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MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice.

ABSTRACT: BACKGROUND & AIMS:Intestinal epithelial homeostasis depends on a tightly regulated balance between intestinal epithelial cell (IEC) death and proliferation. While the disruption of several IEC death regulating factors result in intestinal inflammation, the loss of the anti-apoptotic BCL2 family members BCL2 and BCL2L1 has no effect on intestinal homeostasis in mice. We investigated the functions of the antiapoptotic protein MCL1, another member of the BCL2 family, in intestinal homeostasis in mice. METHODS:We generated mice with IEC-specific disruption of Mcl1 (Mcl1?IEC mice) or tamoxifen-inducible IEC-specific disruption of Mcl1 (i-Mcl1?IEC mice); these mice and mice with full-length Mcl1 (controls) were raised under normal or germ-free conditions. Mice were analyzed by endoscopy and for intestinal epithelial barrier permeability. Intestinal tissues were analyzed by histology, in situ hybridization, proliferation assays, and immunoblots. Levels of calprotectin, a marker of intestinal inflammation, were measured in intestinal tissues and feces. RESULTS:Mcl1?IEC mice spontaneously developed apoptotic enterocolopathy, characterized by increased IEC apoptosis, hyperproliferative crypts, epithelial barrier dysfunction, and chronic inflammation. Loss of MCL1 retained intestinal crypts in a hyperproliferated state and prevented the differentiation of intestinal stem cells. Proliferation of intestinal stem cells in MCL1-deficient mice required WNT signaling and was associated with DNA damage accumulation. By 1 year of age, Mcl1?IEC mice developed intestinal tumors with morphologic and genetic features of human adenomas and carcinomas. Germ-free housing of Mcl1?IEC mice reduced markers of microbiota-induced intestinal inflammation but not tumor development. CONCLUSION:The antiapoptotic protein MCL1, a member of the BCL2 family, is required for maintenance of intestinal homeostasis and prevention of carcinogenesis in mice. Loss of MCL1 results in development of intestinal carcinomas, even under germ-free conditions, and therefore does not involve microbe-induced chronic inflammation. Mcl1?IEC mice might be used to study apoptotic enterocolopathy and inflammatory bowel diseases.

SUBMITTER: Healy ME

PROVIDER: S-EPMC7397524 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice.

Healy Marc E ME Boege Yannick Y Hodder Michael C MC Böhm Friederike F Malehmir Mohsen M Scherr Anna-Lena AL Jetzer Jasna J Chan Lap Kwan LK Parrotta Rossella R Jacobs Kurt K Clerbaux Laure-Alix LA Kreutzer Susanne S Campbell Andrew A Gilchrist Ella E Gilroy Kathryn K Rodewald Ann-Katrin AK Honcharova-Biletska Hanna H Schimmer Roman R Vélez Karelia K Büeler Simone S Cammareri Patrizia P Kalna Gabriela G Wenning Anna S AS McCoy Kathy D KD Gomez de Agüero Mercedes M Schulze-Bergkamen Henning H Klose Christoph S N CSN Unger Kristian K Macpherson Andrew J AJ Moor Andreas E AE Köhler Bruno B Sansom Owen J OJ Heikenwälder Mathias M Weber Achim A

Gastroenterology 20200314 1

<h4>Background & aims</h4>Intestinal epithelial homeostasis depends on a tightly regulated balance between intestinal epithelial cell (IEC) death and proliferation. While the disruption of several IEC death regulating factors result in intestinal inflammation, the loss of the anti-apoptotic BCL2 family members BCL2 and BCL2L1 has no effect on intestinal homeostasis in mice. We investigated the functions of the antiapoptotic protein MCL1, another member of the BCL2 family, in intestinal homeostas ...[more]

PMID: 32179094

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Project description:ObjectiveRecent studies using whole-body clock-disrupted animals identified a disruption in the circadian rhythm of the intestinal L-cell incretin hormone, glucagon-like peptide-1 (GLP-1). Although GLP-1 plays an essential role in metabolism through enhancement of both glucose-stimulated insulin secretion and satiety, recent evidence has also demonstrated its importance in regulating intestinal and microbial homeostasis. Therefore, using in vivo and in vitro models, this study assessed the role of the core circadian clock gene Arntl in the regulation of time-dependent GLP-1 secretion and its impact on the intestinal environment.MethodsOral glucose tolerance tests were conducted at zeitgeber time 2 and 14 in control and inducible Gcg-Arntl knockout (KO) mice. Colonic intraepithelial lymphocytes were isolated, mucosal gene expression analysis was conducted, and 16S rRNA gene sequencing of colonic feces as well as analysis of microbial metabolites were performed. Time-dependent GLP-1 secretion and transcriptomic analysis were conducted in murine (m) GLUTag L-cells following siRNA-mediated knockdown of Arntl.ResultsGcg-Arntl KO mice displayed disrupted rhythmic release of GLP-1 associated with reduced secretion at the established peak time point. Analysis of the intestinal environment in KO mice revealed a decreased proportion of CD4+ intraepithelial lymphocytes in association with increased proinflammatory cytokine gene expression and increased colonic weight. Moreover, increased Actinobacteria within the colonic microbiome was found following L-cell Arntl disruption, as well as reductions in the microbial products, short chain fatty acids, and bile acids. Finally, siRNA-mediated knockdown of Arntl in mGLUTag L-cells resulted in both impaired time-dependent GLP-1 secretion and the disruption of pathways related to key cellular processes.ConclusionsThese data establish, for the first time, the essential role of Arntl in the intestinal L-cell in regulating time-dependent GLP-1 secretion. Furthermore, this study revealed the integral role of L-cell Arntl in mediating the intestinal environment, which ultimately may provide novel insight into the development of therapeutics for the treatment of intestinal and metabolic disorders.

Project description:Background & aimsThe amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis.MethodsWe used human colon tissue messenger RNA samples and publicly available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis.ResultsWe found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS messenger RNA and DHPS protein and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show down-regulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis.ConclusionsHypusination in intestinal epithelial cells has a key role in the prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have a therapeutic impact.

Dataset Information

MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice.

Publications

MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice.

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