Genetic and clinical evidence implicates a potential Parasutterella-sphingomyelin pathway in diabetic nephropathy

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.

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.

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.

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.