Microbiota-assisted iron uptake promotes immune tolerance in the intestine

Lizhen Zhu, Geng Li, Zhixin Liang, Tuan Qi, Kui Deng, Jiancheng Yu, Yue Peng, Jusheng Zheng, Yan Song and Xing Chang ()
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Lizhen Zhu: Westlake University
Geng Li: Westlake University
Zhixin Liang: Westlake University
Tuan Qi: Westlake University
Kui Deng: Westlake University
Jiancheng Yu: Westlake University
Yue Peng: Westlake University
Jusheng Zheng: Westlake University
Yan Song: University of California San Diego
Xing Chang: Westlake University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Iron deficiencies are the most common nonenteric syndromes observed in patients with inflammatory bowel disease, but little is known about their impacts on immune tolerance. Here we show that homeostasis of regulatory T cells in the intestine was dependent on high cellular iron levels, which were fostered by pentanoate, a short-chain fatty acid produced by intestinal microbiota. Iron deficiencies in Treg caused by the depletion of Transferrin receptor 1, a major iron transporter, result in the abrogation of Treg in the intestine and lethal autoimmune disease. Transferrin receptor 1 is required for differentiation of c-Maf+ Treg, major constituents of intestinal Treg. Mechanistically, iron enhances the translation of HIF-2α mRNA, and HIF-2α in turn induces c-Maf expression. Importantly, microbiota-produced pentanoate promotes iron uptake and Treg differentiation in the intestine. This subsequently restores immune tolerance and ameliorated iron deficiencies in mice with colitis. Our results thus reveal an association between nutrient uptake and immune tolerance in the intestine.

Date: 2023
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DOI: 10.1038/s41467-023-38444-2

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