Probiotics Mechanism of Action on Immune Cells and Beneficial Effects on Human Health

Abstract

Immune cells and commensal microbes in the human intestine constantly communicate with and react to each other in a stable environment in order to maintain healthy immune activities. Immune system-microbiota cross-talk relies on a complex network of pathways that sustain the balance between immune tolerance and immunogenicity. Probiotic bacteria can interact and stimulate intestinal immune cells and commensal microflora to modulate specific immune functions and immune homeostasis. Growing evidence shows that probiotic bacteria present important health-promoting and immunomodulatory properties. Thus, the use of probiotics might represent a promising approach for improving immune system activities. So far, few studies have been reported on the beneficial immune modulatory effect of probiotics. However, many others, which are mainly focused on their metabolic/nutritional properties, have been published. Therefore, the mechanisms behind the interaction between host immune cells and probiotics have only been partially described. The present review aims to collect and summarize the most recent scientific results and the resulting implications of how probiotic bacteria and immune cells interact to improve immune functions. Hence, a description of the currently known immunomodulatory mechanisms of probiotic bacteria in improving the host immune system is provided.

Keywords: beneficial microbes; human health; immune cells; immune modulation; immune response; immune system; microbial modulation effects; microbiome; microbiota; probiotics.

Figure 1

Schematic representation of the interaction between host intestinal immune cells and probiotics. Probiotics play a role in host innate and adaptive immune responses by modulating immune cells such as dendritic cells (DCs), macrophages, and B and T lymphocytes. Interactions between host intestinal cells and probiotics mainly occur at the surface of the intestinal barrier, including the intestinal epithelium and the underlying lamina propria. Intestinal microbiota is separated from the intestinal epithelium by a mucus layer secreted by goblet cells. Consumed probiotic bacteria adhere to intestinal epithelial cells and activate them by pattern recognition receptors (PRRs). Cytokines stimulated by probiotic bacteria lead to the activation of T regulatory (Treg) cells, which maintain immune homeostasis in the intestinal mucosa. Tregs are effective suppressors of the immune response and play a key role in limiting immune response. Intestinal antigens are transferred to DCs via specialized enterocytes known as microfold cells (M cells), which are located in the epithelium overlying Peyer’s patch. Probiotics are processed directly by DCs in lamina propria in the intestinal lumen. Intestinal DCs can activate CD8+/CD4+ naïve T cells and direct helper T cell responses towards Th1, Th2, Th17, or regulatory patterns. The Th1 immune response is mainly characterized by interferon (IFN)-γ production and is involved in cell-mediated immunity. The Th2 immune response includes interleukin (IL)-4, IL-5 release, thus inducing humoral immunity. The Th17 immune response is characterized by IL-17 production. Induction of Tregs releases IL-10 or transforming growth factor (TGF)-β. In addition, probiotics induce maturation of B cells into immunoglobulin (Ig)A-producing plasma cells. Intestinal epithelial cells release cytokines and chemokines, creating a microenvironment in the lamina propria of the intestine that allows the clonal expansion of B cells to produce IgAs. IgAs migrate through the epithelium into the mucus layer where they control bacterial adhesion to the host tissue.

Figure 2

Mechanisms of action of probiotic bacteria. Lactobacillus can (i) stimulate T cell regulatory cells (Treg cells) to produce TGF-β, interleukin-10 (IL-10), and IL-8, (ii) increase levels of secreted IL-6 secreted in a Toll-like receptor (TLR)-2-dependent manner, thereby inducing the clonal expansion of all IgA-producing B cells, while also stimulating the expression of macrophage mannose receptor CD206, (iii) inhibit the expression of Janus kinase (JAK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) genes, (iv) increase the release of IL-12p70 and IL-4, (v) reduce the TLR expression and increase CD40 and CD80 expressions, (vi) degrade the proinflammatory chemokine IFN-γ-inducible protein 10 (IP-10), (vii) increase the expression of TLR-9, and (viii) favor the expression of nucleotide binding oligomeric domain-like receptor protein 3 (NLRP3), cysteine proteinase-1 (Caspase-1), and IL-18. Lacticaseibacillus and limocaseibacillus can induce β-defensins 2 and 4 and IL-8 expressions. Distinct studies reported opposing data on TLR expression. Bifidobacterium can (i) inhibit the expression JAK and NF-κB genes, (ii) favor the overexpression of IL-10 and TGF-β, while, at the same time, stimulate the production of IgAs, (iii) favor Treg cell differentiation, (iv) increase the total helper (CD4+) and activated (CD25+) T lymphocytes and NK cells, (v) reduce the expression of CD19 on B cells, (vi) induces the production of monocyte chemoattractant protein 1 (MCP-1) and TNF-α through TLR-9 stimulation, and (vii) increase the number of Foxp3(+) T regulatory cells and the release of CCL20, CCL22, CXCL10, and CXCL11. Escherichia coli can induce the expression of TLR-5 and TNF-α as well as increase the number of CD4+ cells. Bacteroidales stimulates the release of IL-6 accompanied by the expression of mucin-2 and claudin-1. Lactobacillus, lacticaseibacillus, limocaseibacillus, bifidobacterium, and streptococcus can favor the release of TNF-α, IL-6, IL-1β. Streptococcus can induce clonal expansion of B cells stimulated to release IgAs. Dash arrow: conflicting data have been reported on the effect of lactobacilli in increasing CD4+ T cell number.