PROJECT SUMMARY: In the U.S, 91.8 million adults have prediabetes (PreD). High PreD prevalence
represents a prominent public health problem as up to 70% of individuals with PreD convert to type 2 diabetes
(T2D). Cardiovascular disease (CVD) risk is high among those with PreD and T2D, and nearly $330 billion/year
is spent treating T2D. The American Heart Association and American Diabetes Association have thus called for
continued investigation into mechanisms connecting health behaviors to pre-clinical cardiometabolic disease
(CMD; e.g., PreD). Physical activity (PA) is a key modifiable determinant of good health. Literature suggests PA
recommendation adherence is related to a 25-35% dose-dependent reduction in all-cause mortality, with as little
as 75 min/week of regular moderate-intensity PA beneficial. Data from the Diabetes Prevention Program has
suggested that, among those with PreD, a behavioral intervention emphasizing PA and diet is at least as
successful as the drug metformin in preventing T2D. Yet, many individuals do not fully realize the cardiometabolic
benefits of PA, and mechanistic pathways linking PA and cardiometabolic improvements remain incompletely
understood. The gut microbiome has been posited as a mechanistic intermediate linking heath behaviors, such
as PA, to CMD development. Indeed, the gut microbiome may be important in immunological, metabolic,
inflammatory, and neurobehavioral processes, some of which might partially explain how health behaviors
influence CMD risk. Yet, limited evidence exists characterizing the effect of PA on the human gut microbiome.
To date, most research examining the potential effect of regular chronic PA (i.e., exercise) on the gut microbiome
has used animal models. Animal studies often reported exercise-related beneficial alterations to microbial
community diversity and short chain fatty acid (SCFA)-producing taxa. SCFAs potentially promote increased
energy expenditure and are related to a lean phenotype. While there is support for these findings in a limited
number of human studies in apparently healthy adults, all but one study employed a randomized design, most
studies were completed in small samples, and the metabolic potential of the gut microbiome was rarely assessed.
Therefore, we propose a 100-participant randomized controlled 2-arm parallel trial in individuals 30-64 years old
who are overweight or obese and have PreD, to examine how 8 weeks of supervised moderate-intensity treadmill
walking exercise for 30-45 min 3 times/week alters the human gut microbiome and gut microbe-derived serum
SCFAs. We will further evaluate whether any observed changes in the gut microbiome and/or serum SCFAs
impact cardiometabolic profile, body weight, and body composition of study participants. Results will inform the
design and implementation of future trials to reduce pre-clinical diseases such as PreD in a mechanistically-
informed manner. Pursuant with PA-18-720, this research will also provide the opportunity to “establish specific
body composition or other phenotypic features as indicators of risk for obesity, response to its treatment, or its
co-morbidities relevant to NIDDK in well characterized…adult patients.”