Maternal aryl hydrocarbon receptor activation protects newborns against necrotizing enterocolitis

Peng Lu (), Yukihiro Yamaguchi, William B. Fulton, Sanxia Wang, Qinjie Zhou, Hongpeng Jia, Mark L. Kovler, Andres Gonzalez Salazar, Maame Sampah, Thomas Prindle, Peter Wipf, Chhinder P. Sodhi and David J. Hackam ()
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Peng Lu: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
Yukihiro Yamaguchi: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
William B. Fulton: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
Sanxia Wang: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
Qinjie Zhou: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
Hongpeng Jia: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
Mark L. Kovler: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
Andres Gonzalez Salazar: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
Maame Sampah: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
Thomas Prindle: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
Peter Wipf: University of Pittsburgh
Chhinder P. Sodhi: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center
David J. Hackam: Johns Hopkins University School of Medicine and the Johns Hopkins Children’s Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Necrotizing enterocolitis (NEC) is a disease of premature infants characterized by acute intestinal necrosis. Current dogma suggests that NEC develops in response to post-natal dietary and bacterial factors, and so a potential role for in utero factors in NEC remains unexplored. We now show that during pregnancy, administration of a diet rich in the aryl hydrocarbon receptor (AHR) ligand indole-3-carbinole (I3C), or of breast milk, activates AHR and prevents NEC in newborn mice by reducing Toll-like receptor 4 (TLR4) signaling in the newborn gut. Protection from NEC requires activation of AHR in the intestinal epithelium which is reduced in mouse and human NEC, and is independent of leukocyte activation. Finally, we identify an AHR ligand (“A18”) that limits TLR4 signaling in mouse and human intestine, and prevents NEC in mice when administered during pregnancy. In summary, AHR signaling is critical in NEC development, and maternally-delivered, AHR-based therapies may alleviate NEC.

Date: 2021
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DOI: 10.1038/s41467-021-21356-4

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