation of immune-related transcriptional programs, including IL4R in DR B cells and CTSD in DR monocytes\/NK cells. This prior-guided study identifies FLNA within a ten-gene GMMRG set as a circulating host-response signal that links curated microbe\/metabolite\u2013host records to immune-vascular and cytoskeletal remodeling in DR.<\/jats:p>","DOI":"10.3390\/ijms27146182","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:16:28Z","timestamp":1783689388000},"page":"6182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GutMGene-Guided Peripheral Blood Transcriptomics Identifies an FLNA-Associated Host-Gene Signal in Diabetic Retinopathy"],"prefix":"10.3390","volume":"27","author":[{"given":"Chuanxue","family":"Ma","sequence":"first","affiliation":[{"name":"Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujun","family":"Wang","sequence":"additional","affiliation":[{"name":"Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[{"name":"Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16012","DOI":"10.1038\/nrdp.2016.12","article-title":"Diabetic retinopathy","volume":"2","author":"Wong","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1016\/j.ophtha.2021.04.027","article-title":"Global prevalence of diabetic retinopathy and projection of burden through 2045: Systematic review and meta-analysis","volume":"128","author":"Teo","year":"2021","journal-title":"Ophthalmology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105115","DOI":"10.1016\/j.phrs.2020.105115","article-title":"Regulation of blood-retinal barrier cell-junctions in diabetic retinopathy","volume":"161","author":"Rudraraju","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1111\/febs.16330","article-title":"The blood-retina barrier in health and disease","volume":"290","author":"Campbell","year":"2023","journal-title":"FEBS J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/S0140-6736(09)62124-3","article-title":"Diabetic retinopathy","volume":"376","author":"Cheung","year":"2010","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.preteyeres.2015.08.001","article-title":"The progress in understanding and treatment of diabetic retinopathy","volume":"51","author":"Stitt","year":"2016","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_7","first-page":"1183","article-title":"Diabetic retinopathy: Current understanding, mechanisms, and treatment strategies","volume":"127","author":"Duh","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Forrester, J.V., Kuffova, L., and Delibegovic, M. (2020). The role of inflammation in diabetic retinopathy. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.583687"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"976","DOI":"10.4103\/1673-5374.355743","article-title":"Inflammation in diabetic retinopathy: Possible roles in pathogenesis and potential implications for therapy","volume":"18","author":"Tang","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gomu\u0142ka, K., and Ruta, M. (2023). The role of inflammation and therapeutic concepts in diabetic retinopathy-a short review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021024"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"107505","DOI":"10.1016\/j.phrs.2024.107505","article-title":"Mechanism and therapeutic targets of circulating immune cells in diabetic retinopathy","volume":"210","author":"Zhao","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/s41392-023-01400-z","article-title":"Diabetic vascular diseases: Molecular mechanisms and therapeutic strategies","volume":"8","author":"Li","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111667","DOI":"10.1016\/j.diabres.2024.111667","article-title":"Circulating immune cell phenotyping is potentially relevant for diabetic retinopathy risk assessment","volume":"211","author":"Li","year":"2024","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Seo, H., Jung, Y., Lee, H., Kim, J., and Park, J. (2025). Diabetic retinopathy: Mechanisms, current therapies and emerging therapeutic approaches. Cells, 14.","DOI":"10.3390\/cells14050376"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41579-020-0438-4","article-title":"Gut microbial metabolites as multi-kingdom intermediates","volume":"19","author":"Krautkramer","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1136\/gutjnl-2020-323071","article-title":"Gut microbiota-derived metabolites as central regulators in metabolic disorders","volume":"70","author":"Agus","year":"2021","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.2337\/db18-0158","article-title":"Restructuring of the gut microbiome by intermittent fasting prevents retinopathy and prolongs survival in db\/db mice","volume":"67","author":"Beli","year":"2018","journal-title":"Diabetes"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"114994","DOI":"10.1016\/j.biopha.2023.114994","article-title":"Gut microbiota and metabolites in diabetic retinopathy: Insights into pathogenesis for novel therapeutic strategies","volume":"164","author":"Cai","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s00253-024-13316-x","article-title":"Gut microbiota predict retinopathy in patients with diabetes: A longitudinal cohort study","volume":"108","author":"Qin","year":"2024","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106590","DOI":"10.1016\/j.micpath.2024.106590","article-title":"Gut microbiome in diabetic retinopathy: A systematic review and meta-analysis","volume":"189","author":"Zhao","year":"2024","journal-title":"Microb. Pathog."