Gut microbiota-derived short-chain Fatty acids, T cells, and inflammation

Abstract

T cells are central players in the regulation of adaptive immunity and immune tolerance. In the periphery, T cell differentiation for maturation and effector function is regulated by a number of factors. Various factors such as antigens, co-stimulation signals, and cytokines regulate T cell differentiation into functionally specialized effector and regulatory T cells. Other factors such as nutrients, micronutrients, nuclear hormones and microbial products provide important environmental cues for T cell differentiation. A mounting body of evidence indicates that the microbial metabolites short-chain fatty acids (SCFAs) have profound effects on T cells and directly and indirectly regulate their differentiation. We review the current status of our understanding of SCFA functions in regulation of peripheral T cell activity and discuss their impact on tissue inflammation.

Keywords: Colitis; FoxP3; IL-10; Inflammation; Microbial metabolites; Microbiota; Short-chain fatty acids; Th1; Th17.

Figure 1

Regulation of T cells by SCFAs. SCFAs are actively produced by anaerobic microbiota in the colon as fermentation products of dietary materials. Most carbohydrates and proteins are completely digested and absorbed in the stomach and small intestine, and don't efficiently make SCFAs. SCFAs are mainly produced from digestion-resistant dietary fibers that reach the colon to be processed by the microbiota. SCFAs are absorbed or transported into colonocytes. They are metabolized in colonocytes or transported into blood circulation to reach other organs such as the liver and muscles. SCFAs exert their regulatory effects on epithelial cells, antigen presenting cells and T cells. Multiple mechanisms are involved including metabolic regulation, HDAC inhibition, and GPCR activation by SCFAs. These activation signals are combined to regulate T cell differentiation directly or indirectly. The direct effect of SCFAs on T cells enhances the generation of Th1 and Th17 cells in appropriate cytokine conditions, which is important to boost immunity to fight pathogens. SCFAs efficiently promote T cell production of IL-10, which is important to prevent inflammatory responses. It has been reported that SCFAs can expand FoxP3⁺ T cells in certain activation conditions. SCFAs may exert their regulatory effects on developing DCs to generate DCs that are limited in their ability to present antigens and cytokines to make effector T cells. These effects are combined to create the overall tolerogenic gut environment with a strong barrier function.

Figure 2

Regulation of tissue inflammation by SCFAs. SCFAs have the potential to regulate tissue inflammation through their effects on multiple cell types. The first cell type that is regulated by SCFAs is intestinal epithelial cells. SCFAs condition these cells to produce immune mediators that enhance the gut barrier function. Also, the response to pathogens and commensal bacteria is heightened by SCFAs during inflammatory responses. The next cell type that is affected is antigen presenting cells. SCFAs act on DCs to limit the expression of T cell-activating molecules such as MHC II molecules, co-stimulatory molecules, CCR7 and cytokines, leading to generation of tolerogenic T cells rather than inflammatory T cells. The tolerogenic effect of SCFAs on DCs can lower inflammatory responses. SCFAs can directly affect naïve T cells to steer their differentiation into both effector and IL-10-producing T cells. Moreover, SCFAs attract neutrophils to the gut during immune responses. Together, the enhanced barrier function, T cell immunity, and neutrophil recruitment help prevent infection by pathogens and invasion by commensal bacteria. By the same token, the activating activity of SCFAs for the immune cells and epithelial cells may boost inflammatory responses, if not properly regulated.