Advanced Science (Aug 2024)

Gut Dysbiosis Drives Inflammatory Bowel Disease Through the CCL4L2‐VSIR Axis in Glycogen Storage Disease

  • Jiaoli Lan,
  • Yuxin Zhang,
  • Cuiyuan Jin,
  • Huan Chen,
  • Zexiong Su,
  • Jiaxing Wu,
  • Ni Ma,
  • Xiaoyan Zhang,
  • Yiyun Lu,
  • Yongxin Chen,
  • Xiaolu Zeng,
  • Huiqiong Zhang,
  • Guilang Zheng,
  • Yueyu Sun,
  • Chun Wang,
  • Yan Hu,
  • Yifei Wang,
  • Yumei Liu,
  • Zhaoyang Zeng,
  • Liyun Shi,
  • Jun He,
  • Aihua Cao,
  • Yichao Wang,
  • Xu Pan,
  • Gulei Jin,
  • Ying Wang,
  • Xun Jiang,
  • Huiqing Shen,
  • Qing Tang,
  • Xiaoli Xie,
  • Yuan Xiao,
  • Xuemei Zhong,
  • Xuchao Zhang,
  • Liang Zeng,
  • Liping Ye,
  • Jing Xie,
  • Lanlan Geng,
  • Zhiling Li,
  • Xiaohui Wu,
  • Ying Wang,
  • Ren Mao,
  • Shaojun Zhang,
  • Siyuan Huang,
  • Suling Liu,
  • Hanshi Zeng,
  • Wanfu Xu,
  • Sitang Gong,
  • Yuxiong Guo,
  • Min Yang

DOI
https://doi.org/10.1002/advs.202309471
Journal volume & issue
Vol. 11, no. 30
pp. n/a – n/a

Abstract

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Abstract Patients with glycogen storage disease type Ib (GSD‐Ib) frequently have inflammatory bowel disease (IBD). however, the underlying etiology remains unclear. Herein, this study finds that digestive symptoms are commonly observed in patients with GSD‐Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo‐polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single‐cell clustering of colonic mucosae in patients with GSD are conducted. Heterogeneous oral pathogenic enteric outgrowth induced by GSD is a potent inducer of gut microbiota immaturity and colonic macrophage accumulation. Specifically, a unique population of macrophages with high CCL4L2 expression is identified in response to pathogenic bacteria in the intestine. Hyper‐activation of the CCL4L2‐VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD‐Ib. Collectively, the microbiota‐driven pathomechanism of IBD is demonstrated in GSD‐Ib and revealed the active role of the CCL4L2‐VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and/or the CCL4L2‐VISR axis may represent a potential therapy for GSD‐associated IBD.

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