{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:08:15Z","timestamp":1784189295199,"version":"3.55.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The gut microbiota is closely associated with the onset and progression of diabetic nephropathy. We aimed to define metabolite mediators in this pathway and to validate their relevance in patient samples and podocyte models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed Mendelian randomization and colocalization analyses on 889 gut microbiota features and 1,400 metabolic biomarkers for diabetic nephropathy risk, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. Mediation analysis evaluated potential indirect microbiota effects through metabolites, and a multi-step genetic locus strategy was used to prioritize candidate variants. We then conducted plasma metabolomics in healthy controls, patients with diabetes mellitus without DN, and patients with biopsy-confirmed DN, assessed correlations with eGFR and creatinine, quantified total sphingomyelin, and performed sphingomyelin intervention in human podocytes under high-glucose conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>After excluding reverse causality, 25 species, 22 higher-level taxa, and 12 microbial metabolic pathways were associated with at least one diabetic nephropathy phenotype. Mediation analysis prioritized three candidate microbiota-metabolite-DN pathways, including a potential genus Parasutterella-sphingomyelin (d18:1\/24:1, d18:2\/24:0)-DN pathway. Colocalization analysis provided exploratory support for a possible shared genetic signal in this candidate pathway. Seven candidate metabolites were detected in patient plasma, and exploratory group comparisons showed that SM (d18:1\/16:0) differed among groups. SM (d18:1\/16:0) was negatively correlated with eGFR and positively correlated with creatinine, and total sphingomyelin was markedly elevated and correlated with renal dysfunction. In podocytes, sphingomyelin treatment under high-glucose conditions aggravated injury-related, fibrotic\/extracellular matrix-related, and inflammatory-related changes, supporting a potential functional role of sphingomyelin dysregulation under DN-related injury conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This integrative analysis provides genetic evidence supporting potential links among gut microbiota, plasma metabolites, and DN. The results prioritize a potential Parasutterella-sphingomyelin-DN pathway, while exploratory clinical and experimental data support sphingomyelin dysregulation in DN, particularly under established renal injury or high-glucose conditions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1848678","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T07:49:30Z","timestamp":1784188170000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic and clinical evidence implicates a potential Parasutterella\u2013sphingomyelin pathway in diabetic nephropathy"],"prefix":"10.3389","volume":"17","author":[{"given":"Chunling","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Nephrology, Zhengzhou University People's Hospital, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Henan Provincial Clinical Research Center for Kidney Disease of Zhengzhou University People\u2019s Hospital, Henan Key Laboratory of Kidney Disease and Immunology of Zhengzhou University People\u2019s Hospital, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhengzhou University People's Hospital, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]},{"name":"Henan Provincial Clinical Research Center for Kidney Disease of Zhengzhou University People\u2019s Hospital, Henan Key Laboratory of Kidney Disease and Immunology of Zhengzhou University People\u2019s Hospital, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]},{"name":"Blood Purification Center, Zhengzhou University People's Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhengzhou University People's Hospital, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]},{"name":"Henan Provincial Clinical Research Center for Kidney Disease of Zhengzhou University People\u2019s Hospital, Henan Key Laboratory of Kidney Disease and Immunology of Zhengzhou University People\u2019s Hospital, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengmin","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhengzhou University People's Hospital, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]},{"name":"Henan Provincial Clinical Research Center for Kidney Disease of Zhengzhou University People\u2019s Hospital, Henan Key Laboratory of Kidney Disease and Immunology of Zhengzhou University People\u2019s Hospital, Henan Provincial People\u2019s Hospital","place":["Zhengzhou, China"]},{"name":"Blood Purification Center, Zhengzhou University People's Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1038\/ki.2012.440","article-title":"The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease","volume":"83","author":"Anders","year":"2013","journal-title":"Kidney Int."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1093\/ije\/dyr036","article-title":"Avoiding bias from weak instruments in Mendelian randomization studies","volume":"40","author":"Burgess","year":"2011","journal-title":"Int. J. Epidemiol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/s41588-022-01270-1","article-title":"Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases","volume":"55","author":"Chen","year":"2023","journal-title":"Nat. Genet."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"3988","DOI":"10.7150\/thno.84650","article-title":"Outer membrane vesicles derived from gut microbiota mediate tubulointerstitial inflammation: a potential new mechanism for diabetic kidney disease","volume":"13","author":"Chen","year":"2023","journal-title":"Theranostics"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1016\/j.kint.2023.03.033","article-title":"A central role for mesangial cells in the initiation of diabetic nephropathy","volume":"104","author":"Fang","year":"2023","journal-title":"Kidney Int."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"4961","DOI":"10.1007\/s00018-019-03155-9","article-title":"Microbiome-metabolomics reveals gut microbiota associated with glycine-conjugated metabolites and polyamine metabolism in chronic kidney disease","volume":"76","author":"Feng","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.2337\/dc18-2585","article-title":"Characterization of glycolytic enzymes and pyruvate kinase M2 in type 1 and 2 diabetic nephropathy","volume":"42","author":"Gordin","year":"2019","journal-title":"Diabetes Care"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"2057778","DOI":"10.1080\/19490976.2022.2057778","article-title":"A dietary carbohydrate \u2013 gut Parasutterella - human fatty acid biosynthesis metabolic axis in obesity and type 2 diabetes","volume":"14","author":"Henneke","year":"2022","journal-title":"Gut Microbes"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/j.matbio.2018.01.006","article-title":"Sphingolipid signaling in renal fibrosis","author":"Huwiler","year":"2018","journal-title":"Matrix Biol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1038\/s41396-019-0364-5","article-title":"Defining the role of Parasutterella, a previously uncharacterized member of the core gut microbiota","volume":"13","author":"Ju","year":"2019","journal-title":"ISME J."