Akkermansia muciniphila confers renal protection in chronic kidney disease: a multi-omics mechanistic investigation.

backgroundAkkermansia muciniphila (A. muciniphila) improved serum metabolism and renal fibrosis in the mouse model of chronic kidney disease (CKD) via the gut-kidney axis, slowing renal function decline. However, the biological components and underlying metabolic pathways remain unclear. Using a CKD mouse model, we aimed to identify the biological constituents of A. muciniphila that drive its regulatory effects in renal injury. Integrated microbiome and metabolomics analyses further elucidated the metabolic mechanisms of renoprotection, providing a theoretical foundation for the development of evidence-based clinical interventions.

methodsA CKD mouse model was established using 5/6 nephrectomy, with sham-operated mice (n = 7) serving as controls. Twenty-eight CKD mice were randomly assigned to four groups and treated with PBS, A. muciniphila, pasteurised A. muciniphila, or A. muciniphila combined with vancomycin by gavage. Serum and kidney tissues were collected to assess renal function, and histopathology was performed to identify the key biological components of A. muciniphila. Faecal samples were subjected to integrated microbiome and metabolomic analyses to identify the metabolic pathways involved in renoprotection. Behavioural experiments were performed to observe the effect of A. muciniphila on the behaviour of CKD mice. Single-factor analysis of variance and post-hoc tests were used for intergroup comparisons.

resultsSerum analysis showed that the levels of serum creatinine, urea nitrogen and cystatin C in mice treated with A. muciniphila combined with vancomycin were significantly decreased. Reverse-transcription polymerase chain reaction showed that the renal injury marker Kim-1 was significantly decreased after A. muciniphila intervention. The levels of the renal injury (Ngal) and fibrosis (Col1a1, TIMP-1 and Fibronectin) markers showed a downward trend. 16 S rRNA analysis revealed that, following A. muciniphila intervention, the health index of the intestinal flora in CKD mice was significantly increased; however, the abundances of Turicibacter, Dubosiella and norank_f_UCG-010 were decreased. Metabolomic analysis revealed a strong correlation between A. muciniphila and the tryptophan metabolic pathway. Behavioural experiments showed that the exercise activity and anxiety-like behaviour of CKD mice were significantly improved after intervention with A. muciniphila, and the effect of A. muciniphila combined with vancomycin was better than that of A. muciniphila or pasteurised A. muciniphila alone.

conclusionOur findings demonstrate that A. muciniphila combined with vancomycin intervention ameliorates kidney injury, body dysfunction, and anxiety-like behaviour, while delaying disease progression in CKD mice. These effects suggest that bioactive substances secreted by A. muciniphila play a key regulatory role and are closely related to tryptophan metabolism in the intestine. In addition, our results indicate that dysbiosis of the gut microbiota in CKD mice suppresses the regulatory potential of A. muciniphila. This study lays an experimental foundation for future biological mechanism research.