Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
Division of Neuroscience, Oregon National Primate Research Center, Portland, OR, USA.
Mucosal Immunol. 2021 Sep;14(5):1113-1126. doi: 10.1038/s41385-021-00418-2. Epub 2021 Jun 22.
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，但由于缺乏研究整个肠道样本的研究，我们对其后遗症的了解受到了严重阻碍。婴儿恒河猴易受人类肠道病原体感染，并能重现腹泻病的特征，如肠道炎症和生长迟缓。在这里，我们检查了健康婴儿和经历生长迟缓以及急性或慢性活动性腹泻的婴儿的肠道活检、固有层白细胞、腔内容物和粪便样本。我们表明，无论是否存在活动性腹泻，生长迟缓都与以结肠为中心的全身和黏膜促炎状态有关。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。我们还在包括小肠和大肠之间链球菌和普雷沃菌属物种迁移在内的多个肠道部位检测到腔微生物组的功能和分类转变，这表明肠道微生物群落的去隔间化。我们的研究为人类无法获得的腹泻病和生长迟缓的结果提供了有价值的见解，并为在可控和可重复的环境中测试干预措施奠定了基础。
