Gut microbiota related steroid hormone biosynthesis provide novel insights into high-salt diet related renal injury vit gut-kidney axis

High-salt diet (HSD) is a major risk factor for renal injury, and gut microbiota may play a role in this process. In this study, we investigated the potential role of gut microbiota in HSD-related renal injury and the microbial mechanisms involved. Through function observation, mechanism screening, and further verification using transcriptomic and metabolomic profiling and bioinformatics, we found that HSD caused renal dysfunction, inflammation, hypoimmunity, and serious renal damage in conventional mice, but this effect was absent in germ-free (GF) mice. Differential gene set enrichment analyses of the gut and kidney identified the steroid hormone biosynthesis pathway as a main culprit. For further verification, differential metabolite set enrichment analyses of feces indicated the involvement of the steroid hormone biosynthesis pathway. Through comprehensive profiling of intestinal and renal tissues along with fecal samples, we detected three genes and two metabolites showing prominent enrichment in the steroid hormone biosynthesis pathway. RT-qPCR suggested that the core gene Cyp1a1, which depends on the interplay between HSD and gut microbiota, was inhibited in both the gut and kidney in HSD-related renal injury. Finally, dehydroepiandrosterone decreased the mRNA expression of Cyp1a1 in the gut and kidney. The data suggest that HSD promotes renal injury by manipulating the gut-kidney axis via gut microbiota and strengthening the steroid hormone biosynthesis pathway. The study expands the current knowledge on the gut microbial control of the gut-kidney axis in HSD-related renal injury, which finally provides novel insights into the therapeutic strategies for preventing or attenuating HSD-related kidney diseases.