Toward Personalized Nutrition: Comprehensive Phytoprofiling and

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Toward Personalized Nutrition: Comprehensive Phytoprofiling and Metabotyping Guoxiang Xie,†,‡ Xin Li,§ Houkai Li,‡ and Wei Jia*,†,∥ †

Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina 28081, United States § School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China ∥ University of Hawaii Cancer Center, Honolulu, Hawaii 96813, United States ‡

ABSTRACT: Nutrition research is increasingly concerned with the complex interactions between multicomponent dietary ingredients and the human metabolic regulatory system. The substantiation of nutritional health benefits is challenged by the intrinsic complexity of macro- and micronutrients and individualized human metabolic responses. Metabonomics, uniquely suited to assess metabolic responses to deficiencies or excesses of nutrients, is used to characterize the metabolic phenotype of individuals integrating genetic polymorphisms, metabolic interactions with commensal and symbiotic partners such as gut microbiota, as well as environmental and behavioral factors including dietary preferences. The two profiling strategies, metabolic phenotyping (metabotyping) and phytochemical profiling (phytoprofiling), greatly facilitate the measurement of these important health determinants and the discovery of new biomarkers associated with nutritional requirements and specific phytochemical interventions. This paper presents an overview of the applications of these two profiling approaches for personalized nutrition research, with a focus on recent advances in the study of the role of phytochemicals in regulating the human or animal metabolic regulatory system. KEYWORDS: nutrition, phytochemicals, gut microbiota, phytochemical profiling, metabotyping, metabonomics

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INTRODUCTION

Traditionally, nutrition research has focused on investigating nutrient components, with the aim of promoting enhanced nourishment and human health. With the development of modern genetics, molecular biology, biochemistry and systems biology, the study of nutrition has become increasingly concerned with human metabolism, especially in regards to the complex metabolic regulatory system.6 However, the substantiation of nutritional health benefits is challenged by the intrinsic complexity of individualized human metabolic responses and macro- and micronutrients (particularly phytochemicals). Individual differences in genes have been identified that distinctly influence the metabolic response to nutrition. In addition, plant-derived phytochemicals have been found to exert their activity through altering epigenetic markings and interactions with gut microflora. Thus, the investigation of the epigenome and the gut microbiome, and their interplay with diet and nutrition, is pivotal to understanding the complex gene−diet−disease interaction. Currently, nutritional science mainly investigates the physiological and metabolic response of the human body to nutrients and focuses more on improving the health of individuals through nutritional (diet) intervention,7 i.e.,

Nutrition, or nourishment, is the provision of the materials to cells and organisms, in the form of food, that are necessary to support and maintain life.1 The nutrients required for human nutrition are generally classified into two categories: macronutrients, which include carbohydrates, lipids, proteins, fiber and water, and micronutrients, which include minerals (both macrominerals and trace elements) and vitamins. Phytochemicals, another type of nutrient, are typically derived from plants, especially colorful vegetables, fruits and herbs, as well as marine life, algae and fungi.2 Most foods are rich in both macronutrients and micronutrients. Some nutrients are an integral part of daily requirements, while others are required at minimal levels or only occasionally. Poor health status can be caused by an imbalance, either an excess or a deficiency, of macro- or micronutrients.3 The human metabolic regulatory system is both extensive and complex. The functional integrity of human physiology (or pathology), or biological homeostasis or dysbiosis that is ultimately reflected in the phenotype, depends not only on internal genetic contributors (such as nucleotide polymorphisms) but also on external conditions, such as environmental and nutritional factors, as well as symbiotic organisms such as gut microbiota.4,5 © 2013 American Chemical Society

