Maternal aryl hydrocarbon receptor activation protects newborns against necrotizing enterocolitis

Peng Lu,Maame Sampah,Mark L Kovler,Qinjie Zhou,Peter Wipf,Thomas Prindle,William B Fulton,Yukihiro Yamaguchi,Sanxia Wang,Chhinder P Sodhi,Andres Gonzalez Salazar,David J Hackam,Hongpeng Jia

doi:10.1038/s41467-021-21356-4

Peng Lu, Maame Sampah + Show 11 more

Open Access

https://doi.org/10.1038/s41467-021-21356-4

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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.

Highlights

Necrotizing enterocolitis (NEC) is a disease of premature infants characterized by acute intestinal necrosis
We reveal that the administration of a maternal diet that is rich in the aryl hydrocarbon receptor (AHR) ligand indole-3-carbinol (I3C) during pregnancy can prevent NEC in the offspring, and that subsequent AHR signaling in the newborn intestinal epithelium prevents NEC by curtailing the extent of Toll-like receptor 4 (TLR4) signaling
We show that breast milk prevents NEC through activation of AHR in the newborn gut and reducing TLR4 signaling in the newborn intestinal epithelium

Summary

Introduction

Necrotizing enterocolitis (NEC) is a disease of premature infants characterized by acute intestinal necrosis. The administration of I3C still protected IEL-depleted pups from NEC (Supplementary Fig. 5e–h), making it unlikely that the effects of I3C can be attributed to IELs. Based upon these studies, and given that TLR4 plays a critical role in NEC pathogenesis[4,5,11,24], we turned to the potential role of AHR activation in reducing TLR4 signaling or expression in the neonatal intestinal epithelium.

Results

Conclusion