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The manganese transporter SLC39A8 links alkaline ceramidase 1 to inflammatory bowel disease

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  • Eun-Kyung Choi

    (University of Michigan School of Public Health)

  • Thekkelnaycke M. Rajendiran

    (University of Michigan Medical School
    University of Michigan Medical School)

  • Tanu Soni

    (University of Michigan Medical School)

  • Jin-Ho Park

    (University of Michigan School of Public Health)

  • Luisa Aring

    (University of Michigan School of Public Health)

  • Chithra K. Muraleedharan

    (University of Michigan Medical School)

  • Vicky Garcia-Hernandez

    (University of Michigan Medical School)

  • Nobuhiko Kamada

    (University of Michigan Medical School
    University of Michigan Medical School)

  • Linda C. Samuelson

    (University of Michigan Medical School
    University of Michigan Medical School)

  • Asma Nusrat

    (University of Michigan Medical School)

  • Shigeki Iwase

    (University of Michigan Medical School)

  • Young Ah Seo

    (University of Michigan School of Public Health)

Abstract

The metal ion transporter SLC39A8 is associated with physiological traits and diseases, including blood manganese (Mn) levels and inflammatory bowel diseases (IBD). The mechanisms by which SLC39A8 controls Mn homeostasis and epithelial integrity remain elusive. Here, we generate Slc39a8 intestinal epithelial cell-specific-knockout (Slc39a8-IEC KO) mice, which display markedly decreased Mn levels in blood and most organs. Radiotracer studies reveal impaired intestinal absorption of dietary Mn in Slc39a8-IEC KO mice. SLC39A8 is localized to the apical membrane and mediates 54Mn uptake in intestinal organoid monolayer cultures. Unbiased transcriptomic analysis identifies alkaline ceramidase 1 (ACER1), a key enzyme in sphingolipid metabolism, as a potential therapeutic target for SLC39A8-associated IBDs. Importantly, treatment with an ACER1 inhibitor attenuates colitis in Slc39a8-IEC KO mice by remedying barrier dysfunction. Our results highlight the essential roles of SLC39A8 in intestinal Mn absorption and epithelial integrity and offer a therapeutic target for IBD associated with impaired Mn homeostasis.

Suggested Citation

  • Eun-Kyung Choi & Thekkelnaycke M. Rajendiran & Tanu Soni & Jin-Ho Park & Luisa Aring & Chithra K. Muraleedharan & Vicky Garcia-Hernandez & Nobuhiko Kamada & Linda C. Samuelson & Asma Nusrat & Shigeki , 2024. "The manganese transporter SLC39A8 links alkaline ceramidase 1 to inflammatory bowel disease," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49049-8
    DOI: 10.1038/s41467-024-49049-8
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    References listed on IDEAS

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    1. Gabe Haller & Kevin McCall & Supak Jenkitkasemwong & Brooke Sadler & Lilian Antunes & Momchil Nikolov & Julia Whittle & Zachary Upshaw & Jimann Shin & Erin Baschal & Carlos Cruchaga & Matthew Harms & , 2018. "A missense variant in SLC39A8 is associated with severe idiopathic scoliosis," Nature Communications, Nature, vol. 9(1), pages 1-7, December.
    2. Lijun Dong & Jingwen Xie & Youyi Wang & Honglian Jiang & Kai Chen & Dantong Li & Jing Wang & Yunzhi Liu & Jia He & Jia Zhou & Liyun Zhang & Xiao Lu & Xiaoming Zou & Xiang-Yang Wang & Qingqing Wang & Z, 2022. "Mannose ameliorates experimental colitis by protecting intestinal barrier integrity," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Michelle Reed & Anny-Claude Luissint & Veronica Azcutia & Shuling Fan & Monique N. O’Leary & Miguel Quiros & Jennifer Brazil & Asma Nusrat & Charles A. Parkos, 2019. "Epithelial CD47 is critical for mucosal repair in the murine intestine in vivo," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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