Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.

损害肠道细菌感应的先天免疫遗传缺陷与炎症性肠病（IBD）的发展有关。尽管许多证据支持肠道病毒组在肠道稳态中的作用，但大多数研究关注肠道病毒组成而不是宿主肠道病毒敏感性。旨在证明极早发型 IBD (VEOIBD) 的发展与编码 MDA5（病毒核酸的关键胞质传感器）的IFIH1基因变异之间的关联。在意大利 ( n  = 18) 和美国 ( n  = 24)登记的两个独立的 VEIOBD 儿童队列中进行了全外显子组测序 (WES) 。采用荧光素酶报告基因测定来评估 MDA5 活性。对IFIH1进行了富集分析，将 42 名 VEIOBD 先证者与 1527 名没有胃肠道或免疫学问题的无关个体进行比较。我们在 42 名儿童的联合队列中的 8 名 VEIOBD 患者中发现了罕见的、可能功能丧失 (LoF) 的IFIH1变异。一名受试者携带导致完全 LoF 的纯合截短变异，经历了新生儿发病、全胃肠道、IBD 样肠病以及多次感染发作。其余 7 名受 VEIOBD 影响但无免疫缺陷的受试者是IFIH1中一种 LoF 变异的携带者。其中，两名患者还携带第二种亚效基因变异，当 MDA5 受到微弱刺激时，其部分功能明显。此外，与对照组相比，患有 VEIOBD 的儿童的IFIH1变异显着丰富 ( p  = 0.007)。完全和部分 MDA5 缺乏与具有可变外显率和表达性的 VEIOBD 相关，表明肠道病毒感应受损在 IBD 发病机制中发挥着作用。