The race against helminths: physiological and evolutionary impacts of endurance exercise on the IL-13 immune response

Abstract

Mounting evidence that the type 2 cytokine IL-13 is upregulated by endurance training to jointly mediate helminth resistance and endurance capacity suggests an energetic tug-of-war between endurance exercise and helminth infection playing out in evolutionary time. First, this study examined the link between IL-13 and exercise in an ecologically viable rewilded mouse model, testing the prediction that more active mice are more likely to launch an IL-13 response against antigenic stimuli in MLN assays. Considering two cohorts of rewilded mice (N = 97), activity was a unique predictor of binomial production of IL-13 (p < 0.05) among the cytokines examined including IL-10, IFNγ, and IL-17. Furthermore, this effect was mediated directly by host pathways rather than the gut microbiome, with no clear association between activity and microbiome profile or diversity. The exercise-IL-13 link was then examined across a larger group of 34 laurasiatherian mammals to test an expected endurance-helminth species richness evolutionary correlation and look for signals of intensified selection on IL-13 pathway genes in species with high endurance capacities. No evolutionary correlation was found in OLS or PGLS models, suggesting co-evolutionary complexity across the phylogeny. However, selection was intensified on Il13ra1 (p < 0.01) and relaxed on Gata3 (p < 0.001) among high-endurance test lineages, implicating the IL-13 pathway in endurance capacity evolution and implying potential constitutive GATA-3 production or Th2-regulatory evolution in high-endurance states. These findings highlight endurance as a crucial factor in the helminth-host co-evolutionary race, mediated by the IL-13 pathway at physiological and evolutionary scales.