The coevolution of mammalian hosts and their beneficial commensal microbes has led to development of symbiotic host–microbiota relationships 1 . Epigenetic machinery permits mammalian cells to integrate environmental signals 2 ; however, how these pathways are fine-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 the abundant presence of HDAC inhibitors such as butyrate in the intestine, we found that HDAC3 activity was sharply increased in intestinal epithelial cells of microbiota-replete mice compared with germ-free mice. This divergence was reconciled by the finding that commensal bacteria, including Escherichia coli , stimulated HDAC activity through metabolism of phytate and production of inositol-1,4,5-trisphosphate (InsP 3 ). Both intestinal exposure to InsP 3 and phytate ingestion promoted recovery following intestinal damage. Of note, InsP 3 also induced growth of intestinal organoids derived from human tissue, stimulated HDAC3-dependent proliferation and countered butyrate inhibition of colonic growth. Collectively, these results show that InsP 3 is a microbiota-derived metabolite that activates a mammalian histone deacetylase to promote epithelial repair. Thus, HDAC3 represents a convergent epigenetic sensor of distinct metabolites that calibrates host responses to diverse microbial signals. Phytate metabolism and production of inositol trisphosphate by commensal bacteria activates epithelial histone deacetylase 3 and promotes intestinal repair.

中文翻译：

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微生物群衍生代谢物促进肠道中的 HDAC3 活性

哺乳动物宿主及其有益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 1 。表观遗传机制允许哺乳动物细胞整合环境信号 2；然而，这些途径如何通过来自共生细菌的不同线索进行微调尚不清楚。在这里，我们揭示了一种高度选择性的途径，微生物群来源的肌醇磷酸盐通过该途径调节肠道中的组蛋白脱乙酰酶 3 (HDAC3) 活性。尽管肠道中大量存在诸如丁酸盐之类的 HDAC 抑制剂，但我们发现与无菌小鼠相比，微生物群充足小鼠的肠上皮细胞中的 HDAC3 活性急剧增加。发现共生细菌，包括大肠杆菌，调和了这种分歧。通过植酸盐的代谢和肌醇-1,4,5-三磷酸 (InsP 3 ) 的产生刺激 HDAC 活性。肠道暴露于 InsP 3 和摄入植酸盐都促进了肠道损伤后的恢复。值得注意的是，InsP 3 还诱导了源自人体组织的肠道类器官的生长，刺激了 HDAC3 依赖性增殖并抵消了丁酸盐对结肠生长的抑制。总的来说，这些结果表明 InsP 3 是一种源自微生物的代谢物，可激活哺乳动物组蛋白脱乙酰酶以促进上皮修复。因此，HDAC3 代表了不同代谢物的聚合表观遗传传感器，可校准宿主对不同微生物信号的反应。植酸盐代谢和共生菌产生三磷酸肌醇激活上皮组蛋白脱乙酰酶 3 并促进肠道修复。