Manchester Immunology Group, Faculty of Life Sciences, University of Manchester, Manchester, UK.
PLoS Pathog. 2013 Jan;9(1):e1003122. doi: 10.1371/journal.ppat.1003122. Epub 2013 Jan 17.
Gastrointestinal infection is often associated with hypophagia and weight loss; however, the precise mechanisms governing these responses remain poorly defined. Furthermore, the possibility that alterations in feeding during infection may be beneficial to the host requires further study. We used the nematode Trichinella spiralis, which transiently inhabits the small intestine before migrating to skeletal muscle, as a biphasic model of infection to determine the cellular and molecular pathways controlling feeding during enteric and peripheral inflammation. Through the infection of genetically modified mice lacking cholecystokinin, Tumor necrosis factor α receptors and T and B-cells, we observed a biphasic hypophagic response to infection resulting from two separate immune-driven mechanisms. The enteroendocrine I-cell derived hormone cholecystokinin is an essential mediator of initial hypophagia and is induced by CD4+ T-cells during enteritis. In contrast, the second hypophagic response is extra-intestinal and due to the anorectic effects of TNFα during peripheral infection of the muscle. Moreover, via maintaining naive levels of the adipose secreted hormone leptin throughout infection we demonstrate a novel feedback loop in the immunoendocrine axis. Immune driven I-cell hyperplasia and resultant weight loss leads to a reduction in the inflammatory adipokine leptin, which in turn heightens protective immunity during infection. These results characterize specific immune mediated mechanisms which reduce feeding during intestinal or peripheral inflammation. Importantly, the molecular mediators of each phase are entirely separate. The data also introduce the first evidence that I-cell hyperplasia is an adaptively driven immune response that directly impinges on the outcome to infection.
胃肠道感染通常与食欲减退和体重减轻有关；然而，控制这些反应的确切机制仍不清楚。此外，感染期间进食的改变可能对宿主有益，这一可能性需要进一步研究。我们使用短暂寄居在小肠中然后迁移到骨骼肌的旋毛虫作为感染的双相模型，以确定控制肠道和外周炎症期间进食的细胞和分子途径。通过感染缺乏胆囊收缩素、肿瘤坏死因子-α受体和 T 细胞和 B 细胞的基因修饰小鼠，我们观察到感染引起的双相食欲减退反应是由两种独立的免疫驱动机制引起的。肠内分泌细胞 I 细胞衍生的激素胆囊收缩素是初始食欲减退的必需介质，在肠炎期间由 CD4+T 细胞诱导。相比之下，第二次食欲减退反应是肠外的，是由于肌肉外周感染期间 TNFα 的厌食作用。此外，通过在整个感染过程中维持脂肪分泌激素瘦素的幼稚水平，我们证明了免疫内分泌轴中的一个新的反馈回路。免疫驱动的 I 细胞增生和由此导致的体重减轻导致炎症脂肪因子瘦素减少，这反过来又在感染期间增强了保护性免疫。这些结果描述了特定的免疫介导机制，这些机制可减少肠道或外周炎症期间的进食。重要的是，每个阶段的分子介质完全是分开的。该数据还首次表明，I 细胞增生是一种适应性驱动的免疫反应，直接影响感染的结果。
