The human microbiome plays an important role in human health and disease. Meta-omics analyses provide indispensable data for linking changes in microbiome composition and function to disease etiology. Yet, the lack of a mechanistic understanding of, e.g., microbiome-metabolome links hampers the translation of these findings into effective, novel therapeutics. Here, we propose metabolic modeling of microbial communities through constraint-based reconstruction and analysis (COBRA) as a complementary approach to meta-omics analyses. First, we highlight the importance of microbial metabolism in cardiometabolic diseases, inflammatory bowel disease, colorectal cancer, Alzheimer disease, and Parkinson disease. Next, we demonstrate that microbial community modeling can stratify patients and controls, mechanistically link microbes with fecal metabolites altered in disease, and identify host pathways affected by the microbiome. Finally, we outline our vision for COBRA modeling combined with meta-omics analyses and multivariate statistical analyses to inform and guide clinical trials, yield testable hypotheses, and ultimately propose novel dietary and therapeutic interventions. Expected final online publication date for the , Volume 75 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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