Inflammatory bowel disease (IBD) is a complex disorder that imposes a growing health burden. Multiple genetic associations have been identified in IBD, but the mechanisms underlying many of these associations are poorly understood. Animal models are needed to bridge this gap, but conventional laboratory mouse strains lack the genetic diversity of human populations. To more accurately model human genetic diversity, we utilized a panel of chromosome (Chr) substitution strains, carrying chromosomes from the wild-derived and genetically divergent PWD/PhJ (PWD) strain on the commonly used C57BL/6J (B6) background, as well as their parental B6 and PWD strains. Two models of IBD were used, TNBS- and DSS-induced colitis. Compared with B6 mice, PWD mice were highly susceptible to TNBS-induced colitis, but resistant to DSS-induced colitis. Using consomic mice, we identified several PWD-derived loci that exhibited profound effects on IBD susceptibility. The most pronounced of these were loci on Chr1 and Chr2, which yielded high susceptibility in both IBD models, each acting at distinct phases of the disease. Leveraging transcriptomic data from B6 and PWD immune cells, together with a machine learning approach incorporating human IBD genetic associations, we identified lead candidate genes, including Itga4, Pip4k2a, Lcn10, Lgmn, and Gpr65.

炎症性肠病（IBD）是一种复杂的疾病，给健康带来越来越大的负担。已在 IBD 中发现多种遗传关联，但其中许多关联背后的机制尚不清楚。需要动物模型来弥补这一差距，但传统的实验室小鼠品系缺乏人类群体的遗传多样性。为了更准确地模拟人类遗传多样性，我们利用了一组染色体 (Chr) 替换菌株，在常用的 C57BL/6J (B6) 背景上携带来自野生且遗传分化的 PWD/PhJ (PWD) 菌株的染色体，如及其亲本 B6 和 PWD 菌株。使用两种 IBD 模型：TNBS 和 DSS 诱导的结肠炎。与B6小鼠相比，PWD小鼠对TNBS诱导的结肠炎高度敏感，但对DSS诱导的结肠炎具有抵抗力。使用体鼠，我们鉴定了几个 PWD 衍生的位点，这些位点对 IBD 易感性表现出深远的影响。其中最明显的是 Chr1 和 Chr2 上的位点，它们在两种 IBD 模型中产生高易感性，每种模型在疾病的不同阶段发挥作用。利用 B6 和 PWD 免疫细胞的转录组数据，结合人类 IBD 遗传关联的机器学习方法，我们确定了主要候选基因，包括Itga4、Pip4k2a、Lcn10、Lgmn和Gpr65 。