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    Epigenoma

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    PHILOSOPHICAL TRANSACTIONS B rstb.royalsocietypublishing.org Review 8 ® te this article: Gethauser 2018 Impac of lctary gut migabial metabolites onthe epigenme, Pil. Tas. &. Soc. 8 373 ror703s9. htpfxdoiorg/10.1098stb 20170359, Accepted: 30 January 2018 (ne contioution of 18 toa dscusion meeting Isue Frontiers in epigenetic chemical bislogy Subject Areas: health and dlease and epidemiology, rmoleiar biology, physiology Keywords: epigenomis, gut microbiota, metabalsm, le, human health Author for correspondence: Carissa Gerhauser emai cgerhauseradl.de THE ROYAL SOCIETY PUBLISHING Impact of dietary gut microbial metabolites on the epigenome Clarissa Gerhauser Eloi and Gn Rk Fao, Geman Cana ese ener (AD, Heer, Gerany © 6 owoann.s2350 Within the past decade, epigenetic mechanisms and their modulation by natu- ral products have gained increasing interest, Dietary bioactive compounds from various sources, including green tea, soya, fruit and berries, cruciferous vegetables, whole grain foods, fish and others, have been shown to target ‘enzymes involved in epigenetic gene regulation, including DNA methyltrans- fetases, histone acetyltransferases, deacetylases and demethylases jn vitro and in cell culture. Also, many dietary agents were shown to alter miRNA expression, In vivo studies in animal models and humans are still limited, Recent research has indicated that the gut microbiota and gut microbial ‘metabolites might be important mediators of diet-epigenome interactions, Inter individual differences in the gut microbiome might affect release, metab olism and bioavailability of dietary agents and explain variability in response to intervention in human studies, Only a few microbial metabolites, including, folate, phenolic acids, S{—Jequol, urolithins, isothiocyanates, and short- and. long-chain fatty acids have been tested with respect to their potential to influence epigenetic mechanisms. Considering that a complex mixture of inter- mediary and microbial metabolites is present in human circulation, a more systematic interdisciptinary investigation of nutri-epigenctic activities and their impact on human health is called for. ‘This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’. Introduction (a) The gut microbiome: our second genome Studies have identified large inter individual differences in gut microbial compo sition, with consequences for human health [1.2] A recent large-ecale sequencing programme of 124 individuals identified about 3 milion ‘non-redundant Inicrbial genes, derived from $767 gigabases of sequence [3], Thus the gutmeta genome (he collective genetic information derived directly frm a faecal sample by deep sequencing) is about 150 times larger than the human genome. Eighteen bacterial species were detected in all individuals, 57 in greater than or equal t 90% and 75 in greater than or equal to 50% of individuals [3] A following study revealed that based on their predominant gut bacterial communities, ind viduals could be grouped into three main clusters or enterotypes, namely Bacteroides, Prevoela and Ruminococes, Host properties such as age, body mass index or gender did not explain the enterotypes, Rather, enterotypes seem to ifr in their choice of energy source [4]. Wucet al (5] postulated that enterotypes ‘were strongly associated with longrterm dit, particularly protein and animal fat (Bacteroides versus plant-derived carbohydrates and fibre (reel), Subsequent studies questioned the existence of distinc enterotypes [6] and instead proposed that microbial gene richness (he rumba of microbial genes per individual) ight be more relevant for human health status [7], Populations could be separated by a bimodal distribution of gene counts. Low gene richness was related to overall adiposity, insulin resistance, dyslipidaemia and an indlammatory phenotype compared with the high gene group [78]. In two large metagenomics analyses (© 201 The Authors, Pblied by the Royal Sacty ander the tems ofthe Cte Commons Atibton cers hrpieetivecsnans arg/cnsstby/4, which pets unesiced use, proved the ogral ‘thor and sauce ate cuted of Dutch and Belgian populations, low microbial diversity has ‘been linked to consumption of high-fat whole milk, sugar- sweetened drinks, higher total energy and carbohydrate intake, and snacking, whereas high microbial diversity has ‘been associated with consumption of coffee, tea, red wine and dark chocolate as sources of polyphenols [9,10]. Overall, these studies indicate that the metagenomic composition can, ‘be modified by (long-term) dietary patterns [1,2]. (b) Regulation of the epigenome The term ‘epigenetic’ refers to modifications in_gene expresion caused by heritable, but potentially reverble, changes in DNA methylation and chromatin structure, Major epigenetic mechanisms inckide DNA hyper- and hypo- methylation [11] remodeling of the chromatin, modification