BACKGROUND: The rising incidence of Crohn's disease (CD) in Asia underscores the need to explore its underlying mechanisms. The interaction between gut microbiota and the host is strongly linked to CD onset and progression, yet the precise mechanisms remain unclear. Previous studies have demonstrated that Ruminococcus gnavus (R. gnavus) is closely associated with the development and progression of CD. Therefore, this study focuses on the inflammatory role of R. gnavus in CD pathogenesis. METHODS: We performed comprehensive 16 S rRNA sequencing on fecal samples from active CD patients, inactive CD patients, and healthy controls. Alongside this, we conducted clinical data and correlation analyses. To identify key microbial genera, we developed and validated a random forest classification model. Additionally, we utilized a dextran sulfate sodium (DSS)-induced colitis model in C57BL/6 mice to explore the inflammatory role of R. gnavus (ATCC 29149). RESULTS: Our analysis revealed significant shifts in gut microbiome composition across different stages of CD compared to healthy controls. Notably, there was a marked decrease in Agathobacter and an increase in R. gnavus in patients with active CD. The random forest classification model, which was based on six specific genera (Agathobacter, Vicinamibacteraceae, Arthrobacter, Eubacterium coprostanoligenes group, Ruminococcus gnavus group, and Prevotella 9), achieved an AUC of 0.912, effectively distinguishing CD patients from healthy controls. In the DSS-induced colitis model, R. gnavus exacerbated inflammation, significantly increasing levels of IL-6 and TNF-α, and significantly decreasing levels of Claudin-1 and MUC2, further underscoring its critical role in CD pathogenesis. CONCLUSION: The identified genera demonstrate potential as diagnostic biomarkers for CD, with R. gnavus playing a key role in the disease's pathogenesis by inducing inflammation in colitis models.