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Herein, this study finds that digestive symptoms are commonly observed in patients with GSD\u2010Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo\u2010polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single\u2010cell 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\u2010activation of the CCL4L2\u2010VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD\u2010Ib. Collectively, the microbiota\u2010driven pathomechanism of IBD is demonstrated in GSD\u2010Ib and revealed the active role of the CCL4L2\u2010VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and\/or the CCL4L2\u2010VISR axis may represent a potential therapy for GSD\u2010associated IBD.<\/jats:p>","DOI":"10.1002\/advs.202309471","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T14:08:52Z","timestamp":1718719732000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Gut Dysbiosis Drives Inflammatory Bowel Disease Through the CCL4L2\u2010VSIR Axis in Glycogen Storage Disease"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5236-6678","authenticated-orcid":false,"given":"Jiaoli","family":"Lan","sequence":"first","affiliation":[{"name":"Department of Pediatrics Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Southern Medical University  Guangzhou 510080 China"},{"name":"Research Center of Medical Sciences Guangdong Provincial People's Hospital Guangdong Academy of Medical 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