Metabolomics View on Gut Microbiome Modulation ... - ACS Publications

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Metabolomics View on Gut Microbiome Modulation by Polyphenolrich Foods Sofia Moco,*,†,‡ François-Pierre J. Martin,†,‡ and Serge Rezzi†,‡ †

BioAnalytical Science, Nestle Research Center, Vers-chez-les-Blanc, PO Box 44, 1000 Lausanne 26, Switzerland ABSTRACT: Health is influenced by genetic, lifestyle, and diet determinants; therefore, nutrition plays an essential role in health management. Still, the substantiation of nutritional health benefits is challenged by the intrinsic macroand micronutrient complexity of foods and individual responses. Evidence of healthy effects of food requires new strategies not only to stratify populations according to their metabolic requirements but also to predict and measure individual responses to dietary intakes. The influence of the gut microbiome and its interaction with the host is pivotal to understand nutrition and metabolism. Thus, the modulation of the gut microbiome composition by alteration of food habits has potentialities in health improvement or even disease prevention. Dietary polyphenols are naturally occurring constituents in vegetables and fruits, including coffee and cocoa. They are commonly associated to health benefits, although mechanistic evidence in vivo is not yet fully understood. Polyphenols are extensively metabolized by gut bacteria into a complex series of end-products that support a significant effect on the functional ecology of symbiotic partners that can affect the host physiology. This review reports recent nutritional metabolomics inspections of gut microbiota−host metabolic interactions with a particular focus on the cometabolism of cocoa and coffee polyphenols. KEYWORDS: nutrition, metabolism, metabolomics, metabonomics, systems biology, cocoa, coffee, polyphenols, flavonoids, gut microbiome

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INTRODUCTION Over the last decades, increasing awareness has been raised in the way nutrient content changes of the human diet would lead to changes in metabolism by means of metabolic profiles.1,2 Probably not as pronounced as drug-induced effects, nutritional interventions lead to subtle but chronic modulations of metabolism, an effect often obscured by inherent interindividual metabolic heterogeneity, as a result from variable genetic background, environmental factors and lifestyle. Nevertheless, all individuals eat, and it is hardly the case that some maintain constant or extreme diets, making it particularly challenging to associate health effects with specific nutritional habits or nutrients. Food is processed by our gastrointestinal system primarily to supply energy and key functional elements to the body. Dietary carbohydrates, proteins and fats are respectively catabolized into monosaccharides, amino acids and fatty acids that serve as fuel to maintain organ function and promote cellular growth and recycling. In particular, the central, protein and lipid metabolism that probably hold most of the nutritionally driven molecular species often strongly associate with either healthy status or homeostatic loss, which can lead to increasing likelihood to develop disease. Furthermore, the biological organization of mammalian superorganisms introduces a complex noneukaryotic compartment that also interplays with food components and key regulatory physiological processes of the host, the gut microbiota. Increasingly, scientific evidence identifies gut microbiota as a key biological interface between © 2012 American Chemical Society

human genetics and environmental conditions encompassing nutrition. Microbiota dysbiosis or variation in metabolic activity has been associated to metabolic deregulation (e.g., obesity, inflammatory bowel disease), disease risk factor (e.g., coronary heart disease) or even in the etiology of various pathologies (e.g., autism, cancer), although a causal role into impaired metabolism still needs to be established.3 The advent of systems biology opens new opportunities to deepen and model the complex web of molecular interactions between nutrition and health, encompassing the understanding on how to modulate gut microbiota. Here, we will discuss recent studies on gut microbiota nutritional modulation with emphasis on nutritional components widely recognized for their potential health beneficial effects, the dietary polyphenols.

