Anoxic conditions promote species-specific mutualism between gut microbes in silico

The human gut is inhabited by thousands of microbial species, most of which are still uncharacterized. Gut microbes have adapted to each other’s presence as well as to the host and engage in complex cross-feeding. Constraint-based modeling has been successfully applied to predicting microbe-microbe interactions, such as commensalism, mutualism, and competition. Here, we apply a constraint-based approach to model pairwise interactions between 11 representative gut microbes. Microbe-microbe interactions were computationally modeled in conjunction with human small intestinal enterocytes and subjected to three diets with varying levels of carbohydrate, fat, and protein in normoxic or anoxic environments. Each microbe engaged in species-specific commensal, parasitic, mutualistic, or competitive interactions. For instance, Streptococcus thermophilus efficiently outcompeted paired microbes in agreement with the domination of streptococci in the small intestinal microbiota. Under anoxic conditions, the probiotic Lactobacillus plantarum displayed mutualistic behavior towards six other species, which, surprisingly, were almost entirely abolished under normoxic conditions. This finding suggests that the anoxic conditions in the large intestine drive mutualistic cross-feeding, leading to the evolvement of a more complex ecosystem than the small intestinal microbiota. Moreover, we predict that the presence of the small intestinal enterocyte induces competition over host-derived nutrients. The presented framework can readily be expanded to a larger gut microbial community. This modeling approach will be of great value for subsequent studies aiming to predict conditions favoring desirable microbes or suppressing pathogens.