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Summary: The human gut microbiota comprises various microorganisms engaged in intricate interactions among themselves and with the host, affecting its health. While advancements in omics technologies have led to the inference of clear associations between microbiome composition and health conditions, we usually lack a causal and mechanistic understanding of these associations. For modeling mechanisms driving the interactions, we simulated the organism’s metabolism using in silico genome-scale metabolic models (GEMs). We used multi-objective optimization to predict and explain metabolic interactions among gut microbes and an intestinal epithelial cell. We developed a score integrating model simulation results to predict the type (competition, neutralism, mutualism) and quantify the interaction between several organisms. This framework uncovered a potential cross-feeding for choline, explaining the predicted mutualism between Lactobacillus rhamnosus GG and the epithelial cell. Finally, we analyzed a five-organism ecosystem, revealing that a minimal microbiota can favor the epithelial cell’s maintenance.