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Background Mounting evidence indicates that the gut microbiome (GMB) plays an essential role in kidney stone (KS) formation. In this study, we conducted a systematic review and meta-analysis to compare the composition of gut microbiota in kidney stone patients and healthy individuals, and further understand the role of gut microbiota in nephrolithiasis. Results Six databases were searched to find taxonomy-based comparison studies on the GMB until September 2022. Meta-analyses were performed using RevMan 5.3 to estimate the overall relative abundance of gut microbiota in KS patients and healthy subjects. Eight studies were included with 356 nephrolithiasis patients and 347 healthy subjects. The meta-analysis suggested that KS patients had a higher abundance of Bacteroides (35.11% vs 21.25%, Z = 3.56, P = 0.0004) and Escherichia_Shigella (4.39% vs 1.78%, Z = 3.23, P = 0.001), and a lower abundance of Prevotella_9 (8.41% vs 10.65%, Z = 4.49, P < 0.00001). Qualitative analysis revealed that beta-diversity was different between the two groups (P < 0.05); Ten taxa (Bacteroides, Phascolarctobacterium, Faecalibacterium, Flavobacterium, Akkermansia, Lactobacillus, Escherichia coli, Rhodobacter and Gordonia) helped the detection of kidney stones (P < 0.05); Genes or protein families of the GMB involved in oxalate degradation, glycan synthesis, and energy metabolism were altered in patients (P < 0.05). Conclusions There is a characteristic gut microbiota dysbiosis in kidney stone patients. Individualized therapies like microbial supplementation, probiotic or synbiotic preparations and adjusted diet patterns based on individual gut microbial characteristics of patients may be more effective in preventing stone formation and recurrence.

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Rationale: The role of histone methylation modifications in renal disease, particularly in sepsis-induced acute kidney injury (AKI), remains unclear. This study aims to investigate the potential involvement of the histone methyltransferase zeste homolog 2 (EZH2) in sepsis-induced AKI and its impact on apoptosis and inflammation. Methods: We first examined the expression of EZH2 in the kidney of sepsis-induced AKI (LPS injection) mice and LPS-stimulated tubular epithelial cells. We next constructed the EZH2 knockout mice to further confirm the effects of EZH2 on apoptosis and inflammatory response in AKI. And the inflammatory level of epithelial cells can be reflected by detecting chemokines and the chemotaxis of macrophages. Subsequently, we constructed the EZH2 knocked-down cells again and performed Chromatin Immunoprecipitation sequencing to screen out the target genes regulated by EZH2 and the enrichment pathway. Then we confirmed the EZH2 target gene and its regulatory pathway in vivo and in vitro experiments. Experimental results were finally confirmed using another in vivo model of sepsis-induced AKI (cecal perforation ligation). Results: The study found that EZH2 was upregulated in sepsis-induced AKI and that silencing EZH2 could reduce renal tubular injury by decreasing apoptosis and inflammatory response of tubular epithelial cells. EZH2 knockout mice showed significantly reduced renal inflammation and macrophage infiltration. Chromatin immunoprecipitation sequencing and polymerase chain reaction identified Sox9 as a target of EZH2. EZH2 was found to be enriched on the promoter of Sox9. Silencing EZH2 resulted in a significant increase in the transcriptional level of Sox9 and activation of the Wnt/β-catenin signaling pathway. The study further reversed the effects of EZH2 silencing by silencing Sox9 or administering the Wnt/β-catenin inhibitor icg001. It was also found that Sox9 positively regulated the expression of β-catenin and its downstream pathway-related genes. Finally, the study showed that the EZH2 inhibitor 3-deazaneplanocin A significantly alleviated sepsis-induced AKI. Conclusion: Our results indicate that silencing EZH2 can protect renal function by relieving transcriptional inhibition of Sox9, activating the Wnt/β-catenin pathway, and attenuating tubular epithelial apoptosis and inflammatory response of the renal interstitium. These results highlight the potential therapeutic value of targeting EZH2 in sepsis-induced AKI.

Acute renal injury (AKI) is a complex clinical syndrome, involving a series of pathophysiological processes, in which inflammation plays a key role. Identification and verification of gene signatures associated with inflammatory onset and progression are imperative for understanding the molecular mechanisms involved in AKI pathogenesis. Non-coding RNAs (ncRNAs), involved in epigenetic modifications of inflammatory responses, are associated with the aberrant expression of inflammation-related genes in AKI. However, its regulatory role in gene expression involves precise transcriptional regulation mechanisms which have not been fully elucidated in the complex and volatile inflammatory response of AKI. In this study, we systematically review current research on the intrinsic molecular mechanisms of ncRNAs that regulate the inflammatory response in AKI. We aim to provide potential research directions and strategies for developing ncRNA-targeted gene therapies as an intervention for the inflammatory damage in AKI.