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METABOLOMICS

Metabolomics aims at the quantitative analysis of a large number of molecules (metabolites) participating as substrates or products in biochemical reactions. It is therefore characterized by capturing mostly small molecules endogenously and exogenously present in a complex biological system, such as a cell, tissue, or a whole organism. By obtaining biochemical information about the abundance of metabolites, as Received: June 28, 2012 Published: August 21, 2012 4781

dx.doi.org/10.1021/pr300581s | J. Proteome Res. 2012, 11, 4781−4790

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(INADEQUATE)18 or computational strategies for the deconvolution of complex spectra such as constrained totalline-shape41,42 are developments to consider for facilitating the assignment of metabolites directly from complex mixtures. Data fusion strategies, such as pairing of LC−MS to NMR data, have presented interesting approaches to the analysis of metabolomics data with the potential of enlarging the list of identified compounds in mixtures.43−45 In the frame of nutrition research, human studies are crucial to dissect the influence of particular nutrients, as food constituents, in the modulation of overall metabolism. However, human metabolome analysis has to be inferred mostly by measuring biofluids (such as blood plasma or serum, urine, saliva) or tissue biopsies (such as liver, muscle, adipose tissues). Targeted and untargeted approaches using NMR spectroscopy, gas chromatography (GC)−MS, thin layer chromatography (TLC)/GC−MS, LC−MS, and direct flow injection (DFI)−MS/MS have been recently used to putatively assign over 3500 metabolites in human serum.46 Nowadays, the Human Metabolome Database47 contains an impressive amount of information on human metabolites. It reports over 10 000 metabolites present in blood and over 2000 in urine. Given the inherent complexity of foods (macro- and micronutrients), it becomes extremely challenging to assign effects of particular nutrients to the overall benefit of healthy individuals. Nevertheless, metabolomics approaches can be also applied in the biochemical characterization of food itself to identify major nutritional constituents and particular metabolites. Thus, metabolomics approaches applied to food screening, foodomics, can be used in a wide range of foods (milk, cereals, wine, fruits, vegetables, meat48) and when combined with human nutritional interventions can give insight on nutrient bioavailability and metabolic fate of nutrients.

an ensemble, a phenotypic trait can be ascribed to a specific biological read-out. Analytical methodologies targeted to specific metabolites or class of compounds have been around for decades; however, the ability to obtain hundreds to thousands of metabolites in a single measurement allows a high-resolution biochemical characterization of a biological status, feasible to be used at a system (biofluids) and biological compartment (tissue, organ, cell) levels. Even though capturing the metabolome can be achieved by a wide range of analytical techniques, nuclear magnetic resonance (NMR) and mass spectrometry (MS) are widely used for this purpose.4 Ranging from untargeted to targeted methods, methodologies have been reported for screening the most established biochemical pathways so far: central carbon metabolism, including glycolysis and tricarboxylic acid cycle, amino acid pathways, lipid pathways, and selected secondary metabolism pathways.5−7 In the quest to achieve the maximum metabolite information with a minimum analysis time, high throughput MS and NMR methods have been described to handle ballistic analysis times, below 10 min, with little compromise in robustness.8,9 Consistency among different laboratories has been proven by undertaking ring experiments within the metabolomics community, both for NMR and MS analyses.10,11 Advanced methods are defying routine protocols, by proposing enhanced analytical or data analysis improvements. In the NMR field, quantification of metabolites directly from mixture spectra is being increasingly developed, either using 1D or 2D NMR spectra, internal standards, metabolite spectral databases, and innovative data processing routines.12−20 High magnetic field strengths,21 dynamic nuclear polarization,22 and the usage of small volume probes23 are some of the developments that revealed enhanced NMR sensitivity and therefore should be considered in metabolomics applications. Furthermore, NMR spectroscopy, using high resolution-magic angle spinning (HRMAS) NMR, offers the possibility of profile metabolites in intact tissue biopsies with the unique feature of ensuring the integrity and organizational compartmentalization of the biological samples.24,25 In terms of MS developments, single cell analysis 26 or tissues imaging techniques, such as nanostructure initiator mass spectrometry,27 provide metabolite localization that can be crucial for metabolite function. Enlargement of metabolite coverage and metabolite identification are known bottlenecks in metabolomics. More and more strategies appear describing a wider coverage of the metabolome by MS.28−30 Surely, given the high sensitivity of MS instruments, thousands of ions corresponding to metabolites can be detected. Feature extraction, alignment of chromatograms or spectra and strategies for the interrogation of spectra in databases are being extensively developed, so that the gap between signal and metabolite identification is constantly minimized.31−34 Hyphenated methods such as liquid chromatography (LC)−MS, LC−NMR and LC−NMR-MS, including dedicated MS and NMR experiments, have proven to be of great assistance in metabolite identification.4,35,36 MS and NMR analytical strategies such as fragmentation trees obtained by MS/MS,37 the introduction of more complex pulse sequences in NMR experiments such as diffusion-ordered spectroscopy (DOSY),38 heteronuclear single quantum coherence-total correlation spectroscopy (HSQC-TOCSY),39 doubly indirect covariance HSQC-correlation spectroscopy (COSY)HSQC,40 fast 2D NMR methods, such as the 2D 1H-incredible natural abundance double quantum transfer experiment

