Characterizing individual responsiveness to exercise to enable engineering of mitohormetic probiotics

University Of Oregon, Eugene OR

Investigators

Abstract

SUMMARY Regular endurance exercise is the most effective intervention known to promote metabolic health. In animal models, the fitness benefits of endurance exercise can be partially transferred through fecal microbiome transplantations from exercised donors into sedentary recipients, demonstrating the possibility of designing engineered probiotics that act as exercise mimetics. Before this goal can be realized, however, more information is needed on the sources of variability in microbiome-transmissible fitness. This project will explore the hypothesis that microbiomes confer metabolic fitness through their stimulation of host cell mitochondrial adaptations, mimicking the mitochondrial adaptations induced by exercise through “mito-stimulatory” processes. We have identified a secreted bacterial protein, BefA, with mito-stimulatory activity that is representative of activities produced by many members of human and other animal gut microbiomes. BefA promotes metabolic health in germ-free animals, but its efficacy is diminished in colonized animals, leading to the corollary hypothesis that the baseline mito-stimulatory activity of individuals’ microbiomes determines their capacity to respond to exogenous mito-stimulatory interventions. In the R61 phase of this project, we propose to establish a robust method for measuring the collective mito-stimulatory activity of fecal samples. We will document variation in mito-stimulatory activity from human fecal samples as a function of donor metabolic fitness. To enable subsequent mechanistic studies, we will establish whether patterns of exercise-associated fecal mito-stimulatory activity observed in humans are also observed in the preclinical animal model of exercise trained zebrafish. We have clearly defined Go/No Go criteria for the establishment of robust mito-stimulatory assays and the documentation of relationships between exercise and microbiome function to guide our transition to the next phase of the project. In the R33 phase, we will use the exercise trained zebrafish model to test how differing baseline fecal mito-stimulatory activities modulate the efficacy of a prototypical mito-stimulatory probiotic engineered to secrete BefA.