Fusobacterium varium Exacerbates Neutrophil-driven Intestinal Inflammation Associated with Succinate-SUCNR1-NF-κB...

Disruption of gut microbial homeostasis is a hallmark of ulcerative colitis (UC), yet the specific pathobionts and effector molecules driving mucosal inflammation remain unclear. In this study, metagenomic sequencing of fecal samples from 37 patients with UC and 30 healthy controls was performed to identify differentially enriched bacterial species. Fusobacterium varium (F. varium) was found to be significantly enriched in patients with UC and was therefore selected for further functional investigation. Germ-free mice colonized with F. varium developed more severe dextran sulfate sodium (DSS)-induced colitis, accompanied by enhanced mucosal inflammation. In addition, F. varium culture supernatants increased NF-κB reporter activity and inflammatory signaling at the protein level. Bioactivity-guided fractionation combined with mass spectrometry identified succinate as a major candidate bacterial-derived bioactive metabolite. Succinate exacerbated colonic inflammation in vivo and promoted neutrophil recruitment, whereas inhibition of CXCR2 signaling reduced neutrophil infiltration and alleviated disease severity. In vitro experiments further demonstrated that succinate activated NF-κB signaling in HL-60-derived neutrophils through succinate receptor 1 (SUCNR1) and induced the production of inflammatory mediators, including CXCL8. Collectively, these findings support a role for F. varium in exacerbating intestinal inflammation under colitic conditions, at least in part through succinate-associated neutrophil recruitment.