Host-microbiota interactions: epigenomic regulation

Abstract

The coevolution of mammalian hosts and their commensal microbiota has led to the development of complex symbiotic relationships between resident microbes and mammalian cells. Epigenomic modifications enable host cells to alter gene expression without modifying the genetic code, and therefore represent potent mechanisms by which mammalian cells can transcriptionally respond, transiently or stably, to environmental cues. Advances in genome-wide approaches are accelerating our appreciation of microbial influences on host physiology, and increasing evidence highlights that epigenomics represent a level of regulation by which the host integrates and responds to microbial signals. In particular, bacterial-derived short chain fatty acids have emerged as one clear link between how the microbiota intersects with host epigenomic pathways. Here we review recent findings describing crosstalk between the microbiota and epigenomic pathways in multiple mammalian cell populations. Further, we discuss interesting links that suggest that the scope of our understanding of epigenomic regulation in the host-microbiota relationship is still in its infancy.

Figure 1. Epigenomic regulation of immune homeostasis by the intestinal microbiota

The intestinal microbiota and microbiota-derived metabolites such as short-chain fatty acids (SCFAs) regulate the epigenome of various hematopoietic cell types. (1) Macrophages and dendritic cells can sense SCFAs in part through G-protein-coupled-receptors (GPCRs). This regulation correlates with increased global histone H3 acetylation, expression of anti-inflammatory cytokines, retinoic acid (RA) signaling and regulation of regulatory T cells (Tregs) [–39]. (2) SCFAs butyrate and propionate promote Treg generation through activation of GPR43 signaling and suppression of HDAC activity. This results in increased histone acetylation in the Foxp3 gene and increased Foxp3 expression [35,59,61]. (3) The microbiota suppresses the generation of invariant natural killer cells (iNKTs) by reducing Cxcl16 5′ CpG methylation and reducing Cxcl16 expression [57]. (4) Microbiota may influence intestinal innate lymphoid cell (ILC) homeostasis through epigenomic modifications [41,42].

Figure 2. Microbiota-dependent regulation of epigenomic pathways in intestinal epithelial cells

The microbiota provide signals to the intestinal epithelium that contribute to effective intestinal barrier function. (1) Neonatal exposure to a complex microbiota establishes CpG methylation patterning in intestinal stem cells that are linked to stem cell renewal and IEC differentiation [76]. Short chain fatty acids (SCFAs) are taken up as energy by superficial colonocytes lining intestinal crypts and thus prevent diffusion to the stem cell niche where these metabolites inhibit stem cell proliferation [79]. (2) Interactions between IECs and the microbiota involve regulation of histone deacetylases (HDACs) to modify the host epigenome and influence gene expression and barrier functions [80]. HDAC expression in IECs maintains intestinal homeostasis and barrier integrity [–83].