Characteristics of gut microbiota and metabolites in rats with ketamine-induced cystitis.

Abstract

Ketamine-induced cystitis (KC) manifests as lower urinary tract symptoms stemming from prolonged ketamine abuse, yet its precise pathogenesis remains unclear. It is widely recognized that gut microbiota dysregulation can trigger metabolic aberrations in many diseases. This study aimed to address the dearth of knowledge regarding the functional characteristics of gut microbiota and their metabolites in KC, and to explore the underlying mechanisms of KC from the perspective of the gut-bladder axis. Metagenomic and untargeted metabolomic analyses were employed to elucidate critical features of gut microbiota and metabolism in KC rats. Metagenomic sequencing revealed significant gut microbiota dysregulation, characterized by discrepancies in 46 bacterial taxa at the species level, including Bifidobacterium pseudolongum, Erysipelotrichaceae bacterium OPF54, Firmicutes bacterium CAG: 424, and Phocaeicola sartorii. Untargeted metabolomics identified 13 dysregulated metabolites, encompassing Stachydrine, Quinoline, Sedanolide, and others. Correlation analyses among differential gut microbiota, metabolites, and bladder inflammatory factors in KC rats suggested a potential interconnectivity between these factors. Furthermore, the anti-inflammatory property of Stachydrine was experimentally validated using an in vitro model. These findings collectively indicate that KC rats exhibit alterations in gut microbiota composition and metabolites profiles, establishing a preliminary association among gut microbiota, metabolites, and KC pathogenesis. Finally, validation of the anti-inflammatory effects of Stachydrine provides insight into a potential pathogenic pathway involving gut-bladder axis crosstalk, in which dysregulation of gut microbiota and metabolites contributes to the development of KC.