},{"key":"ref11","first-page":"1287","article-title":"Decreased plasma levels of select very long chain ceramide species are associated with the development of nephropathy in type 1 diabetes","volume-title":"Metabolism","author":"Klein","year":"2014"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s41588-020-00763-1","article-title":"Large-scale association analyses identify host factors influencing human gut microbiome composition","volume":"53","author":"Kurilshikov","year":"2021","journal-title":"Nat. Genet."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1681\/ASN.2021060843","article-title":"Intestinal bacterial translocation contributes to diabetic kidney disease","volume":"33","author":"Linh","year":"2022","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/s41588-021-00992-y","article-title":"Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch microbiome project","volume":"54","author":"Lopera-Maya","year":"2022","journal-title":"Nat. Genet."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1007\/s11306-011-0343-y","article-title":"Sphingomyelin is associated with kidney disease in type 1 diabetes (the FinnDiane study)","volume":"8","author":"M\u00e4kinen","year":"2012","journal-title":"Metabolomics"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/s41581-019-0172-1","article-title":"Intestinal microbiome and fitness in kidney disease","volume":"15","author":"Meijers","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"18439","DOI":"10.1073\/pnas.1005572107","article-title":"ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis","volume":"107","author":"Ohno","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e1002584","DOI":"10.1371\/journal.pgen.1002584","article-title":"Genome-wide association and functional follow-up reveals new loci for kidney function","volume":"8","author":"Pattaro","year":"2012","journal-title":"PLoS Genet."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"10023","DOI":"10.1038\/ncomms10023","article-title":"Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function","volume":"7","author":"Pattaro","year":"2016","journal-title":"Nat. Commun."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1847","DOI":"10.1007\/s00125-020-05201-9","article-title":"Sphingomyelin and progression of renal and coronary heart disease in individuals with type 1 diabetes","volume":"63","author":"Pongrac Barlovic","year":"2020","journal-title":"Diabetologia"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1038\/nm.4328","article-title":"Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction","volume":"23","author":"Qi","year":"2017","journal-title":"Nat. Med."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1038\/s41588-021-00991-z","article-title":"Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort","volume":"54","author":"Qin","year":"2022","journal-title":"Nat. Genet."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/nature11450","article-title":"A metagenome-wide association study of gut microbiota in type 2 diabetes","volume":"490","author":"Qin","year":"2012","journal-title":"Nature"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1016\/j.bbalip.2012.04.008","article-title":"A shift in sphingolipid composition from C24 to C16 increases susceptibility to apoptosis in HeLa cells","volume":"1821","author":"Sassa","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.1172\/JCI12849","article-title":"Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin","volume":"108","author":"Schwarz","year":"2001","journal-title":"J. Clin. Invest."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1016\/S0002-9440(10)61782-8","article-title":"Involvement of lipid rafts in nephrin phosphorylation and organization of the glomerular slit diaphragm","volume":"159","author":"Simons","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/35036052","article-title":"Lipid rafts and signal transduction","volume":"1","author":"Simons","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF diabetes atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"803","DOI":"10.2337\/db15-1313","article-title":"Genome-wide association studies identify genetic loci associated with albuminuria in diabetes","volume":"65","author":"Teumer","year":"2016","journal-title":"Diabetes"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"16398","DOI":"10.1038\/s41598-019-52916-w","article-title":"Lipidomic analysis reveals sphingomyelin and phosphatidylcholine species associated with renal impairment and all-cause mortality in type 1 diabetes","volume":"9","author":"Tofte","year":"2019","journal-title":"Sci. Rep."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"581","DOI":"10.4093\/dmj.2019.0063","article-title":"Inhibition of ceramide accumulation in podocytes by Myriocin prevents diabetic nephropathy","volume":"44","author":"Woo","year":"2020","journal-title":"Diabetes Metab. J."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"2473506","DOI":"10.1080\/19490976.2025.2473506","article-title":"Machine-learning assisted discovery unveils novel interplay between gut microbiota and host metabolic disturbance in diabetic kidney disease","volume":"17","author":"Wu","year":"2025","journal-title":"Gut Microbes"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"154712","DOI":"10.1016\/j.metabol.2021.154712","article-title":"Role of the gut microbiota in type 2 diabetes and related diseases","volume":"117","author":"Yang","year":"2021","journal-title":"Metabolism"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"889131","DOI":"10.3389\/fnut.2022.889131","article-title":"Reno-protective effect of low protein diet supplemented with \u03b1-Ketoacid through gut microbiota and fecal metabolism in 5\/6 Nephrectomized mice","volume":"9","author":"Zhu","year":"2022","journal-title":"Front. Nutr."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1848678\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T07:49:32Z","timestamp":1784188172000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1848678\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":35,"alternative-id":["10.3389\/fmicb.2026.1848678"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2026.1848678","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]},"article-number":"1848678"}}