Abstract
To date it remains unclear how probiotics affect the immune system. Bacterial envelope components may play an essential role, as these are the first to establish bacterial-host cell interactions. Teichoic acids (TAs), and especially lipoteichoic acids, are the most pro-inflammatory components of the gram-positive bacterial envelope. This effect is dependent on D-alanyl substitution of the TA backbone and interactions with TLR2 on host cells. Although the pro-inflammatory properties of TAs have been established in vitro, it remains unclear how TAs affect immunomodulation in vivo. In this study, we investigated the role of TA D-alanylation on L. plantarum–induced intestinal and systemic immunomodulation in vivo. For this, we compared the effect of L. plantarum WCFS1 and its TA D-Alanylation negative derivative (dltX-D) on the distribution of dendritic cell and T cell populations and responses in healthy mice. We demonstrated that the majority of the L. plantarum-induced in vivo immunomodulatory effects were dependent on D-alanylation (D-Ala), as some L. plantarum WCFS1-induced immune changes were not observed in the dltX-D-treated group and some were only observed after treatment with dltX-D. Strikingly, not only pro-inflammatory immune responses were abolished in the absence of D-Ala substitution, but also anti-inflammatory responses, such as the L. plantarum-induced generation of regulatory T cells in the spleen. With this study we provide insight in host-microbe interactions, by demonstrating the involvement of D-alanylation of TAs on the bacterial membrane in intestinal and systemic immunomodulation in healthy mice.
Highlights
The precise mechanisms by which different probiotics impact the mammalian immune system have yet to be discovered
In murine dendritic cell (DC) absence of D-Ala substitution did not affect the L. plantarum-induced pro-inflammatory TNFa response (Figure 1B), whereas a trend towards an increased IL10 response and IL10/TNFa ratio (P = 0.06) was observed after co-incubation with dltX-D as compared to wild-type strain (WT) (Figure 1B). These results demonstrate that absence of L. plantarum teichoic acids (TAs) D-Ala affects its proand anti-inflammatory immunomodulatory capacity in murine host cells in vitro
[24,48,49,50,51,52,53,54,55], the exact mechanisms of action remain obscure, especially in the healthy population. It is still subject of debate where in the intestine probiotic bacteria are sensed and whether direct interactions between the bacteria and the immune system are necessary for immunomodulation in vivo
Summary
The precise mechanisms by which different probiotics impact the mammalian immune system have yet to be discovered. It is likely that extracellular bacterial factors play a pivotal role, as these molecules establish the first interactions between the bacteria and host cells [1,2,3]. Even subtle differences in the composition of these molecules can induce large differences in the host cell immune response [6,7,8]. The exact role of these molecules and the type of host response they generate in vivo remains to be identified. The majority of LAB produce two types of teichoic acids (TAs); wall teichoic acid (WTA) and lipoteichoic acid (LTA). While the biosynthesis of LTA is conserved among LAB, some LAB, such as L. rhamnosus, L. casei, L. fermentum, and L. reuteri, are unable to produce WTA [15]
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