Gut Dysbiosis Drives Inflammatory Bowel Disease Through the CCL4L2-VSIR Axis in Glycogen Storage Disease.
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Lan Jiaoli, Zhang Yuxin, Jin Cuiyuan, Chen Huan, Su Zexiong, Wu Jiaxing, Ma Ni, Zhang Xiaoyan, Lu Yiyun, Chen Yongxin, Zeng Xiaolu, Zhang Huiqiong, Zheng Guilang, Sun Yueyu, Wang Chun, Hu Yan, Wang Yifei, Liu Yumei, Zeng Zhaoyang, Shi Liyun, He Jun, Cao Aihua, Wang Yichao, Pan Xu, Jin Gulei, Wang Ying, Jiang Xun, Shen Huiqing, Tang Qing, Xie Xiaoli, Xiao Yuan, Zhong Xuemei, Zhang Xuchao, Zeng Liang, Ye Liping, Xie Jing, Geng Lanlan, Li Zhiling, Wu Xiaohui, Wang Ying, Mao Ren, Zhang Shaojun, Huang Siyuan, Liu Suling, Zeng Hanshi, Xu Wanfu, Gong Sitang, Guo Yuxiong, Yang Min
Аннотация
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.