Role of gut microbe composition in psychosocial symptom response to exercise training in breast cancer survivors

Growing evidence supports the importance of the gut microbiota composition for health and well-being. Breast cancer survivors are at increased risk for altered microbiota composition (dysbiosis) which may contribute to cancer risk and symptoms such as fatigue. Animal models and human studies (including work by our investigative team) have linked exercise with favorable changes in gut microbial diversity, an abundance of select microbes, and production of beneficial metabolites. As such, exercise is a promising strategy for reversing dysbiosis yet only one human study has used a randomized design, none have strictly controlled diet, and none have enrolled cancer survivors. Determining exercise training effects on gut microbiota composition in cancer survivors and potential mechanistic links between exercise, gut microbiota composition, and fatigue can be applied to optimizing exercise benefits and developing new therapeutic applications. Doing so in fatigued breast cancer survivors provides the opportunity to reduce a distressing symptom suffered by many of the 3.1 million breast cancers survivors living in the U.S. Therefore, we propose a randomized controlled trial among breast cancer survivors with fatigue and low cardiorespiratory fitness. Assessments will occur at baseline, 6 weeks, 12 weeks, and 18 weeks. Our specific aims are as follows: Primary aim: Determine effects of a progressive 12-week aerobic exercise training intervention (focused on improving cardiorespiratory fitness [peak VO2]) compared to standard attention control on gut microbiota composition (primary outcome) while standardizing diet across all participants with controlled feeding. Based on our preliminary work, we hypothesize that compared to control, the aerobic exercise training group will demonstrate significant differences in gut microbial diversity with increased Bacteroides (g), increased Firmicutes (p), and decreased Actinomycetales (o) and Proteobacteria (p). Week 12 is our primary time point; week 6 will explore interim changes and week 18 will explore durability of effects. Secondary aim: 1) Test if the aerobic exercise training effect on gut microbiota composition is directly and/or indirectly mediated through inflammation (interleukin [IL] – 6, IL – 10), autonomic nervous system (heart rate variability), or hypothalamic-pituitary-adrenal axis (cortisol). Given the dynamic brain-gut-microbiota axis, we will test mediation relationships by ordering our outcome measures within the assessment period such that hypothesized mediators are assessed in the week prior to the fecal collection. 2) Test if the aerobic exercise training effect on fatigue is directly and/or indirectly mediated through changes in the gut microbiota composition. We will explore these mediation relationships within each assessment time points by collecting the fecal sample prior to fatigue measurement. Determining exercise effects on gut microbiota composition in cancer survivors holds the potential to identify targets for enhancing exercise benefits while also providing foundational data for personalized exercise prescriptions based on gut microbiota composition and gut microbiota composition manipulation for improved health.