| Objective:IgA nephropathy is one of the most common kidney diseases causing endstage renal disease,whose pathogenesis is not quite clear.Previous studies have proved that the abnormal galactose-deficient IgA1(Gd-IgA1)can be produced after infection in the patients with IgA nephropathy.Gd-IgA1 will be deposited in the kidney tissue,activate the immune response,and cause inflammation and renal fibrosis,which may be an important pathogenesis of IgA nephropathy.The source of Gd-IgA1 is still controversial,but recent studies have suggested that the gut-associated lymphoid tissue and intestinal microbes may be closely related to its production.Gut microbiota participates in nutrient absorption,metabolism and resistance to pathogens.The intestinal flora restricts each other and maintains dynamic balance.The disturbance of the gut microbiota can lead to chronic kidney disease,diabetes,and autoimmune system diseases.At present,a small number of studies have indicated that IgA nephropathy may have gut microbiota dysbiosis,but whether the imbalance of flora is involved in the pathogenesis of IgA nephropathy is still unclear.Therefore,this study focused on the intestinal bacteria and explored whether gut microbiota dysbiosis was associated with IgA nephropathy.Besides,the efficacy and the mechanism of improving the structure of gut microbiota in IgA nephropathy were also evaluated in this study.Materials and Methods:35 patients with IgA nephropathy and 25 healthy control volunteers were enrolled,and a C57BL/6 mouse model of IgA nephropathy was also constructed in this study.The kinds of microbes on stool were analyzed by 16 S r RNA high-throughput sequencing to find the differential strain between IgA nephropathy and healthy control,which might be closely related to the severity and progression of IgA nephropathy.Afterwards,the probiotics including Bifidobacterium longum,Lactobacillus bulgaricus,and Streptococcus thermophilus were used to treat the mice with IgA nephropathy.The impact of the probiotics on the structure of the intestinal flora was assessed.The efficacy of the probiotics in the treatment of IgA nephropathy were also evaluated.In addition,we also constructed an IgA nephropathy model in NLRP3 gene knock-out mice,and used the same protocol to intervene,in an attempt to explain the relevant mechanism of the treatment with the probiotics.Finally,the short-chain fatty acids,the metabolites of the probiotics,were used to treat IgA nephropathy,in order to further clarify the specific molecular mechanism of the probiotics on kidney tissue.Results:The Alpha and Beta diversity of the gut microbiota in IgA nephropathy were significantly different from those of healthy controls,suggesting that patients with IgA nephropathy have obvious gut dysbiosis.The gut dysbiosis in IgA nephropathy was mainly manifested as the decreased abundance of Bifidobacterium and Prevotella 9 and the increased proportion of Bacteroides and Escherichia-Shigella.Among them,the proportion of Bifidobacterium was negatively correlated with the levels of proteinuria and hematuria,presenting that the decrease of Bifidobacterium may be closely related to the development and the severity of IgA nephropathy.Compared with the normal control,a greater change in the structure of gut microbiota was occurred in the IgA nephropathy mice.The main manifestations were that the probiotics,especially Lactobacillus and Bifidobacterium,were sharply reduced,while norank-f-Muribaculaceae,Prevotellaceae＿UCG-001,PrevotellaceaeNK3B31-group,and Helicobacter increased significantly.Although the differences in gut microbiota between human beings and mice could not be ignored,both of them had a significant decrease in the abundance of Bifidobacterium.Hence,we speculated that Bifidobacterium might be the key flora for the occurrence and development of IgA nephropathy.Interestingly,the structure of the gut microbiota was significantly improved in the IgA nephropathy mice treated by the probiotics,whose Bifidobacterium levels were markedly increased.Further experiments presented that both probiotics and NLRP3 gene knock-out could significantly reduce IgA complex deposition and mesangial hyperplasia,effectively decrease urine protein-creatinine ratio and blood creatinine concentration,obviously suppress the expression levels of Collagen1 and greatly lower the levels of pro-inflammatory factors such as TNF-α and IL-18.It should be noted that the effect of the probiotics and NLRP3 gene knock-out was equivalent.However,the treatment of the probiotics seemed to have no effect on NLRP3 gene knock-out mice with IgA nephropathy.The probiotics might improve the clinicopathological manifestations by inhibiting the NLRP3/ASC/Caspase 1 signaling pathway since the protein and/or m RNA levels of NLRP3,ASC,Caspase 1,IL-1β and IL-18 could be decreased by the treatment of the probiotics.In order to further verify how the probiotics colonizing the intestines played a role in the kidney tissue,we used the short-chain fatty acids(sodium acetate and sodium propionate)to treat the IgA nephropathy mice.Sodium acetate and sodium propionate could improve the clinicopathological symptoms of IgA by inhibiting the NLRP3/ASC/Caspase 1 signaling pathway,whose effect was similar to those of the probiotics.Therefore,we speculated that the probiotics might act on renal tissue through the systemic circulation of the short-chain fatty acids and then play a significant role in renal protection.Conclusion:There was a significant gut microbiota dysbiosis in IgA nephropathy,mainly manifested as a significant decrease in the abundance of Bifidobacterium.The reduction of Bifidobacterium was strongly correlated with the severity of IgA nephropathy.Supplementing the probiotics could markedly improve the gut dysbiosis in IgA nephropathy.Moreover,the probiotics might attenuate the clinicopathological manifestations by inhibiting the NLRP3/ASC/Caspase 1signaling pathway in IgA nephropathy,which might be caused by its metabolite short-chain fatty acid that acted on the kidney tissue through the systemic circulation. |
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