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

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 Iwase and Young Ah Seo ()
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Eun-Kyung Choi: University of Michigan School of Public Health
Thekkelnaycke M. Rajendiran: 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
Linda C. Samuelson: 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

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49049-8

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