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GUT MICROBIAL ACTIVITY, NUTRITION AND METABOLISM Understanding the long-range (organ and system-specific) metabolic interactions between human and gut microbial metabolism is of importance on health and nutrition status.49 Major advances in metabolomics and metagenomics technologies have shown that the contribution of the intestinal microbiota to the overall health status of the host has so far been underestimated. Apart from the obvious role in digestion, the gut microbiota has been associated with diverse body functions such as gastrointestinal tract permeability, vitamin synthesis, detoxification of xenobiotics and immune system homeostasis.2,50 Nutrition remains a key modulator of the gut microbiota and strong evidence has associated diet and microbial composition in the gut.51 The gut microbiome is composed by the totality of microorganisms inhabiting the gastrointestinal tract. The gut is mainly populated by bacteria accounting for about 100 trillion cells. The bacterial communities vary in composition along the digestive tract and adapt through life according to lifestyle and nutrition of the host.52,53 In terms of genetic diversity, the microbiome surpasses the human genome by 100fold.54 Given these numbers, it is no surprise that a great deal of the genes involved in energy production and metabolism are present in the gut microbiome, conferring humans the capacity to live on widely diverse diets.55 In fact, about half of the total number of genes found in the gut relate to the central carbon and amino acid metabolism and biosynthesis of secondary metabolites.56 4782



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microbiome to maintain or re-establish a balanced and welladapted microbiota could help in preventing some microbialrelated metabolic disorders. As an example, Calvani et al.71 applied a NMR-based metabolomic approach on urinary samples of morbidly obese subjects and age-matched controls. Obesity-associated metabolic phenotype included gut floraderived metabolites such as hippuric acid, trigonelline, 2hydroxyisobutyric acid and xanthine. Here, the metabolic changes of two obese patients following bariatric surgery were monitored, leading to a loss of the typical obese metabotype after intervention. It is therefore crucial to decipher the foundations of the reciprocal metabolic influences between host and microbiota to better define the role of gut microbes in determining gastrointestinal functional ecology. The gut microbiota determine not only absorption, digestion, metabolism and excretion of dietary nutrients but also the metabolism of ingested nutrients and host cell molecular machinery, with possibly long-term effects. This knowledge will thus be fundamental for developing individual disease and nutritional management solutions.

