Immunoregulatory Effects Triggered by Lactic Acid Bacteria Exopolysaccharides: New Insights into Molecular Interactions with Host Cells

Abstract

Researchers have demonstrated that lactic acid bacteria (LAB) with immunomodulatory capabilities (immunobiotics) exert their beneficial effects through several molecules, including cell wall, peptidoglycan, and exopolysaccharides (EPS), that are able to interact with specific host cell receptors. EPS from LAB show a wide heterogeneity in its composition, meaning that biological properties depend on the strain and. therefore, only a part of the mechanism of action has been elucidated for these molecules. In this review, we summarize the current knowledge of the health-promoting actions of EPS from LAB with special focus on their immunoregulatory actions. In addition, we describe our studies using porcine intestinal epithelial cells (PIE cells) as a model to evaluate the molecular interactions of EPS from two immunobiotic LAB strains and the host cells. Our studies showed that EPS from immunobiotic LAB have anti-inflammatory capacities in PIE cells since they are able to reduce the production of inflammatory cytokines in cells challenged with the Toll-like receptor (TLR)-4-agonist lipopolysaccharide. The effects of EPS were dependent on TLR2, TLR4, and negative regulators of TLR signaling. We also reported that the radioprotective 105 (RP105)/MD1 complex, a member of the TLR family, is partially involved in the immunoregulatory effects of the EPS from LAB. Our work described, for the first time, that LAB and their EPS reduce inflammation in intestinal epithelial cells in a RP105/MD1-dependent manner. A continuing challenge for the future is to reveal more effector-receptor relationships in immunobiotic-host interactions that contribute to the beneficial effects of these bacteria on mucosal immune homeostasis. A detailed molecular understanding should lead to a more rational use of immunobiotics in general, and their EPS in particular, as efficient prevention and therapies for specific immune-related disorders in humans and animals.

Keywords: PIE cells; RP105; TLR2; TLR4; exopolysaccharides; immunobiotics; lactic acid bacteria.

Figure 1

Toll-like receptor 4 (TLR4) signaling pathway in porcine intestinal epithelial (PIE) cells. Upon recognition of its cognate ligand, TLR4 dimerizes and initiates a signaling cascade that leads to the activation of a pro-inflammatory response. Ligand binding can induce two signaling pathways, the myeloid differentiation primary response gene 88 (MyD88)-dependent and MyD88-independent pathways, which induce the production of pro-inflammatory cytokines and type I IFNs. In MyD88-dependent signaling, upon ligand recognition, MyD88 is recruited to, and associates, with the cytoplasmic domain of the TLRs. Then IL-1R-associated kinase 4 (IRAK-4) and IRAK-1 are recruited and activated by phosphorylation. Activated IRAK-4 phosphorylates IRAK-1, which subsequently associates with tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). TRAF6 activates transforming growth factor (TGF)-activating kinase 1 (TAK1). TAK1 phosphorylates IKK-b and mitogen-activated protein kinase (MAPK) kinase 6 (MKK6), leading to degradation of I-κB and thereby leading to the nuclear translocation of NF-κB, which results in the induction of genes involved in inflammatory responses. Activation of the MyD88-dependent pathway also results in the activation of MAPKs such as p38 and JNK, which leads to the activation of AP-1 (Jun/Fos). Various negative regulatory mechanisms have evolved to attenuate TLR signaling and maintain the immune balance, including the activity of the TLR-negative regulators TOLLIP, IRAK-M, SIGIRR, MKP-1, A20, and Bcl3.

Figure 2

Modulation of Toll-like receptor 4 (TLR4) signaling pathway in porcine intestinal epithelial (PIE) cells by acidic (APS) and neutral (NPS) exopolysaccharides produced by Lactobacillus plantarum N14 and Lactobacillus delbrueckii TUA4408L. Treatment of PIE cells with L. plantarum N14, L. delbrueckii TUA4408L or their APS and NPS induce the expression of TLR negative regulators TOLLIP, IRAK-M, SIGIRR, MKP-1, A20, and/or Bcl3 via TLR2, TLR4, and/or RP105. Treated-PIE cells showed a reduced inflammatory response in terms of chemokines and cytokines production after the subsequent challenge of with TLR4 agonists.