of histones by histone acetylation and methylation (among, others), and noncoding RNAs [12 “The DNA methyitransferase (DNMTS family of enzymes catalyses the transfer of methyl groups from. S-adenosyl~ ‘methionine (SAM) to DNA. In mammals, this occurs at the 5:porition of eytosine (Cin the context of CpG dinucleotides, generating S-methylcytosine (Gm), CpG dinucleotides are not evenly distributed in the genome: CpG-dense regions (CpG islands or Cla) are located in the prometer regions of genes, and are mostly unmethylated in healthy tisues, allowing active gene transcription, Conversely, inta- and intergenic regione have lower CpG density and ate highly methylated, ‘hus listing DNA accessibility and maintaining genomic stab- ity. Focal gain in methylation at CIs in promoter regions, for ‘example, of timer euppreasor genes concomitant with global Joss of methylation (hypomethylation), especially at repetitive sequences, is thought tobe involved in the aetiology of cancer. In contrat to irreversible genetic alterations (mutations, del- etions, ete), genes silenced by epigenetic modifications are still intact and can be reactivated [13,14]. Chromatin accensbility and gene expression is contelled by various postéranslational modifications of ‘N-terminal histone tal, including acetylation, methylation, phospho ation, ubiquitinyltion, eumoytation and ADP ribosylati {1516}. Acetylation of histone tails by histone acetytrans- ferases (HATS) opens up the chromatin structure, allowing transcription facts to acces the DNA [17]. Histone acetyl- ation is reversed by histone deacetylases (HDACS) that remove histone acety! groups by catalysing their transfer to comzyme A (CoA), leading to chromatin condensation and transcriptional repression. Beside the currently known HDACs 1-11, structurally unrelated sirtuins (SIRTS) possess deacetyatng activity, using NAD! asa cofactor [18]. Histone Iysine methylation has activating or repressive effects on gene expression, dependent on the ysne residue that is modified by methylation andthe numberof methyl groups [15] More than 30histone methyltransferases have been identified in humans that transfer methyl groups from SAM to lysine residues [19-21]. Histone methylation marks are removed by histone Iysine demethylases (HDMSs) for example, by lysine-xpeciic demethylase 1 (LSD1) and the family of about 20 Jumonjt dlomain-containing Grn) histone demathylases [22] Noncoding (nc) RNAS also possess a regulatory effect on gene expression, MicroRNA (ctiRNASs) are small ncRNAS of 20-22 nt that inhibit gene expression at the postiranscrip- tional level ether by imperfect base-pairing to the mRNA, ‘untranslated regions to repress protein synthesis, or by affecting mRNA stability (reviewed in (23). Identification and functional evaluation of long noncoding (Ine) RNAs (greater than 200nt) has become an additional area of scientific interest [24,25] 2. Impact of microbial metabolites on the epigenome Dietary agents from various sources, including green tea, fruit and berries, cruciferous vegetables and soya, directly target enzymatic activities or modulate expression of enzymes involved in epigenetic gene regulation. Therefore, they might affect numerous biological mechanisms, including. signal transduction mediated by nuclear receptors and transcrip- tion factors such as NF-xB, cell proliferation and celheyele progression, cellular differentiation, DNA repair, apoptos induction, cell motility, metastasis formation and cellular senescence (reviewed in (26-28). Recent research has indi- cated that the gut microbiota and gut microbial metabolites right be important mediators of the diet—epigenome inter- action (previously reviewed in [29-31)). The present overview is intended to summarize recent evidence from in vitro analyses (table 1) and in vivo investigations in rodent models and human intervention studies (table 2) (a) Folate and B-vitarins Folic acid and other B-vitamins are important cofactors in ‘one carbon metabolism’ to generate SAM for methylation reactions [32]. Dietary sources of folate inchude green leafy vegetables, asparagus, pulses, nuts, cruciferous vegetables, avocado, papaya, ec Ina dietary intervention study with postmenopau sal women altering plasma levels of folate directly influenced lymphocyte DNA methylation levels [33]. The gut microbiota is also involved in the metabolism of folate and B-vitamins [63]. Selected bacteria are able to synthesize folie acid from pteridine precursors and paminobenzoie acid [34]. Folate deficiency after antibiotic use indicates that colonic folate pro- duction can be significant [63] In addition to folate, the gut microbiota provides a vaticty of dictary energy metabolites, such as ATP, NAD* and acetyl-CoA, which are used as cofactors by epigenetic enzymes [35/4] (b) Dietary polyphenols Polyphenols from various sources, inluding green tea, black raspberries (BRB), red wine, coffee, apples, isoflavones from soya, curcumin fom curry and others, have been