ILA-producing bifidobacterium bifidum ameliorates chronic kidney disease via AHR signaling by modulating the gut-kidney axis.

Abstract

Chronic kidney disease (CKD) is associated with gut microbiota dysbiosis and disruption of the gut-kidney axis, making probiotics-which can modulate host metabolism and the gut microbiome-a highly promising intervention strategy. Building on this premise, this study used High-Performance Liquid Chromatography (HPLC) to screen 39 candidate strains and successfully isolate two high indole-3-lactic acid (ILA)-producing strains of Bifidobacterium bifidum: FL228.1 and ZL.1. Whole-genome sequencing subsequently confirmed that both strains possess the aromatic lactate dehydrogenase (Aldh) gene, which is essential for ILA biosynthesis. The strains were then evaluated in an adenine-induced CKD mouse model. ZL.1 exhibited pronounced efficacy: it not only improved renal injury, restored gut barrier function, and corrected dysbiosis, as evidenced by an increased relative abundance of Muribaculaceae and a decreased abundance of Dubosiella, but also significantly elevated the level of the key metabolite ILA. In-depth mechanistic analysis revealed that ILA exerts its effects by activating the aryl hydrocarbon receptor (AHR) signaling pathway, which in turn inhibits NLRP3 inflammasome activation, thereby achieving the dual benefit of mitigating intestinal inflammation and alleviating renal fibrosis. Targeted metabolomics analysis supported the conclusion that high ILA production is a critical characteristic for B. bifidum's modulation of the gut-kidney axis. In contrast, the FL228.1 strain showed moderate effects, with its specific mechanism remaining unclear. In conclusion, our study suggests that ILA-producing B. bifidum may ameliorate CKD by regulating the gut-kidney axis via ILA and AHR signaling. This indicates a potential probiotic strategy targeting tryptophan metabolism for CKD.