Abnormal metabolism of gut microbiota reveals the possible molecular mechanism of nephropathy induced by hyperuricemia

The progression of hyperuricemia disease is often accompanied by damage to renal function.However,there are few studies on hyperuricemia nephropathy,especially its association with intestinal flora.This study combines metabolomics and gut microbiota diversity analysis to explore metabolic changes using a rat model as well as the changes in intestinal flora composition.The results showed that amino acid metabolism was disturbed with serine,glutamate and glutamine being downregulated whilst glycine,hydroxyproline and alanine being upregulated.The combined glycine,serine and glutamate could predict hyperuricemia nephropathy with an area under the curve of 1.00.Imbalanced intestinal flora was also observed.Flavobacterium,Myroides,Corynebacterium,Alcaligenaceae,Oligella and other conditional pathogens increased significantly in the model group,while Blautia and Roseburia,the shortchain fatty acid producing bacteria,declined greatly.At phylum,family and genus levels,disordered nitrogen circulation in gut microbiota was detected.In the model group,the uric acid decomposition pathway was enhanced with reinforced urea liver-intestine circulation.The results implied that the intestinal flora play a vital role in the pathogenesis of hyperuricemia nephropathy.Hence,modulation of gut microbiota or targeting at metabolic enzymes,i.e.,urease,could assist the treatment and prevention of this disease.

Gut microbiota mediates the absorption of FLZ,a new drug for Parkinson’s disease treatment

The gut microbiota plays an important role in regulating the pharmacokinetics and pharmacodynamics of many drugs.FLZ,a novel squamosamide derivative,has been shown to have neuroprotective effects on experimental Parkinson’s disease(PD)models.FLZ is under phase I clinical trial now,while the underlying mechanisms contributing to the absorption of FLZ are still not fully elucidated.Due to the main metabolite of FLZ was abundant in feces but rare in urine and bile of mice,we focused on the gut microbiota to address how FLZ was metabolized and absorbed.In vitro studies revealed that FLZ could be exclusively metabolized to its major metabolite M1 by the lanosterol 14 alpha-demethylase(CYP51)in the gut microbiota,but was almost not metabolized by any other metabolism-related organs,such as liver,kidney,and small intestine.M1 was quickly absorbed into the blood and then remethylated to FLZ by catechol O-methyltransferase(COMT).Notably,dysbacteriosis reduced the therapeutic efficacy of FLZ on the PD mouse model by inhibiting its absorption.The results show that the gut microbiota mediate the absorption of FLZ through a FLZ-M1-FLZ circulation.Our research elucidates the vital role of the gut microbiota in the absorption of FLZ and provides a theoretical basis for clinical pharmacokinetic studies and clinical application of FLZ in the treatment of PD.