Impact of exercise and nutritional manipulations on inflammatory function in humans

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The long-term objective of my NSERC research is to understand the interactions between metabolism and inflammation in humans. Using an integrative physiology approach where exercise and nutrition are used to alter metabolism and study the effects on immune cells, we advance understanding in the fields of metabolism and inflammation. We have two short-term objectives for the next 5 years. 1)To determine how exercise intensity and pattern impact anti-inflammatory cytokine function, and the mechanisms involved. 2)To determine how nutritional ketosis impacts immune cell phenotype and function. Our recent findings indicate that exercise reduces the anti-inflammatory action of IL10 and IL6, and that there was a greater impact of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT). However, our study was limited to fasting blood samples before and after short-term training and the design could not separate the influence of exercise intensity vs. pattern. Accordingly, we will perform time course experiments with blood samples obtained at specific timepoints after acute (single bout) exercise or chronic exercise training (12 wk). Participants will complete HIIT, high-intensity continuous training (HICT), or MICT matched for exercise duration and volume to isolate the impact of exercise intensity or pattern. The main outcomes are IL10/IL6 function, assessed by measuring the ability of these anti-inflammatory cytokines to inhibit TNF-alpha secretion in whole blood cultures from samples obtained before and after exercise. Intracellular signalling pathways activated by IL10 and IL6 will be measured to provide mechanistic insight. Previous research has measured circulating IL10 and IL6 following exercise and inferred anti-inflammatory effects. Our work is the first to explore how these cytokines function and will therefore provide new understanding of how exercise impacts immune cell phenotype and function. To address the second objective, we will use newly developed exogenous ketone supplements that raise circulating beta-hydroxybutyrate (BHB) concentration without the need and confounding influence of restrictive diets. We will study the acute impacts of ketone supplementation on a single day and over four weeks to examine how raising BHB impacts metabolism and inflammation. The major immune outcomes will be caspase-1 activation and cytokine secretion assessed in whole blood cultures obtained before and after ketone supplementation. These studies will help determine whether nutritional ketosis has direct effects on leukocytes and expand our understanding of how B-OHB acts as a signaling molecule to integrate metabolic state and immune function. Impact: This NSERC research program will manipulate metabolism and study molecular pathways in primary human immune cells in an integrated fashion. Findings will provide important new information in the field of immunometabolism with direct relevance to human physiology.