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zhou, P., Hao, Z., Chen, Y., Zhang, Z., Xu, W., and Yu, J. (2024). Association between gut microbiota and diabetic microvascular complications: A two-sample Mendelian randomization study. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1364280"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1167\/iovs.66.6.23","article-title":"Short-chain fatty acids are potential biomarkers of immune regulation in diabetic retinopathy","volume":"66","author":"Qin","year":"2025","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hou, J., Lv, Z., Wang, Y., and Chen, D. (2025). The gut microbiota regulates diabetic retinopathy in adult rats. Front. Microbiol., 16.","DOI":"10.3389\/fmicb.2025.1479792"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1186\/s12967-023-04259-4","article-title":"Sodium butyrate ameliorates diabetic retinopathy in mice via the regulation of gut microbiota and related short-chain fatty acids","volume":"21","author":"Huang","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"144732","DOI":"10.1016\/j.ijbiomac.2025.144732","article-title":"Dendrobium nobile Lindl. polysaccharides ameliorate the inflammatory microenvironment in the retina of diabetic rats: A multi-omics study of the gut-blood-retina axis","volume":"316","author":"Wang","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ciurariu, E., Tirziu, A.T., Varga, N.I., Hirtie, B., Alexandru, A., Ivan, C.S., and Nicolescu, L. (2025). Short-chain fatty acids and the gut-retina connection: A systematic review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26062470"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D783","DOI":"10.1093\/nar\/gkae1002","article-title":"gutMGene v2.0: An updated comprehensive database for target genes of gut microbes and microbial metabolites","volume":"53","author":"Qi","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D795","DOI":"10.1093\/nar\/gkab786","article-title":"gutMGene: A comprehensive database for target genes of gut microbes and microbial metabolites","volume":"50","author":"Cheng","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1160\/TH14-04-0298","article-title":"The role of actin-binding proteins in the control of endothelial barrier integrity","volume":"113","author":"Schnoor","year":"2015","journal-title":"Thromb. Haemost."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1161\/CIRCRESAHA.116.306534","article-title":"Protein interactions at endothelial junctions and signaling mechanisms regulating endothelial permeability","volume":"120","author":"Komarova","year":"2017","journal-title":"Circ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10748","DOI":"10.1074\/jbc.M109.062984","article-title":"Filamin B plays a key role in vascular endothelial growth factor-induced endothelial cell motility through its interaction with Rac-1 and Vav-2","volume":"285","author":"Figueras","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.molmed.2020.11.006","article-title":"Permeability of the endothelial barrier: Identifying and reconciling controversies","volume":"27","author":"Dejana","year":"2021","journal-title":"Trends Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Bandaru, S., Ala, C., Zhou, A.X., and Aky\u00fcrek, L.M. (2021). Filamin A regulates cardiovascular remodeling. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126555"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1002\/jcp.22565","article-title":"R-Ras interacts with filamin A to maintain vascular\/barrier function","volume":"226","author":"Griffiths","year":"2011","journal-title":"J. Cell. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1042\/BCJ20240121","article-title":"Charting the importance of filamin A posttranslational modifications","volume":"481","author":"Shead","year":"2024","journal-title":"Biochem. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1038\/s41594-018-0128-3","article-title":"Structural basis of the filamin A actin-binding domain interaction with F-actin","volume":"25","author":"Iwamoto","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Xiang, Z.Y., Chen, S.L., Qin, X.R., Lin, S.L., Xu, Y., Lu, L.N., and Zou, H.D. (2023). Changes and related factors of blood CCN1 levels in diabetic patients. