Anti-Inflammatory and Immunomodulatory Effects of Probiotics in Gut Inflammation: A Door to the Body

Abstract

Hosting millions of microorganisms, the digestive tract is the primary and most important part of bacterial colonization. On one side, in cases of opportunistic invasion, the abundant bacterial population inside intestinal tissues may face potential health problems such as inflammation and infections. Therefore, the immune system has evolved to sustain the host-microbiota symbiotic relationship. On the other hand, to maintain host immune homeostasis, the intestinal microflora often exerts an immunoregulatory function that cannot be ignored. A field of great interest is the association of either microbiota or probiotics with the immune system concerning clinical uses. This microbial community regulates some of the host's metabolic and physiological functions and drives early-life immune system maturation, contributing to their homeostasis throughout life. Changes in gut microbiota can occur through modification in function, composition (dysbiosis), or microbiota-host interplays. Studies on animals and humans show that probiotics can have a pivotal effect on the modulation of immune and inflammatory mechanisms; however, the precise mechanisms have not yet been well defined. Diet, age, BMI (body mass index), medications, and stress may confound the benefits of probiotic intake. In addition to host gut functions (permeability and physiology), all these agents have profound implications for the gut microbiome composition. The use of probiotics could improve the gut microbial population, increase mucus-secretion, and prevent the destruction of tight junction proteins by decreasing the number of lipopolysaccharides (LPSs). When LPS binds endothelial cells to toll-like receptors (TLR 2, 4), dendritic cells and macrophage cells are activated, and inflammatory markers are increased. Furthermore, a decrease in gut dysbiosis and intestinal leakage after probiotic therapy may minimize the development of inflammatory biomarkers and blunt unnecessary activation of the immune system. In turn, probiotics improve the differentiation of T-cells against Th2 and development of Th2 cytokines such as IL-4 and IL-10. The present narrative review explores the interactions between gut microflora/probiotics and the immune system starting from the general perspective of a biological plausibility to get to the in vitro and in vivo demonstrations of a probiotic-based approach up to the possible uses for novel therapeutic strategies.

Keywords: autism spectrum disorders; celiac disease; inflammation; inflammatory bowel disease; irritable bowel syndrome; microbiota; obesity; probiotics.

Figure 1

Main probiotic immune-modulatory pathways in the gut. (A) T cells are considered the masters of inflammation in that they can differentiate into different pathways promoting or suppressing inflammatory response. However, their fate requires interaction with other cells: for instance, dendritic cells. Probiotics can influence these communications through membrane receptors e.g. PRRs. In particular, TLR-6 and TLR-2, a member of PRRs, expressed on sentinel cells such as macrophages and dendritic cells, might be able to decrease the Th17 polarization and skew T-cells toward Treg subpopulation and production of high levels of IL-10 and lower levels of TNF-α, reducing the inflammatory state which could be one of the mechanisms involved in the immune modulatory effect of probiotics in inflammatory intestinal diseases. Probiotics seem to redirect the Th2 response, characteristic of atopic patients, towards a Th1 type through increased secretion of IFN-γ and a decrease in the IL-4, IL-13, and IgE production with improvement of allergic predisposition and reactions. In the gut, probiotics may activate B cells in the lamina propria that become IgA-producing plasma cells. The IgA, a major functional component of the humoral adaptive immune system specialized in mucosal protection and a first line of defense against gastrointestinal infections, is transported across the epithelial cells and once it is secreted in the gut lumen it can bind to the mucus layer covering them. (B) NK cells are intermediate cells between innate and adapted immunity. They seem to act in different ways through an interplay with intestinal epithelial cells, DCs and T cells. Probiotics can modulate their behavior for instance through the secretion of IFN-γ. (C) Finally, probiotics exert their functions by altering intracellular pathways of immune cells (e.g. macrophage) through kinases (such as MAP kinase cascade) which in the end activate or suppress transcription factors: STAT, NF-κB, Jun-1, Fos. On the other hand, probiotics may act on the same pathway through the metabolism of histamine acting on H2-receptors of antigen presenting cells and inducing a reduction of pro-inflammatory cytokines like TNF-α, IL-12 and monocyte chemotactic protein-1.