Metabolomics studies have proved through microbial and metabolic analyses of stool a description of a range of microbial activities in the colon. Nevertheless, detailed information about the identity of gut bacteria, their functionality, including enzymatic capabilities to metabolize dietary compounds, and identity of the metabolites produced by gut microbial activity is still scarce. An overview of metabolites associated to gut microflora activity has been listed recently, providing correspondences between microbial metabolites (such as short-chain fatty acids, bile acids, cholines, phenyl and indol derivatives), bacteria and potential biological functions.49 Over 50 bacterial phyla have been identified in the human gut; however, four main phyla, Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria, are reported to be dominant.57,58 Wu et al.59 have combined 16s rDNA sequencing of human stool with food questionnaires and identified changes in the gut microbiome already after 24 h of a controlled diet. After the submitted nutritional intervention, proportions of the two main gut microbial communities were altered: Bacteroidetes, found in protein- and animal fat-rich diets (associated with European diet habits) and Prevotella, high in carbohydrate-rich diets (such as African diets). Donohoe et al.54 used a combined omics and biochemical approach to demonstrate that microbiota exerts a strong influence on energy homeostasis, by actively regulating NADH/NAD+ ratios and ATP levels in the colon. As described, the short chain fatty acid butyrate, produced by bacteria in the gut, is used as the primary energy source by colonocytes. Butyrate is then transported to the mitochondria to undergo β-oxidation to acetyl-CoA that enters the TCA cycle and results in ATP production. Recently, applications of top-down system biology approaches described the depth of gut microbial influence on host metabolic functions, resulting in modulation of host lipid, carbohydrate and amino acid metabolism at organ and system levels.60−63 The specific metabolic activities of a single gut bacterial species can provide the host with new biochemical compounds in sufficient amount to be detected in the general blood circulation.64 Martin et al.65,66 exemplified how the gut microbial modulation of the gastrointestinal system and extensive microbial-mammalian cometabolism may fine-tune host metabolic processes and may induce metabolic deregulations. In particular, the authors highlighted the different bacterial modulation of the bile acid metabolism and enterohepatic cycle, with consequent effects on the absorption of dietary fat and concomitant to lipid accumulation in the liver of animals harboring a nonadapted gut microbiota. The gut microbiota exerts a long-range control over multiple host cell metabolic pathways via, for instance, the cometabolism of bile acids and inferred modulation of lipid and cholesterol metabolism.65,67,68 Further investigations were carried out using germfree and conventionalized mice, which investigated the establishment of a stable microbiota environment in a germfree rat model using urine metabolic profiling over a period of 21 days of reconventionalization by exposure to a standard laboratory environment.61,69,70 Important metabolic variations were modeled over time in relation to metabolic dysfunction (glycosuria, down regulation of citric acid intermediates). Changes in gut microbial-related metabolites (hippurate, trimethylamine, phenylacetylglycine) were observed, where patterns characterized by different dynamics were depicted, likely to reflect different stages in the establishment of a new gut functional ecology. Collectively, these studies suggest that controlling the dynamics of the gut

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POLYPHENOLS AND THEIR BIOTRANSFORMATION IN THE GUT Polyphenols are natural compounds widely occurring in plants, including foods such as fruits, vegetables, cereals, tea, coffee, and wine, and therefore are an integrant part of the human diet. Chemically, polyphenols are characterized by hydroxylated phenyl moieties and in planta they are mostly occurring in their glycosylated forms, although modifications such as methylation or polymerization are commonly found. Within this wide group of natural compounds, flavonoids are a major subgroup, where flavones, flavanones, flavonols, catechins and anthocyanins are included. Polyphenols have attracted attention in the last decades for having both antioxidant and pro-oxidant activities in vitro and in animal models.72 Even though there are conflicting results in this area, possible health-promoting effects such as antiinflammatory, antiestrogenic, cardioprotective, chemoprotective and neuroprotective properties have been reported.73,74 In nutrition, polyphenol-rich foods are associated as being healthier foods, yet the mechanisms of action at the molecular level remain poorly understood. In vitro and human studies have been conducted to assess the protective effects and mechanisms of action of polyphenols in human metabolism. Although still poorly understood, polyphenol-rich foods have shown evidence to impact carbohydrate and lipid metabolism, by attenuating postprandial glycaemic responses and fasting hyperglycaemia and improving acute insulin secretion and insulin sensitivity. The interplay between polyphenols and glucose homeostasis might be due to various molecular processes, including inhibition of carbohydrate digestion and glucose absorption, protection of β-cells from glucotoxicity, suppression of glucose release from liver storage and improvement of glucose uptake in tissues.75 During digestion, polyphenols, unlike most compounds, are only partially absorbed in the small intestine. Glycosidic and polymeric forms undergo deconjugation by hydrolases, αrhamnosides, β-glucosidases, and β-glucoronidases.74,76 For example, procyanidins are known to be transformed into phenylacetic acid, mono- and dihydroxyphenylacetic acids, mono- and dihydroxyphenylpropionic acids, and hydroxybenzoic acid, while anthocyanins are mainly metabolized into 4783



