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<p>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. <i>Fusobacterium varium</i> (<i>F. varium</i>) was found to be significantly enriched in patients with UC and was therefore selected for further functional investigation. Germ-free mice colonized with <i>F. varium</i> developed more severe dextran sulfate sodium (DSS)-induced colitis, accompanied by enhanced mucosal inflammation. In addition, <i>F. varium</i> 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 <i>F. varium</i> in exacerbating intestinal inflammation under colitic conditions, at least in part through succinate-associated neutrophil recruitment.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Qian Wang,
  • Han Xiao,
  • Wenxiu Liu,
  • Xiangji Dang,
  • Yanrui Bai,
  • Ruihong Xiao,
  • Liyu Tong,
  • Yan Wang,
  • Mi Li,
  • Shuhan Wang,
  • Sugui Pu,
  • Duoji Pei,
  • Dekui Zhang,
  • Xiang Wang,
  • Guang Hu,
  • Jingjing Guo,
  • Xiaojie Jin,
  • Long Qin,
  • Chunjiang Zhang,
  • Yana Li,
  • Tiansheng Zhang,
  • Jing Yang,
  • Qi Wang,
  • Hui Sun

摘要

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.