Gut microbiota–metabolite interactions in cisplatin-induced acute kidney injury in rats

The interplay between the gut microbiota and metabolites in the early stages of cisplatin-induced acute kidney injury (AKI) remains largely unexplored, especially in the early stages. This study aimed to identify the gut microbiota and metabolomic characteristics following cisplatin-induced AKI and to investigate the underlying mechanisms involved. Male Wistar rats were randomly assigned to a control group (NC) or a cisplatin-induced AKI group (Cis). The gut microbiota composition was analysed using 16 S rRNA sequencing, and faecal metabolomic profiles were characterized using untargeted metabolomics (UPLC‒MS/MS). The relationships among serum creatinine (SCr), blood urea nitrogen (BUN), faecal metabolites, and the gut microbiota were investigated to identify potential biomarkers and therapeutic targets for AKI. The functional impact of the identified metabolites was further assessed in HK-2 human renal tubular epithelial cells using Cell Counting Kit-8 (CCK-8) and flow cytometry assays. Cisplatin administration induced significant dysbiosis of the gut microbiota, altering its composition. The Cis group was enriched in proinflammatory genera such as Enterococcus and Anaerostipes, whereas the NC group was enriched in potentially beneficial genera such as Brotonthovivens, whose abundance was negatively correlated with the SCr and BUN levels. Concurrently, 20 differential faecal metabolites, including elevated dehydroepiandrosterone (DHEA) and N-acetylaspartic acid (NAA), were significantly correlated with impaired renal function. Correlation network analysis further revealed intricate associations between specific bacterial abundances and metabolite levels: Enterococcus was positively correlated with DHEA and NAA but negatively correlated with adenosine, guanine, and linoleic acid, whereas Brotonthovivens exhibited the opposite pattern. Moreover, analysis of colonic tissue revealed significant downregulation of the expression levels of the tight junction proteins ZO-1 and occludin, indicating impaired intestinal barrier integrity. Based on these integrated in vivo findings, targeted in vitro validation in HK-2 cells demonstrated that adenosine significantly attenuated cisplatin-induced cytotoxicity and apoptosis, whereas NAA exacerbated these injuries. Our findings demonstrated that cisplatin-induced AKI significantly reshaped the gut microbiota and faecal metabolome in rats. This study demonstrates potential interactions between specific gut microbes and host metabolites during AKI progression, offering novel insights into the gut–kidney axis and highlighting potential microbial and metabolic targets for future therapeutic interventions.