Human gut bacteria as potent class I histone deacetylase inhibitors in vitro through production of butyric acid and valeric acid

Abstract

Overexpression of histone deacetylase (HDAC) isoforms has been implicated in a variety of disease pathologies, from cancer and colitis to cardiovascular disease and neurodegeneration, thus HDAC inhibitors have a long history as therapeutic targets. The gut microbiota can influence HDAC activity via microbial-derived metabolites. While HDAC inhibition (HDI) by gut commensals has long been attributed to the short chain fatty acid (SCFA) butyrate, the potent metabolic reservoir provided by the gut microbiota and its role in host physiology warrants further investigation in a variety of diseases. Cell-free supernatants (CFS) of 79 phylogenetically diverse gut commensals isolated from healthy human donors were screened for their SCFA profile and their total HDAC inhibitory properties. The three most potent HDAC inhibiting strains were further evaluated and subjected to additional analysis of specific class I and class II HDAC inhibition. All three HDAC inhibitors are butyrate producing strains, and one of these also produced substantial levels of valeric acid and hexanoic acid. Valeric acid was identified as a potential contributor to the HDAC inhibitory effects. This bacterial strain, Megasphaera massiliensis MRx0029, was added to a model microbial consortium to assess its metabolic activity in interaction with a complex community. M. massiliensis MRx0029 successfully established in the consortium and enhanced the total and specific HDAC inhibitory function by increasing the capacity of the community to produce butyrate and valeric acid. We here show that single bacterial strains from the human gut microbiota have potential as novel HDI therapeutics for disease areas involving host epigenetic aberrations.

Histone deacetylase inhibition by gut microbe-generated short chain fatty acids entrains intestinal epithelial circadian rhythms

“…Pathways of interest involve SCFA-induced HDAC inhibition. SCFAs have been reported as potent HDACis with important effects on histone modifications 36,49,50 including a recent study demonstrating that gut microbiota can influence HDAC activity via microbial-derived metabolites such as butyrate and valerate 49 . A recent study has also shown that the intestinal microbiota can mediate daily metabolic cycles epigenetically via the rhythmic induction of HDACs in epithelial cells of the small intestine 22 whereas previous studies have suggested the importance of HDACs in regulating circadian rhythms of hepatic lipid metabolism 20 and their roles in diet induced obesity and rhythmicity of the lipidome 51,52 .…”

The Epigenetic Connection Between the Gut Microbiome in Obesity and Diabetes

“…In addition, M. massiliensis produced significant levels of valeric acid and hexanoic acid, which are medium-chain fatty acids. It was also reported that valeric acid and butyrate cumulatively showed inhibition against Class I HDACs-HDACs1, 2, 3 8, particularly HDAC2 (Yuille et al, 2018).…”

“…Histone deacetylases (HDACs) constitute a class of enzymes that remove an acetyl group from the amino-terminal lysine residues of histones resulting in compacted chromatin (Yuille et al, 2018). Histone deacetylation is primarily associated with transcriptional inactivation and overexpression of HDACs and has been linked to a number of neurological and inflammatory diseases.…”

“…Overall, 13 HDACs have been found in humans, which are classified into four classes-Class I contains HDACs 1, 2, 3, and 8; Class IIa consists of HDACs 4, 5, 7, and 9; Class IIb contains HDACs 6 and 10; Class III is comprised of Sirt1-Sirt7 and Class IV consists of HDAC 11. Each of these plays an important role in cell survival, proliferation and differentiation which can also influence tumorigenesis (Yuille et al, 2018). HDAC inhibitors have well-known potential to act as therapeutic agents in various diseases.…”

“…In addition to the metabolic functions, the gut microbiome also shapes gene expression in the host. Through various microbial-derived metabolites, gut bacteria can influence the host metabolism by inducing epigenetic alterations of key genes which modulate the initiation and progression of diseases (Yuille et al, 2018). Therefore, gut dysbiosis has been associated with an increasing incidence of conditions such as metabolic diseases such as type 2 diabetes (Allin et al, 2015) and obesity (Ley et al, 2006); inflammatory diseases such as inflammatory bowel disease (Pascal et al, 2017) and rheumatoid arthritis (Maeda and Takeda, 2017); liver diseases (Janssen et al, 2017); and cancers (Lofgren et al, 2011;Yu et al, 2017).…”