Modeling approaches for probing cross-feeding interactions in the human gut microbiome

Microbial communities perform emergent activities that are essentially different from those carried by their individual members. The gut microbiome and its metabolites have a significant impact on the host, contributing to homeostasis or disease. Food molecules shape this community, being fermented through cross-feeding interactions of metabolites such as lactate, acetate, and amino acids, or products derived from macromolecule degradation. Mathematical and experimental approaches have been applied to understand and predict the interactions between microorganisms in complex communities such as the gut microbiota. Rational and mechanistic understanding of microbial interactions is essential to exploit their metabolic activities and identify keystone taxa and metabolites. The latter could be used in turn to modulate or replicate the metabolic behavior of the community in different contexts. This review aims to highlight recent experimental and modeling approaches for studying cross-feeding interactions within the gut microbiome. We focus on short-chain fatty acid production and fiber fermentation, which are fundamental processes in human health and disease. Special attention is paid to modeling approaches, particularly kinetic and genome-scale stoichiometric models of metabolism, to integrate experimental data under different diet and health conditions. Finally, we discuss limitations and challenges for the broad application of these modeling approaches and their experimental verification for improving our understanding of the mechanisms of microbial interactions.