Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases

Abstract

Epigenetic modulation of gene activity occurs in response to non-genetic factors such as body weight status, physical activity, dietary factors, and environmental toxins. In addition, each of these factors is thought to affect and be affected by the gut microbiome. A primary mechanism that links these various factors together in mediating control of gene expression is the production of metabolites that serve as critical cofactors and allosteric regulators of epigenetic processes. Here, we review the involvement of the gut microbiota and its interactions with dietary factors, many of which have known cellular bioactivity, focusing on particular epigenetic processes affected and the influence they have on human health and disease, particularly cancer and response to treatment. Advances in DNA sequencing have expanded the capacity for studying the microbiome. Combining this with rapidly improving techniques to measure the metabolome provides opportunities to understand complex relationships that may underlie the development and progression of cancer as well as treatment-related sequelae. Given broad reaching and fundamental biology, both at the cellular and organismal levels, we propose that interactive research programs, which utilize a wide range of mutually informative experimental model systems-each one optimally suited for answering particular questions-provide the best path forward for breaking ground on new knowledge and ultimately understanding the epigenetic significance of the gut microbiome and its response to dietary factors in cancer prevention and therapy.

Keywords: Acetylation; Epigenetics; Epigenome; Gut microbiome; Histone proteins; Methylation.

Fig. 1

The basic process of DNA methylation. S-adenosylmethionine (SAM) is used as the methyl (CH3) donor by the enzyme DNA methyltransferase (DNMT) to transfer a methyl group to cytosine rings of the DNA strands. TET proteins are dioxygenase enzymes that hydroxylate 5-methylcytosine residues to form 5-hydroxymethylcytosine (5hmC). They use a metabolite intermediate, α-ketoglutarate (α-KG), and molecular oxygen as enzyme cofactors for this reaction

Fig. 2

The molecular interaction of the gut microbiota is greatly influenced by the dietary compounds consumed. The microbes residing in the human gut produce a number of low molecular weight molecules such as butyrate, folate, propionate, and biotin. These compounds either directly bring about epigenetic modifications such as changes in DNA methylation and histone acetylation or indirectly act via activation or inhibition of certain enzymes such as DNMTs, HDACs, or even hTERTs. Me DNA methylation, Ac histone acetylation