Hydrangea paniculata coumarins attenuate experimental membranous nephritis by bidirectional interaction with gut microbiota

public description: Chronic kidney disease (CKD) is associated with gut dysbiosis. Total coumarins isolated from Hydrangea paniculata (HP) have renal protective effect in experimental membranous nephritis (MN) but mechanisms are still not clear. Currently, we try to investigate whether modulation of gut dysbiosis by HP contributes to its renal protection. Experimental MN rats were treated with HP for six weeks. Fecal 16s rDNA sequencing and metabolomics were examined. Fecal microbiota transplantation (FMT) and pseudo germ-free animals were used for evaluation study. Results demonstrated that deteriorated renal function and gut dysbiosis had been found in MN rats, characterized by higher Firmicutes/Bacteroidetes ratio, and reduced diversity and richness, but both reversed by HP treatment. Improvement of gut dysbiosis was correlated with higher colonic integrity and lower endotoxemia in HP-treated rats. HP normalized the abnormal fecal metabolites by increasing short-chain fatty acid production and reducing uremic toxin precursors. FMT from HP-treated rats to MN animals moderately reduced endotoxia and albuminuria. Moreover, major coumarins in HP only could be biotransformed into more bioactive 7-hydroxycoumarin by gut microbiota, which strengthened HP effect in vivo. Depletion of gut microbiota partially abolished the HP renal protective effect. In conclusion, bidirectional interaction between HP and gut microbiota contributes its renal beneficial effect.