Spencer Paige N, Wang Jiawei, Smith Erin P, Spiga Luisella, Simmons Alan J, Kim Taewoo, Kim William, Brown Monica E, Yang Yilin, Kaur Harsimran, Xu Yanwen, Kang Seung Woo, Helou Matthew D, Lee Mason A, Zheng Lin, Arceneaux Deronisha, Tasneem Naila, Mueller Katherine D, Kuddar Ozge S, Harned Mariah H, Ro James, Li Jing, Banerjee Amrita, Markham Nicholas O, Wilson Keith T, Coburn Lori A, Goettel Jeremy A, Liu Qi, Kay Washington M, Valdivia Raphael H, Zhu Wenhan, Lau Ken S
Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA.
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA.
bioRxiv. 2025 Jan 4:2025.01.04.630951. doi: 10.1101/2025.01.04.630951.
The structure and function of the mammalian gut vary by region, yet why inflammatory diseases manifest in specific regions and not others remains unclear. We use a TNF-overexpressing Crohn's disease (CD) model (Tnf), which typically presents in the terminal ileum (TI), to investigate how environmental factors interact with the host's immune susceptibility to drive region-specific disease. We identified an intracellular bacterium and murine counterpart to the human sexually transmitted , as necessary and sufficient to trigger disease manifestation in the ascending colon (AC), another common site of human CD. Disease manifestation in the AC depends on indoleamine 2,3-dioxygenase (IDO1) activity induced by hypersensitive surface secretory cells in genetically susceptible hosts. Single-cell and microbial analyses of human specimens also implicates this pathobiont-epithelial IDO1 pathway in patients with a history of CD in the AC. Our findings demonstrate that genetic and microbial factors can independently drive region-specific disease and provide a unique model to study CD specific to the AC.
哺乳动物肠道的结构和功能因区域而异，但炎症性疾病为何在特定区域而非其他区域表现出来仍不清楚。我们使用一种过表达肿瘤坏死因子（TNF）的克罗恩病（CD）模型（Tnf），该模型通常出现在回肠末端（TI），以研究环境因素如何与宿主的免疫易感性相互作用，从而引发区域特异性疾病。我们鉴定出一种细胞内细菌以及人类性传播细菌的小鼠对应物，它们是在升结肠（AC）（人类CD的另一个常见部位）引发疾病表现所必需且充分的条件。AC中的疾病表现取决于基因易感宿主中高敏表面分泌细胞诱导的吲哚胺2,3-双加氧酶（IDO1）活性。对人类标本的单细胞和微生物分析也表明，在AC中有CD病史的患者中存在这种致病共生菌-上皮IDO1途径。我们的研究结果表明，遗传和微生物因素可以独立驱动区域特异性疾病，并提供了一个独特的模型来研究AC特有的CD。
