Dataset Information

BATF3 Protects Against Metabolic Syndrome and Maintains Intestinal Epithelial Homeostasis.

ABSTRACT: The intestinal immune system and microbiota are emerging as important contributors to the development of metabolic syndrome, but the role of intestinal dendritic cells (DCs) in this context is incompletely understood. BATF3 is a transcription factor essential in the development of mucosal conventional DCs type 1 (cDC1). We show that Batf3^-/- mice developed metabolic syndrome and have altered localization of tight junction proteins in intestinal epithelial cells leading to increased intestinal permeability. Treatment with the glycolysis inhibitor 2-deoxy-D-glucose reduced intestinal inflammation and restored barrier function in obese Batf3^-/- mice. High-fat diet further enhanced the metabolic phenotype and susceptibility to dextran sulfate sodium colitis in Batf3^-/- mice. Antibiotic treatment of Batf3^-/- mice prevented metabolic syndrome and impaired intestinal barrier function. Batf3^-/- mice have altered IgA-coating of fecal bacteria and displayed microbial dysbiosis marked by decreased obesity protective Akkermansia muciniphila, and Bifidobacterium. Thus, BATF3 protects against metabolic syndrome and preserves intestinal epithelial barrier by maintaining beneficial microbiota.

SUBMITTER: Hamade H

PROVIDER: S-EPMC9257242 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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BATF3 Protects Against Metabolic Syndrome and Maintains Intestinal Epithelial Homeostasis.

Hamade Hussein H Stamps Jasmine T JT Stamps Dalton T DT More Shyam K SK Thomas Lisa S LS Blackwood Anna Y AY Lahcene Nawele L NL Castanon Sofi L SL Salumbides Brenda C BC Shimodaira Yosuke Y Goodridge Helen S HS Targan Stephan R SR Michelsen Kathrin S KS

Frontiers in immunology 20220622

The intestinal immune system and microbiota are emerging as important contributors to the development of metabolic syndrome, but the role of intestinal dendritic cells (DCs) in this context is incompletely understood. BATF3 is a transcription factor essential in the development of mucosal conventional DCs type 1 (cDC1). We show that <i>Batf3<sup>-/-</sup></i> mice developed metabolic syndrome and have altered localization of tight junction proteins in intestinal epithelial cells leading to incre ...[more]

PMID: 35812447

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Project description: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 disease. 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 generated new mouse models with Axin1 conditional knockout in intestinal epithelial cell (IEC; Axin1 ΔIEC) and Paneth cell (PC; Axin1 ΔPC) to compare with control (Axin1 LoxP; LoxP: locus of X-over, P1) mice. We found increased Axin1 expression in the colonic epithelium of human inflammatory bowel disease (IBD). Axin1 ΔIEC 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. Axin1 ΔIEC and Axin1 ΔPC 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 Axin1 Loxp mice. However, the intestinal proliferative cells in Axin1 ΔIEC mice with antibiotic treatment were reduced compared with those in Axin1 ΔIEC 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. muciniphila. Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the microbiota. 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.

Dataset Information

BATF3 Protects Against Metabolic Syndrome and Maintains Intestinal Epithelial Homeostasis.

Publications

BATF3 Protects Against Metabolic Syndrome and Maintains Intestinal Epithelial Homeostasis.

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