Intestinal microbiota and host defense in systemic infectious diseases: Translational studies in the healthy and the ill

In recent years, research interest in understanding the role that the intestinal microbiota plays in human health has increased exponentially. However, few findings from preclinical models have been translated into clinically meaningful microbiota-targeted therapies for treating physicians. This thesis has aimed to translate the findings obtained through preclinical animal models into human cohort and intervention studies linking antibiotic-induced disturbances of the intestinal microbiome to altered function of the innate immune system. We hypothesized that the collateral effects of disruptions of these commensal intestinal microorganisms contribute to increased susceptibility to systemic infections.
Using clinical cohorts and human adult volunteer studies, we were able to demonstrate that alterations of the gut microbiome, specifically a loss of anaerobic butyrate-producing bacteria, are associated with a loss of protection against infectious agents. In addition, we have shown that intestinal bacterial composition is indeed linked with direct innate immune responses. Finally, we show that antibiotic-induced modulation of the bacterial component of the microbiome has implications extending beyond this kingdom alone, enabling the overgrowth of potentially invasive and pathogenic fungi and viruses.
While these findings show promise that specific intestinal bacteria are associated with protection against infections, it is clear that we are only beginning to understand the overarching mechanisms by which such microbial metabolites and micro-organisms influence the immune system. Therefore, future studies aimed at elucidating the underlying mechanisms of action will be vital to understanding how best to improve innate immune responses and induce protection against systemic infectious diseases.