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protocatechuic acid.74 Most of the dietary polyphenols reach the colon where simple phenolics and phenols are produced by breakdown due to microbial activity. The gut microflora has means to undergo O- and C-deglycosilation, ester and amide hydrolysis, and deglucuronidation of large flavonoids, as well as fermentation of the flavonoid backbone. Aglycones can therefore be subjected to dehydroxylation, demethoxylation and demethylation of the aromatic moieties, hydrogenation, αand β-oxidation of substituted aliphatic groups, as well as ring rupture.77 Flavonoids by backbone rupture produce phloroglucinol (derived from A ring) and hydroxylated forms of phenylacetate or phenylpropionate are obtained derived from the B ring, Figure 1. Ultimately, these simple phenolics can be

mostly in the liver after absorption of the microbial metabolites into the bloodstream. Sulphation, glucuronidation, methylation and glycine-conjugation are the most common biotransformations at this stage, so that these metabolites are restricted from potential toxic effects and become easier to excrete by urine or bile, Figure 1. Ingestion of polyphenol-rich foods is associated with benzoic acid formation which is transformed into hippuric acid in the liver and is detected in urine. Likewise, phenylacetic acid, phenylpropionic acid, p-cresol and hydroxybenzoic acid are other microbial metabolites associated to both dietary polyphenols and aromatic amino acids (from dietary proteins) that are recurring in urine.79 In sum, so far, only a limited number of bacterial species have been identified as being involved in the metabolism of polyphenols. Table 1 provides an overview of the metabolites produced from known flavonoids by described gut flora strains. Interestingly, the majority of the bacteria listed belong to the Clostridia group, which is a large component of the gut microbiota. Microbial metabolism therefore not only is a prerequisite for absorption but also modulates the biological activity of polyphenols, leading to the release of more active metabolites in the body. The metabolization of polyphenols is known to be diet- and individual-dependent.75 The bacterial characterization of the gut flora is surely important, but ultimately the enzymatic activity of its microbes becomes vital to map functional metabolic reactions and describe the interaction between host and microbe to understand metabolism.

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COCOA AND COFFEE POLYPHENOLS Coffee is one of the most consumed beverages in the world and accounts for a total consumption worldwide of over 6 million tons80 with a predominance in dietary habits of Europeans and Americans. Likewise, cocoa is widely consumed, accounting for over 3.5 million tons80 of worldwide consumption, mainly as a key ingredient in chocolate products. Both coffee and cocoa beans are naturally rich in polyphenols. The polyphenol composition of coffee beans includes a variety of chlorogenic acids (conjugation of quinic acid with trans-cinnamic acids, mostly caffeic, p-coumaric, and ferulic acid) as main constituents. Fourty-five different chlorogenic acids were identified in green Arabica coffee beans and 69 were identified in the Robusta variety.81,82 Cocoa contains flavanols in monomer (epicatechin and catechin), oligomer, and polymer (proanthocyanidins) forms, as well as anthocyanins, flavonol glycosides, clovamide, dideoxyclovamide, phenylethylamine, Noleoyl- and N-linoleoylethanolamine, and theobromine.83,84 To study the nutritional impact of polyphenols in human metabolism, most studies attempt to detect a metabolic change at a systemic level or to trace typical polyphenols in human blood and urine after a nutritional intervention with a polyphenol-rich food. As systemic effects, cocoa flavanols have been reported to prevent LDL oxidation, enhance endothelial function, or modulate cytokine transcription in peripheral blood mononuclear cells.85,86 Moreover, cocoa polyphenols may increase the concentration of HDL cholesterol, whereas chocolate fatty acids may modify the fatty acid composition of LDL, making the latter less prompt to oxidative damage.87,88 Several other chocolate components, such as phenylethylamine, N-oleoyl- and N-linoleoyl-ethanolamine, may have psychoactive activity that could modulate stress and mood.89,90

