Microbiome-derived metabolite effects on intestinal barrier integrity and immune cell response to infection

Abstract

The gut microbiota exerts a significant influence on human health and disease. While compositional changes in the gut microbiota in specific diseases can easily be determined, we lack a detailed mechanistic understanding of how these changes exert effects at the cellular level. However, the putative local and systemic effects on human physiology that are attributed to the gut microbiota are clearly being mediated through molecular communication. Here we determined the effects of a number of gut microbiome-derived metabolites on the first line of defence in the gut. Usingin vitromodels of intestinal barrier integrity, and studying the interaction of macrophages with pathogenic and non-pathogenic bacteria, we could ascertain the influence of these metabolites at the cellular level at physiologically relevant concentrations. Many metabolites exerted competing influences on intestinal epithelial or immune cells, specific metabolite effects were noted on barrier function, polarised cytokine release and the lifespan of metabolite treated cells. Our findings reiterate the complexity of understanding microbiome effects on host physiology with many metabolites having contrasting effects on host cells. However, our results underline that microbiome metabolites are crucial mediators of barrier function and the innate response to infection. Understanding the effects of these metabolites at the cellular level will allow us to move towards a better mechanistic understanding of microbiome influence over host physiology, a crucial step in advancing microbiome research.