Shealy Nicolas G, Baltagulov Madi, de Brito Camila, McGovern Anna, Castro Pollyana, Schrimpe-Rutledge Alexandra C, Malekshahi Clara, Condreanu Simona G, Sherrod Stacy D, Jana Somnath, Jones Katerina, Ribeiro Tamara Machado, McLean John A, Beiting Daniel P, Byndloss Mariana X
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37203, U. S. A.
Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil.
bioRxiv. 2025 Mar 25:2025.03.25.645332. doi: 10.1101/2025.03.25.645332.
In addition to individual genetics, environmental factors (e.g., dietary changes) may influence host susceptibility to gastrointestinal infection through unknown mechanisms. Herein, we developed a model in which CBA/J mice, a genetically resistant strain that tolerates intestinal colonization by the enteric pathogen Typhimurium ( Tm), rapidly succumb to infection after exposure to a diet rich in L-amino acids (AA). In mice, Tm-gastroenteritis is restricted to the large intestine (cecum), limiting their use to understand . Tm small intestine (ileum) colonization, a feature of human Salmonellosis. Surprisingly, CBA mice fed AA diet developed ileitis with enhanced . Tm ileal colonization. Using germ-free mice and ileal-fecal slurry transplant, we found diet-mediated . Tm ileal expansion to be microbiota-dependent. Mechanistically, . Tm relied on Fructosyl-asparagine utilization to expand in the ileum during infection. We demonstrate how AA diet overrides host genetics by altering the gut microbiota's ability to prevent Tm ileal colonization.
除个体遗传因素外，环境因素（如饮食变化）可能通过未知机制影响宿主对胃肠道感染的易感性。在此，我们构建了一个模型，其中CBA/J小鼠是一种对肠道病原体鼠伤寒沙门氏菌（Tm）的肠道定植具有耐受性的遗传抗性品系，但在接触富含L-氨基酸（AA）的饮食后会迅速死于感染。在小鼠中，Tm性肠胃炎局限于大肠（盲肠），这限制了它们用于理解人类沙门氏菌病的一个特征——Tm在小肠（回肠）的定植。令人惊讶的是，喂食AA饮食的CBA小鼠发生了回肠炎，且Tm在回肠的定植增强。使用无菌小鼠和回肠-粪便浆液移植，我们发现饮食介导的Tm在回肠的扩张依赖于微生物群。从机制上讲，Tm在感染期间依靠利用果聚糖天冬酰胺在回肠中扩张。我们证明了AA饮食如何通过改变肠道微生物群预防Tm在回肠定植的能力来超越宿主遗传学。