Figure 1. Tentative overview of the reported metabolites produced by gut activity from dietary glycosylated flavonoids, such as rutin, widely present in fruits and vegetables. Polyphenols are partially absorbed in the small intestine, being modified by phase I and II reactions in the liver, producing glucuronides and sulphates that can be shunt back into the intestine via bile. Microbial conversion then takes place in the colon, directing the degradation of complex metabolites into simpler forms, leading to absorption, systemic circulation or urinary and fecal excretion. In the case of rutin, Butyrivibrio sp. C3 was reported to convert it to phloroglucinol, 3,4-dihydrobenzaldehyde and 3,4dihydroxyphenylacetic acid. Enterococcus casselif lavus is described to be involved in the hydrolysis of sugar moieties, such as in quercetin-3glucoside, releasing the aglycone quercetin, with acetate, lactate, formate and ethanol production. Eubacterium ramulus, Eubacterium oxidoreducens, Flavonif ractor plautii as well as several Clostridium strains have been associated with the fermentation of the aglycone quercetin, leading to the formation of taxifolin, 3,4-dihydroxyphenylacetic acid, acetate and butyrate.108−112 The catabolism of polyphenols is associated with the production of benzoic acid, which normally undergoes glycine conjugation in the liver, leading to the production of hippuric acid, easily detected in urine.79

further metabolized to nonaromatics, such as short-chain fatty acids, lactate, succinate, oxaloacetate, ethanol and the gases CO2 and H2 by the colonic flora. Hydrogen is kept at low concentrations in colon by the activity of hydrogen utilizing species such as methanogenic, acetogenic and sulfate reducing bacteria. Some individuals, who do not have the ability to produce methane in the colon (nonmethogenic), have instead large numbers of sulfate reducing bacteria such as Desulfovibrio, Desulfobacter, Desulfomonas, Desulfobulbus and Desulfotomaculum. These bacteria use sulfate as electron acceptor during oxidative reactions.78 Phase I and II modifications take place 4784


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a

6,7,4′-trihydroxyisoflavone (2R)-1-(3′,4′-dihydroxyphenyl)-3-(2″,4″,6″-trihydroxyphenyl)propan-2-ol 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone; 5-phenyl-γ-valerolactone; phenylpropionic acid; 4-hydroxy-5-(3,4-dihydroxyphenyl)valeric acid (2S)-1-(3′,4′-dihydroxyphenyl)-3-(2″,4″,6″-trihydroxyphenyl)-propan-2-ol (2S)-1-(3′-hydroxyphenyl)-3-(2″,4″6″-trihydroxyphenyl)propan-2-ol; 5-(3,4dihydroxyphenyl)-γ-valerolactone; 5-phenyl-γ-valerolactone; phenylpropionic acid; 4-hydroxy-5-(3,4-dihydroxyphenyl)valeric acid

eriodictyol; 3-(3,4-dihydroxyphenyl)propionate; phloroglucinol 3-(4-hydroxyphenyl)propionate; phloroglucinol 3-(4-hydroxyphenyl)propionate; phenylacetate; phloroglucinol 4-hydroxyphenylacetate 3-(3,4-dihydroxyphenyl)propionate; 3-(4-hydroxyphenyl)propionate 3-(4-hydroxyphenyl)propionate; phloroglucinol genistein 6′-hydroxy-O-desmethylangolensin; 2-(4-hydroxyphenyl)propionate; phloroglucinol daidzein dihydrodaidzein; O-desmethylangolensin; tetrahydrodaidzein; 2,3-dehydroequol; equol

3,4-dihydroxybenzyldehyde; 3,4-dihydroxyphenylacetate; phloroglucinol quercetin; glucose; acetate; lactate; formate; ethanol; 3,4-dihydroxyphenylacetate; phloroglucinol; butyrate taxifolin; alphitonin; 3,4-dihydroxyphenylpyruvate; 3,4dihydroxyphenylenolpyruvate; 3,4-dihydroxyphenylacetaldehyde; 3,4dihydroxyphenylacetate; phloroglucinol; acetate; butyrate 3,4-dihydroxyphenylacetate; alpha,2′,3,4,4′,6′-hexahydroxydihydrochalcone 3-(3,4-dihydroxyphenyl)propionate

metabolites

Note: Flavonifractor plautii is the former Clostridium orbiscindens.

