The network structure of cross-feeding impacts microbial community diversity under growth-inhibiting stresses

Perturbations such as dietary shifts and drug treatment can reduce gut microbiome diversity, with negative health effects on the host, but predicting changes to community diversity is challenging due to the many mechanisms by which species interact. While both nutrient competition and cross-feeding can play major roles in microbiota assembly, the effect of environmental stresses such as antibiotics is typically studied experimentally in monoculture, and most theoretical studies have focused on communities that interact via nutrient competition alone. To investigate the interplay between nutrient competition, stresses that inhibit growth, and cross-feeding, we introduce a consumer-resource model that includes all three factors and captures a wide range of cross-feeding network architectures with a single parameter. For three-species communities, we found that coexistence during narrow-spectrum growth inhibition was maximal with a cyclic cross-feeding network, while fully connected cross-feeding networks maximized coexistence during broad-spectrum growth inhibition. However, the effects of cyclic cross-feeding were particularly sensitive to community size and the number of targeted species; for communities with more than six species and resources, cyclic cross-feeding can be detrimental to coexistence due to instability. Our findings highlight the complex effects of cross-feeding network architecture on coexistence when growth inhibition reshapes the nutrient competition landscape, with potential applications to microbial communities in all natural environments, where they are often exposed to agents such as drugs, temperature, and pH modulation.