小柯机器人

微生物代谢分子可促进肠道HDAC3活性
2020-08-01 17:07

美国辛辛那提儿童医院医学中心Theresa Alenghat研究小组的最新工作表明,微生物来源的代谢产物可促进肠道HDAC3活性。2020年7月30日,《自然》杂志在线发表了这项成果。

研究人员揭示了一种高度选择性的途径,微生物群通过该途径可调节肠道中的组蛋白去乙酰化酶3(HDAC3)活性。尽管在肠中有丰富的HDAC抑制剂(例如丁酸),但研究人员发现,与无细菌的小鼠相比,在富含微生物群的小鼠的肠上皮细胞(IEC)中HDAC3活性急剧增加。

研究人员发现包括大肠杆菌在内的共生细菌通过肌醇六磷酸的代谢和三磷酸肌醇的产生刺激了HDAC的活性。肠道暴露于三磷酸肌醇以及摄取肌醇六磷酸均可促进肠损伤后的恢复。值得注意的是,三磷酸肌醇还诱导了患者来源的肠类器官的生长,刺激了HDAC3依赖性增殖,并抵消了丁酸对结肠生长的抑制作用。

总的来说,这些数据揭示了肌醇三磷酸酯是微生物群衍生的代谢产物,其可激活哺乳动物组蛋白去乙酰化酶来促进上皮修复。因此,HDAC3是不同代谢物的表观遗传感知分子,可校准宿主对多种微生物信号的反应。

据介绍,哺乳动物宿主及其有益的共生微生物的共同进化导致了共生宿主-微生物群关系的发展。表观遗传学机制能够使哺乳动物细胞整合环境信号,但是,这些来源于共生细菌的各种线索如何对这些途径进行微调尚不清楚。

附:英文原文

Title: Microbiota-derived metabolite promotes HDAC3 activity in the gut

Author: Shu-en Wu, Seika Hashimoto-Hill, Vivienne Woo, Emily M. Eshleman, Jordan Whitt, Laura Engleman, Rebekah Karns, Lee A. Denson, David B. Haslam, Theresa Alenghat

Issue&Volume: 2020-07-30

Abstract: The coevolution of mammalian hosts and their beneficial commensal microbes has led to development of a symbiotic host-microbiota relationship1. Epigenetic machinery permits mammalian cells to integrate environmental signals2, however, how these pathways are finely tuned by diverse cues from commensal bacteria is not well understood. Here, we reveal a highly selective pathway through which microbiota-derived inositol phosphate regulates histone deacetylase 3 (HDAC3) activity in the intestine. Despite abundant HDAC inhibitors in the intestine such as butyrate, we unexpectedly found that HDAC3 activity was sharply increased in intestinal epithelial cells (IECs) of microbiota-replete mice compared to germ-free mice. This discordance was reconciled by finding that commensal bacteria, including E. coli, stimulated HDAC activity through metabolism of phytate and inositol trisphosphate production. Intestinal exposure to inositol trisphosphate and phytate ingestion both promoted recovery following intestinal damage. Remarkably, inositol trisphosphate also induced growth of patient-derived intestinal organoids, stimulated HDAC3-dependent proliferation, and countered butyrate inhibition of colonic growth. Collectively, these data reveal inositol trisphosphate as a microbiota-derived metabolite that activates a mammalian histone deacetylase to promote epithelial repair. Thus, HDAC3 represents a converging epigenetic sensor of distinct metabolites that calibrates host responses to diverse microbial signals.

DOI: 10.1038/s41586-020-2604-2

Source: https://www.nature.com/articles/s41586-020-2604-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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