The Microbiota and Epigenetic Regulation of T Helper 17/Regulatory T Cells: In Search of a Balanced Immune System

Abstract

Immune cells not only affect tissue homeostasis at the site of inflammation but also exert systemic effects contributing to multiple chronic conditions. Recent evidence clearly supports an altered T helper 17/regulatory T cell (Th17/Treg) balance leading to the development and progression of inflammatory diseases that not only affect the gastrointestinal tract but also have whole-body manifestations, including insulin resistance. Epigenetic mechanisms are amenable to both environmental and circulating factors and contribute to determining the T cell landscape. The recently identified participation of the gut microbiota in the remodeling of the epigenome of immune cells has triggered a paradigm shift in our understanding of the etiology of various inflammatory diseases and opened new paths toward therapeutic strategies. In this review, we provide an overview of the contribution of the Th17/Treg balance in the development and progression of inflammatory bowel diseases and metabolic diseases. We discuss the involvement of epigenetic mechanisms in the regulation of T cell function in the particular context of dysbiosis. Finally, we examine the potential for nutritional interventions affecting the gut microbiota to reshape the T cell epigenome and address the inflammatory component of various diseases.

Keywords: T helper 17 cell; epigenetics; gut microbiota; inflammatory bowel diseases; obesity; regulatory T cell; type 2 diabetes.

Figure 1

T helper 17 (Th17) and regulatory T cell (Treg) lineage determination and the Th17/Treg balance in health and diseases. (A) The differentiation of naïve T-cells into different lineages is regulated by specific cytokines. TGF-β in combination with IL-2 induces the expression of the transcription factor Foxp3 and Treg differentiation, which are characterized by the secretion of TGF-β, IL-10, and IL-33. TGF-β combined with IL-6 leads to the differentiation into Th17, which is characterized by the transcription factor Rorc (or RORγt). This process is amplified under the influence of IL-21 and both IL-1β and IL-23 have been reported to potentially contributing to Th17 differentiation. Th17 can secrete different cytokines, including IL-17A, IL-17F, IL-21, IL-22, IL-23, and IL-25. The differentiation into Treg or Th17 is a tightly controlled process regulated, at least partly, by epigenetic mechanisms. In naïve T-cell, the T-bet (or Tbx1) locus is characterized by both H3K4me3 (a permissive histone mark) and H3k27me3 (a repressive histone mark), whereas the Rorc, interferon gamma (Ifng), Foxp3, and Il17a loci show a total absence of such marks, making those five loci susceptible to both repression or expression of these genes. All five genes are hypermethylated in naïve T-cell contributing to gene silencing. Tregs show H3K4me3 on Foxp3 and H3K27me3 on Il17a, supporting the expression of Foxp3 while silencing Il17a. The demethylation of Foxp3 and the hypermethylation of Rorc further contribute to Foxp3 expression. In the same cells, T-bet and Rorc are marked by both histone modifications, whereas Ifng is devoid of these, rendering these loci more unstable. Th17 cells show H3K27me3 on Ifng and H3K4me3 on Rorc, Il17a, Il17f, Il21, and Il23, facilitating the expression of Rorc and supporting the secretion of the signature cytokines by these cells. This process is further supported by the hypermethylation observed in the Ifng and Foxp3 loci, whereas the Il17a, T-bet, and Rorc are characterized by a demethylation, supporting gene expression. microRNAs can also contribute to the differentiation and function of Th17, and both miR-155 and miR-326 contribute to the production of IL-17A. TGF-β, transforming growth factor-beta; IL-2, interleukin-2; Foxp3, forkhead box P3; Rorc (or RORγt), retinoic acid receptor-related orphan receptor; T-bet, T-box1; H3K4me3, trimethylation of histone H3 on lysine 4 (green dot); H3K4me27, trimethylation of histone H3 on lysine 27 (red dot); IFN-γ, interferon gamma. (B) An imbalance between the number and activity of Th17 and Treg has been linked to several diseases. The predominance of Th17 is associated with inflammatory bowel diseases, obesity, and some allergic conditions, whereas Tregs have been linked to different forms of arthritis as well as several types of infections.

Figure 2

Epigenetic regulation of the T helper 17/regulatory T cell (Th17/Treg) balance by the gut microbiota. (A) Metabolites derived from the gut microbiota affect the T-cell epigenome influencing the Th17/Treg balance in the gastrointestinal (GI) tract. SCFAs including propionate, butyrate, and acetate which are mostly produced by clostridial clusters VIV and IV exert HDAC inhibitory activity, thereby increasing Foxp3 and Il10 expression and promoting Treg differentiation and function. SCFAs can also affect dendritic cells and macrophages, thereby inducing IL-10 and RA production and promoting Treg differentiation. PSA derived from Bacteroides fragilis contributes to increased expression of Il10 and Foxp3 in T-cell and reduces Il17 expression. Both Bifidobacterium and Lactobacillus contribute to the production of the methyl donor folate potentially influencing the methylome in T-cells. (B) Effect of microbiota-derived metabolites on the epigenome of peripheral T-cells. Similar to the GI tract, SCFAs increase Foxp3 and Il10 expression in peripheral T-cells through HDAC inhibition favoring Treg differentiation. Through unknown mechanisms, the gut microbiota increases the expression of MIR21 and the levels of miR-10a, potentially promoting Th17 differentiation. SCFAs, short-chain fatty acids; PSA, polysaccharide A; HDAC, histone deacetylase; H3, histone 3; Foxp3, forkhead box P3; Il10, interleukin 10; RA, retinoic acid; Treg, regulatory T cell.