Reduced intestinal GLP-1+ cell numbers are associated with an inflammation-related epithelial metabolic signature.

IF 7.1 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Elisabeth Urbauer, Doriane Aguanno, Katharina Kuellmer, Amira Metwaly, Nadine Waldschmitt, Mohamed Ahmed, Sevana Khaloian, Gabriele Hörmannsperger, Julien Planchais, Tobias Fromme, R Balfour Sartor, Harry Sokol, Dirk Haller, Eva Rath
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引用次数: 0

Abstract

Background & aims: Enteroendocrine cells (EECs) are known for their role in digestion and metabolism, yet their role in intestinal inflammation remains unclear. In inflammatory bowel diseases (IBD), a contribution of EECs to pathogenesis is indicated by autoantibodies affecting EEC function and general disease symptoms like insulin resistance and altered intestinal motility. Particularly, the L cell-derived hormone glucagon-like peptide 1 (GLP-1), suggested to orchestrate metabolic-inflammatory responses may influence inflammatory pathways in the intestine.

Methods: We quantified numbers of GLP-1+ cells in 4 different mouse models of intestinal inflammation and performed transcriptional analyses of colonic epithelial cells from inflamed interleukin (IL)10-deficient mice. Using a publicly available single-cell RNA sequencing dataset including mucosal biopsies from Crohn´s disease (CD) patients, we confirmed findings from the murine models. A model of mitochondrial dysfunction (ClpPΔIEC mice) as well as murine and human intestinal organoids were used to study molecular mechanisms.

Results: Numbers of GLP-1 expressing cells are consistently reduced at the site of active disease in mouse models and CD patients. Despite this reduction, L cells from inflamed IL-10-deficient mice remained functional regarding GLP-1 secretion. Transcriptional analyses of intestinal epithelial cells indicate altered differentiation correlating with an inflammatory metabolic fingerprint. Reduced GLP-1+ cells in ClpPΔIEC mice and inhibition of respiration in organoid cultures supports a causative role for metabolism in steering differentiation.

Conclusion: Reduction of GLP-1+ cells represents a general feature of ileal and colonic inflammation in mice and human. Given the numerous properties of GLP-1, this reduction likely affects inflammatory processes in the mucosa and disease-related symptoms on multiple levels, and therefore, should be considered a therapeutic target in IBD.

肠道GLP-1+细胞数量的减少与炎症相关的上皮代谢特征有关。
背景与目的:众所周知,肠内分泌细胞(EECs)在消化和代谢中起着重要作用,但它们在肠道炎症中的作用尚不清楚。在炎症性肠病(IBD)中,通过自身抗体影响EEC功能和一般疾病症状(如胰岛素抵抗和肠蠕动改变)表明EEC对发病机制的贡献。特别是,L细胞衍生的激素胰高血糖素样肽1 (GLP-1),被认为可以协调代谢炎症反应,可能影响肠道的炎症途径。方法:我们量化了4种不同肠道炎症小鼠模型中GLP-1+细胞的数量,并对炎症性白细胞介素(IL)10缺陷小鼠的结肠上皮细胞进行了转录分析。使用公开可用的单细胞RNA测序数据集,包括克罗恩病(CD)患者的粘膜活检,我们证实了小鼠模型的发现。使用线粒体功能障碍模型(ClpPΔIEC小鼠)以及小鼠和人类肠道类器官来研究分子机制。结果:在小鼠模型和CD患者的活动性疾病部位,GLP-1表达细胞的数量持续减少。尽管这种减少,炎性il -10缺陷小鼠的L细胞在GLP-1分泌方面仍保持功能。肠上皮细胞的转录分析表明分化改变与炎症代谢指纹相关。ClpPΔIEC小鼠中GLP-1+细胞的减少和类器官培养中呼吸的抑制支持了代谢在引导分化中的致病作用。结论:GLP-1+细胞减少是小鼠和人回肠和结肠炎症的一个普遍特征。考虑到GLP-1的众多特性,这种减少可能会在多个层面上影响粘膜的炎症过程和疾病相关症状,因此,应将其视为IBD的治疗靶点。
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来源期刊
CiteScore
13.00
自引率
2.80%
发文量
246
审稿时长
42 days
期刊介绍: "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.
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