Microbiota regulates neonatal disease tolerance to virus-evoked necrotizing enterocolitis by shaping the STAT1-NLRC5 axis in the intestinal epithelium

IF 20.6 1区医学 Q1 MICROBIOLOGY

Cell host & microbe Pub Date : 2024-09-17 DOI:10.1016/j.chom.2024.08.013

Saravanan Subramanian, Hua Geng, Longtao Wu, Chao Du, Amy M. Peiper, Heng-Fu Bu, Pauline M. Chou, Xiao Wang, Stephanie C. Tan, Neha R. Iyer, Nazeer Hussain Khan, Ellen L. Zechner, James G. Fox, Rolf Breinbauer, Chao Qi, Bakhtiar Yamini, Jenny P. Ting, Isabelle G. De Plaen, Stephanie M. Karst, Xiao-Di Tan

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Abstract

Microbiota and feeding modes influence the susceptibility of premature newborns to necrotizing enterocolitis (NEC) through mechanisms that remain unknown. Here, we show that microbiota colonization facilitated by breastmilk feeding promotes NOD-like receptor family CARD domain containing 5 (Nlrc5) gene expression in mouse intestinal epithelial cells (IECs). Notably, inducible knockout of the Nlrc5 gene in IECs predisposes neonatal mice to NEC-like injury in the small intestine upon viral inflammation in an NK1.1⁺ cell-dependent manner. By contrast, formula feeding enhances neonatal gut colonization with environment-derived tilivalline-producing Klebsiella spp. Remarkably, tilivalline disrupts microbiota-activated STAT1 signaling that controls Nlrc5 gene expression in IECs through a PPAR-γ-mediated mechanism. Consequently, this dysregulation hinders the resistance of neonatal intestinal epithelium to self-NK1.1⁺ cell cytotoxicity upon virus infection/colonization, promoting NEC development. Together, we discover the underappreciated role of intestinal microbiota colonization in shaping a disease tolerance program to viral inflammation and elucidate the mechanisms impacting NEC development in neonates.

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微生物群通过塑造肠上皮细胞中的 STAT1-NLRC5 轴来调节新生儿对病毒诱发的坏死性小肠结肠炎的疾病耐受性

微生物群和喂养方式影响早产新生儿对坏死性小肠结肠炎（NEC）的易感性，其机制尚不清楚。在这里，我们发现母乳喂养促进了微生物群的定植，从而促进了小鼠肠上皮细胞（IECs）中 NOD 样受体家族 CARD domain containing 5（Nlrc5）基因的表达。值得注意的是，诱导性敲除 IECs 中的 Nlrc5 基因会使新生小鼠在病毒性炎症时容易受到 NK1.1+ 细胞依赖性的小肠 NEC 样损伤。值得注意的是，替利瓦林会破坏微生物群激活的 STAT1 信号，这种信号通过 PPAR-γ 介导的机制控制 IEC 中 Nlrc5 基因的表达。因此，这种失调阻碍了新生儿肠上皮细胞在病毒感染/定植时对自身 NK1.1+ 细胞毒性的抵抗力，从而促进了 NEC 的发生。我们共同发现了肠道微生物群定植在形成对病毒性炎症的疾病耐受程序中未被重视的作用，并阐明了影响新生儿 NEC 发生的机制。

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来源期刊

Cell host & microbe 生物-微生物学

CiteScore

45.10

自引率

1.70%

发文量

201

审稿时长

4-8 weeks

期刊介绍： Cell Host & Microbe is a scientific journal that was launched in March 2007. The journal aims to provide a platform for scientists to exchange ideas and concepts related to the study of microbes and their interaction with host organisms at a molecular, cellular, and immune level. It publishes novel findings on a wide range of microorganisms including bacteria, fungi, parasites, and viruses. The journal focuses on the interface between the microbe and its host, whether the host is a vertebrate, invertebrate, or plant, and whether the microbe is pathogenic, non-pathogenic, or commensal. The integrated study of microbes and their interactions with each other, their host, and the cellular environment they inhabit is a unifying theme of the journal. The published work in Cell Host & Microbe is expected to be of exceptional significance within its field and also of interest to researchers in other areas. In addition to primary research articles, the journal features expert analysis, commentary, and reviews on current topics of interest in the field.