Microbially-derived short chain fatty acids (SCFAs) in the human gut are tightly coupled to host metabolism, immune regulation, and integrity of the intestinal epithelium. However, the production of SCFAs can vary widely between individuals consuming the same diet, with lower levels often associated with disease. A systems-scale mechanistic understanding of this heterogeneity is lacking. We present a microbial community-scale metabolic modeling (MCMM) approach to predict individual-specific SCFA production profiles. We assess the quantitative accuracy of our MCMMs using in vitro, ex vivo, and in vivo data. Next, we show how MCMM SCFA predictions are significantly associated with blood-derived clinical chemistries, including cardiometabolic and immunological health markers, across a large human cohort. Finally, we demonstrate how MCMMs can be leveraged to design personalized dietary, prebiotic, and probiotic interventions that optimize SCFA production in the gut. Our results represent an important advance in engineering gut microbiome functional outputs for precision health and nutrition.

Microbial community-scale metabolic modeling predicts personalized short chain fatty acid production profiles in the human gut