Adaptive Immunity Alters Distinct Host Feeding Pathways during Nematode Induced Inflammation, a Novel Mechanism in Parasite Expulsion

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.

胃肠道感染常伴随摄食减少与体重减轻，但调控此类反应的确切机制仍未明确。此外，感染期间进食行为改变可能对宿主有益这一假说，仍需进一步研究验证。本研究以旋毛形线虫（Trichinella spiralis）作为双相感染模型——该虫体在迁移至骨骼肌前会短暂寄生于小肠——旨在明确调控肠源性与外周炎症期摄食行为的细胞及分子通路。通过对敲除胆囊收缩素（cholecystokinin）、肿瘤坏死因子α（Tumor necrosis factor α）受体以及T、B细胞的基因工程小鼠进行感染实验，我们观察到感染引发的双相摄食减少反应由两种独立的免疫驱动机制介导。肠内分泌I细胞分泌的胆囊收缩素是初始摄食减少的关键介质，其在肠炎阶段由CD4+ T细胞诱导产生。与之相反，第二次摄食减少反应发生于肠外，由肌肉外周感染时期肿瘤坏死因子α的厌食效应所介导。此外，通过在整个感染过程中维持脂肪分泌激素瘦素（leptin）的基础水平，我们揭示了免疫内分泌轴中一种全新的反馈环路：免疫驱动的I细胞增生以及由此引发的体重减轻会导致炎性脂肪因子瘦素水平降低，而这一变化又会增强感染期间的保护性免疫。本研究明确了介导肠道或外周炎症期摄食减少的特异性免疫机制。值得注意的是，两个阶段的分子介质完全不同。本研究数据还首次证明，I细胞增生是一种适应性免疫应答，可直接影响感染的转归。