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1131993"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/s41422-020-0332-7","article-title":"Interaction between microbiota and immunity in health and disease","volume":"30","author":"Zheng","year":"2020","journal-title":"Cell Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1038\/s41423-021-00661-4","article-title":"Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases","volume":"18","author":"Yang","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nri.2016.42","article-title":"Gut microbiota, metabolites and host immunity","volume":"16","author":"Rooks","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Liu, X.-F., Shao, J.-H., Liao, Y.-T., Wang, L.-N., Jia, Y., Dong, P.-J., Liu, Z.-Z., He, D.-D., Li, C., and Zhang, X. (2023). Regulation of short-chain fatty acids in the immune system. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1186892"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2393270","DOI":"10.1080\/19490976.2024.2393270","article-title":"The interplay between gut microbiota, short-chain fatty acids, and implications for host health and disease","volume":"16","author":"Hays","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"230014","DOI":"10.1098\/rsob.230014","article-title":"Short chain fatty acids: Key regulators of the local and systemic immune response in inflammatory diseases and infections","volume":"13","author":"Ney","year":"2023","journal-title":"Open Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.tim.2021.02.001","article-title":"Microbial regulation of host physiology by short-chain fatty acids","volume":"29","author":"Wells","year":"2021","journal-title":"Trends Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s13098-024-01297-w","article-title":"Chemokines in diabetic eye disease","volume":"16","author":"Pan","year":"2024","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_46","first-page":"8914","article-title":"Transcriptomic profiling reveals chemokine CXCL1 as a potential mediator of blood-retinal barrier disruption in diabetic retinopathy","volume":"13","author":"Monickaraj","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1002\/JLB.3A0820-207R","article-title":"Neutrophil recruitment by chemokines Cxcl1\/KC and Cxcl2\/MIP2: Role of Cxcr2 activation and glycosaminoglycan interactions","volume":"109","author":"Sawant","year":"2021","journal-title":"J. Leukoc. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Casciano, F., Troiano, A., Iaculli, F., De Stefano, D., Mirra, S., and Ungaro, F. (2022). The role of the mTOR pathway in diabetic retinopathy. Front. Pharmacol., 13.","DOI":"10.3389\/fmed.2022.973856"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41392-021-00778-y","article-title":"Targeting lysosomes in human disease: From basic research to clinical applications","volume":"6","author":"Cao","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e23638","DOI":"10.1096\/fj.202400053R","article-title":"IL-10-induced modulation of macrophage polarization suppresses outer-blood-retinal barrier disruption in the streptozotocin-induced early diabetic retinopathy mouse model","volume":"38","author":"Lee","year":"2024","journal-title":"FASEB J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"109003","DOI":"10.1016\/j.isci.2024.109003","article-title":"A single cell atlas of circulating immune cells involved in diabetic retinopathy","volume":"27","author":"Liao","year":"2024","journal-title":"iScience"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: Archive for functional genomics data sets-update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Langfelder, P., and Horvath, S. (2008). WGCNA: An R package for weighted correlation network analysis. BMC Bioinform., 9.","DOI":"10.1186\/1471-2105-9-559"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v033.i01","article-title":"Regularization paths for generalized linear models via coordinate descent","volume":"33","author":"Friedman","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Robin, X., Turck, N., Hainard, A., Tiberti, N., Lisacek, F., Sanchez, J.C., and Muller, M. (2011). pROC: An open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-77"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e1301","DOI":"10.1002\/widm.1301","article-title":"Hyperparameters and tuning strategies for random forest","volume":"9","author":"Probst","year":"2019","journal-title":"Wiley Interdiscip. Rev. Data Min. Knowl. Discov."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"100434","DOI":"10.1016\/j.patter.2022.100434","article-title":"scTenifoldKnk: An efficient virtual knockout tool for gene function predictions via single-cell gene regulatory network perturbation","volume":"3","author":"Osorio","year":"2022","journal-title":"Patterns"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6182\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T04:14:12Z","timestamp":1784175252000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6182"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,10]]},"references-count":59,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146182"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146182","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,10]]}}}