Examining the role of the probiotic candidate Lactobacillus salivarius in intestinal and immune homeostasis

Abstract

A complex interplay exists between commensals of the gut microbiota, pathogenic bacteria and the host organism within the intestinal environment. The homeostasis of the intestinal epithelium and resident immune cells is central to this relationship. Lactobacilli are a genus of commensal bacteria with a well-established reputation for producing health benefits in the host. In this study, Lactobacillus salivarius UCC118TM emerged as an effective probiotic, protecting against severe pathology in a DSS-induced model of colitis and promoting disease recovery. This beneficial effect occurred alongside downregulation of the pathological microRNA miR-21 and subsequent rescue of epithelial barrier integrity. Furthermore, we revealed a novel role for Lb. salivarius in modulating the macrophage, a key driver of intestinal inflammation during disease. Here, Lb. salivarius prevented excessive pro-inflammatory activation of macrophages whereby treatment of macrophages with Lb. salivarius was conducive to the polarisation of an M2 macrophage phenotype. This was evidenced by an increase in phagocytic ability, an increase in M2-associated marker expression and a decrease in glycolytic metabolism in macrophages. Lastly, we examined the potential of Lb. salivarius to protect against extra-intestinal disorders including sepsis and asthma, when administered orally. This revealed a systemic mode of action for Lb. salivarius in protecting against an excessive pro-inflammatory response and septic shock, as well as modulating macrophage phenotype in the peritoneum. In an allergic asthma model, oral administration of Lb. salivarius led to protection against inhaled ovalbumin challenge as evidenced by a reduction in pathological mucin secretion as well as reduced expression of miR-21 and increased expression of the miR-21 target and T-cell balancing cytokine IL-12p35 in lung tissue,. Taken together, we postulate therefore that Lb. salivarius is an effective probiotic with a unique mode of action, whereby it downregulates miR-21 expression in a variety of cell types and furthermore, promotes a regulatory macrophage phenotype. These novel findings suggest that the relationship between microbe and host effectors of disease should be examined to enable therapeutic intervention during disease, through probiotic manipulation of host microRNAs and macrophage re-education.