reported to affect epigenetic mechanisms in vitro in enzymatic reactions and in cell culture (reviewed in [26,27,65]). Studies in. animal models for cancer prevention or ditary interventions in humans are limited. (i) Isoflavones from soya Isoflavones, such as genistein and daidzein, are cancer- preventive phytochemicals with ant-/oestrogenic activity found in soya and other legumes. Epidemiological studies suggest that populations following a typical Asian diet rich in soya products havea reduced risk forhormone-dependent can- cers [28]. $-(-Jequol, a microbial metabolite of daidzein, has higher bioavailability and oestrogenicity than daidzein, Metabolomic investigations have shown that approximately one-third of the Wester population and up to 65% of the ceiosinas GSE0LLOC ELE 8 205 Y SUNY IY BLOG Bd bvaceypubiing ag Phi Tans. 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During the past decade, evidence is accumulating that soya isoflavones including the metabolite S-—Jequol affect epi- geneticenzymes that write, read or erase epigenetic marks, and subsequently modulate gene expression to counteract the ‘hall= marks of cancer’ (review in [28).In the few studies performed jn humans, gut microbial metabolism has not been systema: cally taken into consideration, and its influence on epigenetic endpoints should be addressed in future investigations. In addition, preclinical models should be carefully chosen to reflect human in vivo conditions. For example, rodents very ffi= ciently convert daidzein into $-(—)equol [68]. The outcome of investigations on soya in rodent models might, therefore, not ‘be generally informative for human populations. (ii) Green tea catechins With espec to the modulation ofepigenetic mechanisms, green tea catechins (GTC), with (~)-pigallocatechin gallate (EGCG) as the major catechin, represent one of the best investigated groups of polyphenols. It vitro, EGCG was shown to inhibit the activity and expression of DNMTs and to demethylate and reexpressgenesinvolved incl-cycle contro (pl6,p21),callsig- nalling (RAR), WNT-sigalling (WIE-D), DNA repair (MGMT, MLE) and apoptosis (DAPK) (eview in [85). Lee ef al. suggested that biotransformation of catechins by Phase Il metabolic enzymes might influence the activity of epigenetic enzymes. Catechin metabolism by the catechol ©. rethyltransferase (COMT) leads to consumption of SAM, which is then less available for the catalytic activity of DNA and histone methyltrarsferases. On the other hand, sethylation reactions by COMT produce Sadenosyli- homocysteine (GAH), which is a negative feedback inhibitor of methyltransferaes [69]. Both depletion of SAM as well as elevated levels of SAH might result in reduced levels of DNA. orhistone methylation, which might consequentially influence gene expression. Dietary polyphenols also undergo gut microbial metab- olism, ‘The microbial degradation of catechins such as epicatechin (EC) by cleavage of the © heterocycle and dehydrox ylation results in the formation of phenolic acids (9638). In an enzymatic in vitro assay of DNMT activity, protocatechuic acid {at 20 and 40 uM, respectively) inhibited enzyme activity by 64-80% [39]. Waldecker et l.investigated microbial metabolites of apple juice extracts on enzymatic HDAC activity. Halfmaxi- smal inhibitory concentrations (ICap values) were in the range of 0119-547 mM, exceeding the concentrations of phenolic acids detected in human faecal water [0,41]. Whether these weak in vitro inhibitory effects of phenolic acids have physiological relevance needs to be addressed in future investigations in vito GICs have been repeatedly reported to prevent prostate cancer in “TRansgenic Adenocarcinoma of Mouse Prostate’ (TRAMP) mice (suramary in [65). Morey Kinney etal. used a genome-wide approach to test the influence of GICs on prostate cancer and DNA methylation in the TRAMP mouse todel, Unexpectedly, the intervention with GTCs (03% in drinking water) prevented neither prostate cancer growth nor DNA methylation in prostate, liver and gut (50), Cur. rently i can only be speculated whether differences in gut ‘microbial populations and alterations in GTC metabolism ‘ight explain the observed discrepancies with earlier studies, (ii) Black raspberries RBs are a good source for polyphenols including ellagi acid, quercetin glycosides and anthocyanins. Freeze-dried BRBs have been shown to prevent oesophageal and colon cancer in animal models by targeting carcinogen metabolism, cell pro liferation, inflammation, angiogenesis and apoptosis, and are well tolerated by humans at daily doses of 45 g [70]. In a small Phase I human dietary intervention study with 20 colon cancer patients, 60 g freeze-dried BRBs per day for a minimum of four weeks led to reduced expression of DNMT1 and promoter demethylation of genes involved in the WNT-signalling pathway in tumour tissue, accompanied by reduced expression of WNT-target proteins such as B

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