Intestinal Epithelial Axin1 Deficiency Protects Against Colitis via Altered Gut Microbiota

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外文摘要：Intestinal homeostasis is maintained by specialized host cells and the gut microbiota.Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis,and its dysregulation has been implicated in inflammation and colorectal cancer.Axin1 negatively regulates activated Wnt/β-catenin signaling,but little is known regarding its role in regulating host-microbial interactions in health and dis-ease.Here,we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation.Axin1 expression was analyzed in human inflammatory bowel disease datasets.To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis,we gener-ated new mouse models with Axin1 conditional knockout in intestinal epithelial cell(IEC;Axin1ΔIEC)and Paneth cell(PC;Axin1ΔPC)to compare with control(Axin1LoxP;LoxP:locus of X-over,P1)mice.We found increased Axin1 expression in the colonic epithelium of human inflammatory bowel disease(IBD).Axin1ΔIEC mice exhibited altered goblet cell spatial distribution,PC morphology,reduced lysozyme expression,and enriched Akkermansia muciniphila(A.muciniphila).The absence of intestinal epithelial and PC Axin1 decreased susceptibility to dextran sulfate sodium(DSS)-induced colitis in vivo.Axin1ΔIEC and Axin1ΔPC mice became more susceptible to DSS-colitis after cohousing with control mice.Treatment with A.muciniphila reduced DSS-colitis severity.Antibiotic treatment did not change the IEC proliferation in the Axin1Loxp mice.However,the intestinal proliferative cells in Axin1ΔIEC mice with antibiotic treatment were reduced compared with those in Axin1ΔIEC mice without treatment.These data suggest non-colitogenic effects driven by the gut microbiome.In conclusion,we found that the loss of intestinal Axin1 protects against colitis,likely driven by epithelial Axin1 and Axin1-associated A.mucini-phila.Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the micro-biota.Further mechanistic studies using specific Axin1 mutations elucidating how Axin1 modulates the microbiome and host inflammatory response will provide new therapeutic strategies for human IBD.

外文关键词：

Axin1BacteriaMicrobiome inflammationInflammatory bowel diseaseImmunityMicrobiomePaneth cellsAkkermansia muciniphilaWnt

作者：

Shari Garrett、Yongguo Zhang、Yinglin Xia、Jun Sun

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作者单位：

Division of Gastroenterology and Hepatology,Department of Medicine,University of Illinois Chicago,Chicago,IL 60612,USA

Department of Microbiology and Immunology,College of Medicine,University of Illinois Chicago,Chicago,IL 60612,USA

Cancer Center,University of Illinois Chicago,Chicago,IL 60612,USA

Jesse Brown VA Medical Center,Chicago,IL 60612,USA

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基金：

VA Merit AwardNational Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health GrantsNational Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health GrantsCrohn's & Colitis Foundation Senior Research Award

项目编号：

1 I01BX004824-01R01 DK105118R01DK114126902766

出版年：

2024

DOI：

10.1016/j.eng.2023.06.007

工程(英文)

CSTPCDEI

ISSN：2095-8099

年,卷(期)：2024.35(4)