Microbial Imbalance Induces Inflammation by Promoting Salmonella Penetration through the Mucosal Barrier

The balance of microbial species in the intestine must be maintained to prevent inflammation and disease. Healthy bacteria suppress infection by pathogens and prevent disorders such as inflammatory bowel diseases (IBDs). The role of mucus in the relation between pathogens and the intestinal microbiota is poorly understood. Here, we hypothesized that healthy bacteria inhibit infection by preventing pathogens from penetrating the mucus layer and that microbial imbalance leads to inflammation by promoting the penetration of the mucosal barrier. We tested this hypothesis with an in vitro model that contains mucus, an epithelial cell layer, and resident immune cells. We found that, unlike probiotic VSL#3 bacteria, Salmonella penetrated the mucosal layers and induced the production of interleukin-8 (IL-8) and tumor necrosis factor (TNF)-α. At ratios greater than 10⁴:1, probiotic bacteria suppressed the growth and penetration of Salmonella and reduced the production of inflammatory cytokines. Counterintuitively, low densities of healthy bacteria increased both pathogen penetration and cytokine production. In all cases, mucus increased Salmonella penetration and the production of cytokines. These results suggest that mucus lessens the protective effect of probiotic bacteria by promoting barrier penetration. In this model, a more imbalanced microbial population caused infection and inflammation by selecting pathogens that are more invasive and immunogenic. Combined, the results suggest that the depletion of commensal bacteria or an insufficient dosage of probiotics could worsen an infection and cause increased inflammation. A better understanding of the interactions between pathogens, healthy microbes, and the mucosal barrier will improve the treatment of infections and inflammatory diseases.