(−)-catechin (−)-epicatechin

glycitein (+)-catechin (+)-epicatechin

(+)-taxifolin luteolin-7glucoside luteolin apigenin naringenin kaempferol eriodictyol phloretin formononetin genistein biochanin A daidzein

rutin quercetin-3glucoside quercetin

flavonoid

109,113 108 108−110 109 109,112 108,112 109,108 109,108 114 108 114 108,114−116

Flavonif ractor plautii; Eubacterium sp. SDG-2 Eubacterium ramulus Flavonif ractor plautii; Eubacterium ramulus Flavonif ractor plautii Flavonif ractor plautii; Clostridium spp; Clostridium scindens; Eubacterium desmolans Clostridium spp; Eubacterium ramulus Flavonif ractor plautii; Eubacterium ramulus Flavonif ractor plautii; Eubacterium ramulus Eubacterium limosum Eubacterium ramulus Eubacterium limosum Eubacterium ramulus; Clostridium spp. HGH136; Eggerthella spp. Julong732; Clostridium-like strain TM-40; Slackia spp. DZE; Eggerthella spp. YY7918; Lactobacillus mucosae EPI2; Enterococcus faecium EPI1; Finegoldia magna EPI3; Veillonella spp. EP Eubacterium limosum Eubacterium sp. SDG-2; Eggerthella lenta rK3; Flavonif ractor plautii aK2; Clostridium coccoides −Eubacterium rectale group; Bifidobacterium spp.; Escherichia coli Eubacterium sp. SDG-2 Eggerthella lenta rK3; Flavonif ractor plautii aK2; Clostridium coccoides −Eubacterium rectale group

113,117,118

114 113,117,118

108−112

Flavonif ractor plautii; Eubacterium ramulus; Eubacterium oxidoreducens; Clostridium spp

refs 108 108

gastrointestinal microbiota Butyrivibrio sp. C3; Eubacterium ramulus Enterococcus casselif lavus; Eubacterium ramulus

Table 1. Intestinal Microbiota Involved in the Metabolism of Certain Flavonoidsa

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urinary excretion, leading to the identification of several metabolites, including hippuric acid, 4-hydroxyhippuric acid and 1,3-dihydroxyphenyl-2-O-sulfate derived from microbial fermentation of polyphenols in the gut. Such concepts will, in the future, enable the identification of gut microbial phenotypes in a human population with potential long-term health benefits mediated by specific gut microbial derived bioactives from dietary polyphenols.

In addition, cocoa and coffee polyphenols have been reported to modulate the human gut. Plasma and urine of chocolate eaters led to the discovery of distinct metabolic profiles according to the behavioral/psychological dietary preference for chocolate products.91,92 Among the components of the metabolic signatures, the urinary excretion of various low molecular weight metabolites describing both distinct energy and microbiota metabolism was reported. Variations in many gut microbial cometabolites, including hippuric acid, 2hydroxyhippuric acid, phenylacetylglutamine, p-cresol sulfate, indole-3-acetic acid, and 3-hydroxyisovaleric acid, reflected different metabolism of dietary aromatic amino acids and polyphenols by colon microorganisms.93 In particular, the conversion of 4-hydroxyphenylacetic acid to p-cresol exhibited a negative correlation in the urine profiles of chocolate “likers”, which corresponds to a molecular process that has been associated with the presence of Clostridium dif ficile but also other bacterial strains. This observation suggested a differential management of the metabolic pool of the precursor 4hydroxyphenylacetic acid by gut bacteria.94 Proanthocyanidins seem to be poorly absorbed through the gut barrier because of their high molecular weight. The formation of several phenolic acids, from the biotransformation of proanthocyanidins with human fecal microflora in in vitro studies, suggests their absorption through the colon barrier, and these findings seem to be in accordance with the biological effects of chocolate polyphenols observed in vivo.95−97 Altogether, these studies demonstrate imprinted differences in the gut microbial activity of individuals as a consequence of their dietary habits. The observed changes suggest an adaptation of the gut microbiota to process chocolate constituents.93,94 To better assess the modulation of polyphenols in the gut microbiome, bacterial groups have recently been associated with specific cocoa and coffee polyphenols. For instance, the flavanol monomer (+)-catechin significantly increases the growth of the Clostridium coccoides−Eubacterium rectale group, Bif idobacterium spp., and Escherichia coli and significantly inhibits the growth of the Clostridium histolyticum group98 (Table 1). A metabolic pathway for the catabolism of (epi)cathechins is proposed elsewhere,99 where ring rupture takes place and, as with rutin degradation (Figure 1), simple phenolics are produced, such as 3,4-dihydroxybenzoic acid and 3-hydroxybenzoic acid. In vitro digestion of water-insoluble cocoa fractions with gastrointestinal enzymes was carried out to investigate the biotransformation of polyphenols. Interestingly, bacterial fermentation of the insoluble material was associated with an increase of bifidobacteria and lactobacilli as well as butyrate production. Flavanols were converted into phenolic acids by the microbiota resulting in an increasing concentration of 3-hydroxyphenylpropionic acid. These microbial changes were associated with significant reductions in plasma triacylglycerol and C-reactive proteins, suggesting the potential benefits associated with the dietary inclusion of flavanol-rich foods.100 Finally, the combined use of metabolomics and nutrikinetics offer novel perspectives for phenotyping individuals based on their susceptibility to respond positively to a nutritional intervention. If recently the concept was illustrated for tea consumption based on polyphenol metabolites, one could envision such an approach to any given food bioactive. van Velzen et al.101 described a human nutrikinetic analysis of polyphenol-rich black tea consumption from urine analysis. Mathematical models were generated for the time course of

