Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis

Das Nupur K.; Schwartz Andrew J.; Barthel Gabrielle; Inohara Naohiro; Liu Qing; Sankar Amanda; Hill David R.; Ma Xiaoya; Lamberg Olivia; Schnizlein Matthew K.; Arques Juan L.; Spence Jason R.; Nunez Gabriel; Patterson Andrew D.; Sun Duxin; Young Vincent B.; Shah Yatrik M.

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Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis

机译：Systemic Iron Soyostasis需要微生物代谢物信号

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Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2 alpha (HIF-2 alpha) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2 alpha via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.

机译：铁是所有生物体所需的中央微量营养素。在肠道中对铁的竞争对于维持土着微生物种群和宿主健康至关重要。在铁限制期间宿主和本机微生物之间的共生关系是如何持续的。在这里，我们证明土着细菌具有抑制宿主铁运输和储存的铁依赖机制。使用微生物代谢物的高通量筛网，我们发现肠道微生物会产生抑制缺氧诱导因子2α（HIF-2α）的代谢物，肠道铁吸收的主转录因子，增加了铁储存蛋白铁蛋白，导致通过宿主减少肠道铁吸收。通过抑制异二聚化，我们将1,3-二氨基丙烷（DAP）和Reuterin作为HIF-2α的抑制剂鉴定为HIF-2α的抑制剂。 DAP和Reuterin有效地改善了全身铁过载。这项工作提供了肠 - 微生物群代谢串扰的证据，这对于全身铁稳态至关重要。

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《Cell metabolism》 |2020年第1期|共22页
作者
Das Nupur K.; Schwartz Andrew J.; Barthel Gabrielle; Inohara Naohiro; Liu Qing; Sankar Amanda; Hill David R.; Ma Xiaoya; Lamberg Olivia; Schnizlein Matthew K.; Arques Juan L.; Spence Jason R.; Nunez Gabriel; Patterson Andrew D.; Sun Duxin; Young Vincent B.; Shah Yatrik M.;
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作者单位

Univ Michigan Dept Mol &

Integrat Physiol Ann Arbor MI 48109 USA;

Univ Michigan Dept Mol &

Integrat Physiol Ann Arbor MI 48109 USA;

Univ Michigan Dept Mol &

Integrat Physiol Ann Arbor MI 48109 USA;

Univ Michigan Dept Pathol Ann Arbor MI 48109 USA;

Penn State Univ Dept Vet &

Biomed Sci University Pk PA 16802 USA;

Univ Michigan Dept Pediat Div Hematol Oncol Ann Arbor MI 48109 USA;

Univ Michigan Dept Internal Med Div Gastroenterol Ann Arbor MI 48109 USA;

Univ Michigan Dept Mol &

Integrat Physiol Ann Arbor MI 48109 USA;

Univ Michigan Dept Mol &

Integrat Physiol Ann Arbor MI 48109 USA;

Univ Michigan Dept Microbiol &

Immunol Ann Arbor MI 48109 USA;

INIA Dept Tecnol &

Alimentos Carretera La Coruna Km 7 Madrid 28040 Spain;

Univ Michigan Dept Cell &

Dev Biol Ann Arbor MI 48109 USA;

Univ Michigan Dept Pathol Ann Arbor MI 48109 USA;

Penn State Univ Dept Vet &

Biomed Sci University Pk PA 16802 USA;

Univ Michigan Coll Pharm 428 Church St Ann Arbor MI 48109 USA;

Univ Michigan Dept Internal Med Div Infect Dis Ann Arbor MI 48109 USA;

Univ Michigan Dept Mol &

Integrat Physiol Ann Arbor MI 48109 USA;

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正文语种 eng
中图分类内分泌腺疾病及代谢病;
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专利

1. Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis [J] . Das Nupur K., Schwartz Andrew J., Barthel Gabrielle, Cell metabolism . 2020,第1期

机译：Systemic Iron Soyostasis需要微生物代谢物信号
2. Vacuolar ca~(2+)/H~+ transport activity is required for systemic phosphate homeostasis involving shoot-to-root signaling in arabidopsis [J] . Liu T.-Y., Aung K., Tseng C.-Y., Plant physiology . 2011,第3期

机译：拟南芥中涉及芽到根信号传导的系统性磷酸盐体内平衡需要液泡ca〜（2 +）/ H〜+转运活性
3. Local and systemic signaling of iron status and its interactions with homeostasis of other essential elements [J] . Sheena R. Gayomba, Zhiyang Zhai, Ha-il Jung, Frontiers in Plant Science . 2015,第1期

机译：铁状态的局部和全身信号及其与其他基本元素稳态的相互作用
4. Interplay of Nutrients and Microbial Metabolites in Intestinal Immune Homeostasis: Distinct and Common Mechanisms of Immune Regulation in the Small Bowel and Colon [C] . Jacqueline Perrigoue, Anuk Das, J. Rodrigo Mora Nestlé Nutrition Workshop . 2014

机译：肠免疫稳态中营养和微生物代谢物的相互作用：小肠和结肠中免疫调节的明显和常见机制
5. Metabolite Signaling Mediates Cellular Homeostasis and Proliferation [D] . Krall, Abigail Sarah 2018

机译：代谢物信号传导介导细胞稳态和增殖
6. Red Cells Iron and Erythropoiesis: Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis [O] . Karin E. Finberg, Rebecca L. Whittlesey, Mark D. Fleming, -1

机译：红细胞铁和促红细胞生成：需要通过Tmprss6下调Bmp / Smad信号来维持系统性铁稳态
7. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis [O] . Finberg, Karin E., Whittlesey, Rebecca L., Fleming, Mark D., 2010

机译：维持系统铁稳态需要通过Tmprss6下调Bmp / Smad信号传导

Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis

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