Metabolic network construction reveals probiotic-specific colonization resistance in a synthetic small intestinal community

The gut microbiota plays a crucial role in maintaining overall health and probiotics have emerged as a promising microbiota-targeted therapy for improving human health. However, the molecular mechanisms of probiotics action in general and the targeting of small intestinal microbiota by probiotics are not well understood. To address this, we constructed a synthetic community of three species, which resembles the upper small intestinal microbiota. Our results indicate that probiotic supplementation can directly affect the metabolism of the community, resulting in colonization resistance in a probiotic specific manner. Supplementation with Streptococcus thermophilus led to increased lactate production and a decrease in pH, while Lactobacillus casei supplementation increased the resistance to perturbations and nutrient utilization without affecting lactate production or pH. Additionally, when combined with kynurenine, Lactobacillus casei enhanced the kynurenine pathway metabolism resulting in elevated kynurenic acid levels and possibly indirect colonization resistance. Overall, our study reveals how selecting probiotics with distinct functional capacities can unlock the full potential of microbiota-targeted therapies. ### Competing Interest Statement S. van Hemert is employee in Winclove (Winclove manufactures and markets probiotics). The content of this study was neither influenced nor constrained by this fact. The other authors have no conflicts of interest to declare.