Project summary
The objective of this study is to define associations between gut microbiota, short chain fatty acids
(SCFAs) and obesity in populations spanning the epidemiologic transition, and explore
mechanisms by which these factors may independently and collectively influence the
development of obesity. The gut microbiota and SCFAs have been associated with obesity, yet
the causal mechanisms are unknown, as are the individual obesogenic effects of the individual
SCFAs (butyrate, acetate and propionate). Existing studies are, limited by contradictory findings,
small sample sizes, limited and imprecise measurements of obesity, and lack of detailed dietary
and other environmental exposures/mediators. We propose to overcome these challenges by
leveraging an existing cohort of five diverse, well-defined populations from the Modeling the
Epidemiologic Transition Study (METS, R01-DK080763). METS is comprised of a cohort of 2,500
African-origin adults, living in 5 distinctly different environments; Ghana, South Africa, Jamaica,
the Seychelles and the US, and who have been prospectively followed since 2010. Our
preliminary data suggest that while gut microbiota and SCFAs differences exist across sites,
similar relationships exist across the sites for gut microbiota/SCFAs adiposity effects. In addition
to yearly health measurements; we propose to measure gut microbiota and stool SCFAs in all
participants (2500) during the first year of the current study, thus providing one of the largest gut
microbiota population-based studies to date. We will divide our cohort of 2500 individuals into 2
sets: (1) a test set of 1000 individuals to explore which gut microorganisms and stool SCFAs are
associated with adiposity; (2) a validation set of 1500 individuals to independently verify the
biomarkers identified in the test set, thus minimizing spurious correlations due to large number of
features (e.g., bacterial taxa). We will follow all 2500 individuals for 3 years to assess weight and
adiposity changes, using Bayesian Kernel Machine Regression modeling to explore whether
changes can be predicted by gut microbiota and SCFAs factors. Finally, using a causal mediation
analysis, we will identify the direct and indirect effect of single and/or cumulative gut microbiota
on adiposity as mediated by SCFA. We will thus capitalize upon an existing, extensively well
described cohort of adults of African-origin, with significant variability as a result of the widespread
geographic distributions, and therefore variation in the environmental covariate exposures. The
proposed study will substantially advance the understanding of the role gut microbiota and SCFAs
play in the development of obesity and provide novel obesity therapeutic targets targeting SCFAs
producing features of the gut microbiota.