Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin

Abstract

The mammalian gut microbiota has been linked to host developmental, immunologic, and metabolic outcomes. This collection of trillions of microbes inhabits the gut and produces a myriad of metabolites, which are measurable in host circulation and contribute to the pathogenesis of human diseases. The link between endogenous metabolite availability and chromatin regulation is a well-established and active area of investigation; however, whether microbial metabolites can elicit similar effects is less understood. In this review, we focus on seminal and recent research that establishes chromatin regulatory roles for both endogenous and microbial metabolites. We also highlight key physiologic and disease settings where microbial metabolite-host chromatin interactions have been established and/or may be pertinent.

Figure 1

Endogenous metabolites regulate (A) histone acetylation, (B) histone deacetylation, and (C) histone and DNA methylation and demethylation. PDH = pyruvate dehydrogenase, ACSS1/2 = acetyl-CoA synthetase 1/2, HAT = histone acetyltransferase, NR = nicotinamide riboside, NA = nicotinic acid, NAM = nicotinamide, NMNAT = nicotinamide/nicotinic acid mononucleotide adenylyltransferase, LCFAs = long-chain fatty acids, NAD⁺ = nicotinamide adenine dinucleotide, HDACs = histone deacetylases, β-OHB = β-hydroxybutyrate, SHMT = serine hydroxymethyltransferase, MTHFR = methylenetetrahydrofolate reductase, 5-methyl-THF = 5-methyl- tetrahydrofolate, THF = tetrahydrofolate, MTR = methionine synthase, DMG = dimethylglycine, MAT = S-adenosylmethionine synthase, SAH = S-adenosyl homocysteine, SAM = S-adenosylmethionine, HMTs = histone methyltransferases, LSDs = lysine specific demethylases, JmjCs = Jumonji C family histone demethylases, α-KG = α-ketoglutarate, TETs = Ten Eleven Translocation methylcytosine dioxygenases, DNMTs = DNA methyltransferases

Figure 2

Regulation of histone acetylation by gut microbial metabolites.

Figure 3

Regulation of histone methylation by gut microbial metabolites.

Figure 4

Regulation of DNA methylation by gut microbial metabolites. PUFAs = polyunsaturated fatty acids

Figure 5

A model wherein the mammalian gut microbiota mediates communication between environmental exposures and host epigenetic programming of downstream phenotypes. Environmental exposures known to affect mammalian microbiota include: antibiotics, cold exposure, hormones, natural seasonal cycles in ambient temperature and food sources, and dietary composition, excess, and scarcity. The composition of the mammalian gut microbiota, which resides in the host alimentary tract and is in direct contact with the environment, is altered in response to environmental factors. Alteration of microbial community composition leads to differences in microbial metabolite production, and ultimately altered chemical signaling to host chromatin. Modifications to host chromatin then drive new transcriptional programs to produce an adapted phenotype. The proposed cycle may repeat in response to continued exposure to the same environmental factor or in response to a new exposure.