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

Abstract

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.

Author Summary

Infection with intestinal parasites often results in a period of reduced appetite which can result in weight loss; however the factors which control these feeding alterations and the reason why they occur is unknown. We used the nematode parasite Trichinella spiralis, which during its life cycle causes intestinal and muscular inflammation, as a mouse infection model to study the factors which alter feeding during infection. We found that the mouse immune response to the parasite was driving two periods of reduced feeding by two distinct immune mediators during the intestinal and muscular periods of infection. Interestingly, the immune system was utilizing a hormone which usually terminates feeding during our daily meals to cause a reduction in weight and fat deposits. Furthermore, we found that a reduction in these fat deposits and their associated hormones actually helped the mouse expel the parasite from the intestine. Hence the immune driven weight loss was actually beneficial to the mouse's ability to resolve an infection. Our study provides novel insights into how the immune system interacts with feeding pathways during intestinal inflammation and may help us design new strategies for helping people with parasitic infections of the gut.