Probiotics in Autoimmune and Inflammatory Disorders

Abstract

Probiotics have been used to ameliorate gastrointestinal symptoms since ancient times. Over the past 40 years, probiotics have been shown to impact the immune system, both in vivo and in vitro. This interaction is linked to gut microbes, their polysaccharide antigens, and key metabolites produced by these bacteria. At least four metabolic pathways have been implicated in mechanistic studies of probiotics, based on mechanistic studies in animal models. Microbial⁻immune system crosstalk has been linked to: short-chain fatty acid production and signaling, tryptophan metabolism and the activation of aryl hydrocarbon receptors, nucleoside signaling in the gut, and activation of the intestinal histamine-2 receptor. Several randomized controlled trials have now shown that microbial modification by probiotics may improve gastrointestinal symptoms and multiorgan inflammation in rheumatoid arthritis, ulcerative colitis, and multiple sclerosis. Future work will need to carefully assess safety issues, selection of optimal strains and combinations, and attempts to prolong the duration of colonization of beneficial microbes.

Keywords: adenosine; arthritis; aryl hydrocarbon reductase; bifidobacilli; histamine; inflammatory bowel; lactobacilli; metabolomics; microbiome; short-chain fatty acid.

Figure 1

Critical metabolites produced by probiotics which have anti-inflammatory functions. SCFAs (acetate, butyrate, and propionate) produced by bifidobacilli, lactobacilli, and commensals bind and activate receptors (FFAR2, FFAR3, or GPR109a) on intestinal epithelial cells to inhibit the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway to prevent inflammation. They also inhibit histone deacetylases to promote accumulation of Tregs and may release GLP1/PYY to act on the enteric nervous system and the CNS to affect energy homeostasis and gut motility. SCFAs also induce tolerogenic DC, which educate naïve CD4⁺ T cells to differentiate into Tregs. These actions inhibit cytokine production by neutrophils and macrophages via interaction with receptors. Dietary tryptophan and probiotic-produced indole derivatives interact with AhR expressed on immune cells to produce anti-inflammatory effects. L. reuteri 17938 promotes adenosine generation, most likely by an ectonuclease present on the probiotic itself and on intestinal epithelial cells. Adenosine and its derivative inosine interact with adenosine receptor-2A located on T cells to promote Treg functions and inhibit inflammatory T_H1 and T_H17 subsets. Histamine produced by L. reuteri 6475 interacts with H₂ presented on intestinal epithelial cells and macrophages to reduce levels of proinflammatory cytokines (TNF-α, MCP-1, and IL-12). In summary, the critical metabolites produced by probiotics generate anti-inflammatory effects during diseases. Abbreviations: SCFAs: short-chain fatty acids; FFARs: free fatty acid receptors; GPRs: G-binding protein receptors; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; GLP1: glucagon-like protein-1; PYY: peptide tyrosine tyrosine; CNS: central nervous system; AhR: aryl hydrocarbon receptor; T_H1 and T_H17: T helper cells; H₂: histamine receptor 2; TNF-α: tumor necrosis factor alpha; MCP-1: monocyte chemoattractant protein-1; IL-12: interleukin-12 (illustration by Yuying Liu).