Running title: Gut endocrine cells operate under immune control 1 Immune control of food intake: enteroendocrine cells are regulated by CD4 T- lymphocytes during small intestinal inflammation

Background and aims: Gastrointestinal inflammation reduces food intake, but the biological mechanisms explaining suppressed feeding during inflammation are unknown. We have used a model of upper gut infection (Trichinella spiralis in the mouse) to study the effect of inflammation on food intake, and explored the role of a key enteroendocrine cell (EEC) in the regulation of feeding by the immune response. Methods: Food intake of NIH mice infected with the intestinal nematode Trichinella spiralis was measured. Duodenal cholecystokinin (CCK) cells were counted. Plasma CCK was measured. Infected mice were treated with a specific CCK1 receptor antagonist, and food intake reassessed. The influence of the immune response on food intake and CCK was mechanistically examined by treating mice with CD4 or mast cell neutralising antibodies. The role of the T helper 2 response was further explored in mice genetically deficient for IL-4, IL-13 or IL-4Rα. Results: Food intake of infected mice was significantly reduced at the temporal peak of intestinal inflammation. Cholecystokinin (CCK)-expressing EEC were upregulated in infected mice, and plasma CCK levels were increased. A CCK1 receptor antagonist restored the food intake of infected mice to a significant degree. Furthermore, suppression of food intake was completely abolished in the absence of CD4 Tlymphocytes or IL-4Rα. Conclusions: The data show for the first time that intestinal inflammation results in reduced food intake due to up-regulation of CCK. Moreover, following infection, food intake and CCK expressing cells are under the specific control of CD4 T-cells, via the release of IL-4 and IL-13. group.bmj.com on October 30, 2017 Published by http://gut.bmj.com/ Downloaded from