Abstract
Secreted factors derived from Lactobacillus are able to dampen pro-inflammatory cytokine responses. Still, the nature of these components and the underlying mechanisms remain elusive. Here, we aimed to identify the components and the mechanism involved in the Lactobacillus-mediated modulation of immune cell activation. PBMC were stimulated in the presence of the cell free supernatants (CFS) of cultured Lactobacillus rhamnosus GG and Lactobacillus reuteri DSM 17938, followed by evaluation of cytokine responses. We show that lactobacilli-CFS effectively dampen induced IFN-γ and IL-17A responses from T- and NK cells in a monocyte dependent manner by a soluble factor. A proteomic array analysis highlighted Lactobacillus-induced IL-1 receptor antagonist (ra) as a potential candidate responsible for the IFN-γ dampening activity. Indeed, addition of recombinant IL-1ra to stimulated PBMC resulted in reduced IFN-γ production. Further characterization of the lactobacilli-CFS revealed the presence of extracellular membrane vesicles with a similar immune regulatory activity to that observed with the lactobacilli-CFS. In conclusion, we have shown that lactobacilli produce extracellular MVs, which are able to dampen pro-inflammatory cytokine responses in a monocyte-dependent manner.
Highlights
The influence of gut commensal bacteria on immune development and function is well established[1,2]
We have previously shown that cell free supernatants (CFS) from lactobacilli grown in their regular MRS medium dampen IFN-γ and IL-17A responses from T- and NK cells[17,20]
Peripheral blood mononuclear cells (PBMC) cultured in the presence of CFS from L. rhamnosus GG (LGG) or L. reuteri DSM 17938 secreted IL-6 and IL-10 (Fig. 1a), showing that lactobacilli promote secretion of innate cytokines when grown in cell culture medium
Summary
The influence of gut commensal bacteria on immune development and function is well established[1,2]. The highly abundant surface layer protein A (SlpA) from Lactobacillus, was found to supress NF-κB activation in intestinal cells while at the same time promoting inflammatory tumour necrosis factor (TNF) expression in macrophages[33], highlighting the complexity www.nature.com/scientificreports of the cross-talk between probiotic bacteria and the host. Lactobacilli-derived cell-surface components were shown to be the main inducers of inflammatory TNF production from PBMC cultures[38], suggesting different immune stimulatory capacity of whole lactobacillus cells compared with the CFS. We aimed to investigate the mechanism behind the ability of Lactobacillus-CFS to dampen inflammatory cytokine production in peripheral lymphocytes and to identify the responsible Lactobacillus-derived components. We successfully identified extracellular membrane vesicles (MVs) derived from the Lactobacillus-CFS, which recapitulated both the immune stimulatory and the IFN-γ dampening activity observed with the CFS alone, suggesting that gut bacteria-derived extracellular MVs are important modulators of human immunity with new implications for probiotic design
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