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SYSTEMS BIOLOGY AND PERSPECTIVES FOR NUTRITION RESEARCH

The metabolic relationship between nutrition and host− microbe cometabolism are still poorly characterized, making causality and molecular mechanisms of action difficult to understand. Metabolomics studies have highlighted a set of metabolites associated with gut microbial activity in general, such as short-chain fatty acids, indole and phenyl derivatives, and flavones, including sulphated and glucuronidated species.64 The metabolization of active food components, such as polyphenols, by the gut microbiota leads to the production of a wide variety of metabolites with potential effects in human metabolism and health. A wider understanding of the underlying mechanisms, including the actual benefits of such bioactives, remains to be elucidated. So far, unexpectedly, metaproteomics studies on fecal samples have revealed a higher prevalence of proteins related to translation, energy production and carbohydrate metabolism than ever predicted.102 Also, 16S rDNA sequencing of fecal samples has associated dietary trends and metabolic enzymes to specific bacterial species assemblages.55,59 But we are far from the complete elucidation of the molecular processes linking bacteria, metabolic enzymes, and metabolites with their corresponding biological functions, as an outcome of a particular food. There are indeed several diverting issues to be taken into account, such as the fact that abundant concentrations of either proteins or metabolites may actually be mediated by a low-abundance microbe. Because all studies so far have relied on fecal samples as a mirror of the whole gut microbiome, these might not accommodate local functionalities, as environments between small intestine, distal, transverse and proximal colon are known to be divergent.103 Undoubtedly, the interplay between gut microbiome and host and its modulation by nutrition will benefit from the integration of information on a systems biology-wide approach (Figure 2). Integration of gene sequence of the microbiome, metaproteomics, metatranscriptomics, and metabolomics will pave the way toward a better molecular understanding of the complex mammalian superorganism. System-wide computational approaches will aid testing mechanistic hypothesis in silico on whole systems, such as effects of diet or modulation of metabolic diseases.104−107 As a conclusion, through the modeling of metabolic interactions between diet and the microbiota, metabolomics provides new ventures for modulating the microbiota to ultimately promote health benefits to the host. System-wide approaches using omics integration, including flux estimations, and metabolic network analyses will provide new perspectives into understanding the molecular complexity of mammalian symbiotic systems. 4786



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Figure 2. Sketch of the interplay between microbiota and host as a combined contribution to human metabolism. A possible approach to pursue is systems biology to dissect cause and effect in the impact of nutrition in metabolism and health.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: sofi[email protected]. Tel: +41 21 785 6165. Fax: +41 21 632 6499. Present Address ‡

Nestle Institute of Health Sciences, EPFL campus, Innovation square, 1015 Lausanne, Switzerland. Notes

The authors declare no competing financial interest.

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REFERENCES

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