Gut Microbiota Plays an Essential Role in the Onset of Membranous Nephropathy: Evidence from Multi-Center Case-Control Study and Animal Model

Abstract OBJECTIVE: Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. Here we aim to establish a non-invasive diagnostic model using differential gut microbiome and to explore the relationship between gut microbiome and the pathogenesis of MN in animal experiment.DESIGN: A total of 825 fecal samples including MN patients and healthy controls (HC) were collected from Central, East and South China. We obtained crucial operational taxonomic units (OTUs) by 16S rRNA sequencing and then established a diagnostic model using five-fold cross-validation on random forest model. We subsequently validated its efficiency in cross regional cohort. MN rat model was induced by Sheep Anti-Rat Fx1A Serum and was used to explore the relationship between gut microbiome and the pathogenesis of MN.RESULTS: The diversity and richness of gut microbiome was significantly decreased in MN patients. The diagnostic model based on 7 operational OTUs achieved excellent efficiency with an area under curve (AUC) of 98.36% in training group. The different disease states and cross regional cohort validated high diagnostic efficiency. In rat model, urinary protein was significantly relieved by intestine cleaning, while increased again by fecal microbiome transplant (FMT). Interestingly, fecal microbiome from MN patients seems to play a protective role when compared with that from healthy people.CONCLUSION: Gut microbiome can be used as a non-invasive tool for MN diagnosis. The onset of MN depends partially on the existence of naturally colonized microbiome. Adaptive changes of gut microbiome during MN may help relieve urinary protein.