Despite the impact of childhood diarrhea on morbidity and mortality, our understanding of its sequelae has been significantly hampered by the lack of studies that examine samples across the entire intestinal tract. Infant rhesus macaques are naturally susceptible to human enteric pathogens and recapitulate the hallmarks of diarrheal disease such as intestinal inflammation and growth faltering. Here, we examined intestinal biopsies, lamina propria leukocytes, luminal contents, and fecal samples from healthy infants and those experiencing growth faltering with distant acute or chronic active diarrhea. We show that growth faltering in the presence or absence of active diarrhea is associated with a heightened systemic and mucosal pro-inflammatory state centered in the colon. Moreover, polyclonal stimulation of colonic lamina propria leukocytes resulted in a dampened cytokine response, indicative of immune exhaustion. We also detected a functional and taxonomic shift in the luminal microbiome across multiple gut sites including the migration of Streptococcus and Prevotella species between the small and large intestine, suggesting a decompartmentalization of gut microbial communities. Our studies provide valuable insight into the outcomes of diarrheal diseases and growth faltering not attainable in humans and lays the groundwork to test interventions in a controlled and reproducible setting.

尽管儿童腹泻对发病率和死亡率有影响，但由于缺乏检查整个肠道样本的研究，我们对其后遗症的理解受到了严重阻碍。恒河猴幼崽天生就容易受到人类肠道病原体的影响，并具有腹泻病的特征，例如肠道炎症和生长迟缓。在这里，我们检查了健康婴儿和因远期急性或慢性活动性腹泻而生长缓慢的婴儿的肠道活检、固有层白细胞、管腔内容物和粪便样本。我们发现，在存在或不存在活动性腹泻的情况下，生长缓慢与以结肠为中心的全身和粘膜促炎症状态的升高有关。此外，结肠固有层白细胞的多克隆刺激导致细胞因子反应减弱，表明免疫衰竭。我们还检测到多个肠道位点的腔内微生物组的功能和分类学变化，包括链球菌和普雷沃氏菌在小肠和大肠之间的迁移，这表明肠道微生物群落的分化。我们的研究为人类无法实现的腹泻疾病和生长迟缓的结果提供了宝贵的见解，并为在受控和可重复的环境中测试干预措施奠定了基础。