Received: December 29, 2012 Published: February 19, 2013 1547

dx.doi.org/10.1021/pr301222b | J. Proteome Res. 2013, 12, 1547−1559

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compounds arising from mushrooms or ganoderma (fungi chemicals) have been proposed to have anticancer properties.22 Additionally, studies suggest that microorganisms in the human gastrointestinal tract (gut microbiota) may play an important role by forming chemicals (bacteriochemicals) that may improve or impair human health.23,24 A list of typical natural bioactive components that may influence the human health status is provided in Table 2. Figure 1 illustrates the multiple stages at which phytochemicals may interact with genes, mRNA, proteins and metabolites that function in human health pathways, and may potentially alter health phenotypes. Gene function may influence the absorption, distribution, metabolism and excretion of phytochemicals or the action site of phytochemicals, and thus influence the overall response to the nutrients. Likewise, phytochemicals can also alter the gene expression regulating human cellular functions, and thus influence human disease outcome. For example, data has shown that phytochemicals can influence protein function through inducing modifications such as phosphorylation.25 It is likely that nutritional proteomics is the key to assessing changes in the incidence or behavior in some complex diseases observed in animal models following modification of the diet. Finally, the quantitative and functional changes of the proteome induced by pharmacological or nutraceutical effects of phytochemicals may lead to host metabolome changes and ultimately influence human health status. Collectively, it is clear that the response to phytochemicals is highly dependent on many cellular events and regulatory processes that function to maintain the homeostasis of human regulatory systems and/or respond to impairment of health (Figure 1).

personalized nutrition. The advent of comprehensive profiling technologies, such as metabolic phenotyping (metabotyping) and phytochemical profiling (phytoprofiling, i.e., profiling the metabolites in plants/plant extracts), has greatly facilitated the measurement of these important health determinants and discovered new potential biomarkers associated with nutritional requirements and specific nutrients (phytochemicals).8,9 The fact that plant phytochemicals could reduce the risk of diseases has been observed from epidemiologic studies showing that intake of whole foods, such as fruit, vegetables, and herbs is strongly associated with maintenance of health.10 Therefore, it seems reasonable to focus on identifying bioactive components responsible for the health benefits with the hope of finding the single “magic bullet”, a synergistic combination of several bioactive compounds to prevent particular diseases. Metabonomics,11 or metabolomics,12 provides a comprehensive profiling of metabolites in biofluids and tissues and their systematic and temporal changes mainly by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) coupled with multivariate or univariate data analysis.12,13 To date, numerous metabolic profiling studies involving both animal models and human subjects have been reported in the field of nutrition.8,14−16 Nutritional metabonomics has been proposed and utilized as a novel approach to deliver insights into the understanding of the metabolic regulatory system response to nutrient intervention, as well as to define metabolic phenotypes (metabotyping).17 This review summarizes the recent applications of these technologies in the study of the role of phytochemicals in regulating the human or animal metabolic regulatory system. The future perspectives and challenges of these studies are also discussed.

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METABOLITE PROFILING OF PHYTOCHEMICALSPHYTOPROFILING It is well-known that plants produce a myriad of chemicals in their defense pathways and that many of these compounds have demonstrated abilities in mediating diseases in humans as well.26 However, current studies of phytochemicals are generally focused on specific compounds and their effects on a limited number of markers. New approaches are needed to take into account both the diversity of phytochemicals found in the diet and the complexity of their biological effects.27 In addition, the phytochemical composition and bioefficacy of a given plant are affected by the geographical origin, climatic conditions and cultural practices.28 When evaluating the health benefits of plant phytochemicals in laboratory or clinical trials, one must have an understanding of variations caused by genotype and environment. Certain cultivars and locations may be more amicable to the accumulation of phytochemicals than others, and these differences must be accounted for in both nutrition research and food processing. Phytoprofiling is now one of the most promising approaches to investigate the bioactive components beneficial to human health and has also been proven to be a valuable analytical tool for the identification of secondary metabolites from medicinal plants, particularly for evidence-based development of new phytotherapeutical agents and nutraceuticals.29 Because variation in bioactive compounds and human essential nutrients is evident at the metabolite level, the phytoprofiling techniques could be especially useful to measure variation within a plant population or species to determine nutritionally enhanced cultivars.30 Phytoprofiling starts with the analysis of as many as possibly detectable individual components that are present in plants or extracts from individual plants by means of different techniques

PHYTOCHEMICALS AND INTERACTIONS WITH HUMAN HEALTH Phytochemicals (also referred to as natural bioactive components) are chemical compounds that occur naturally in plants, including vegetables, fruits, grains and herbs. It is estimated that more than 50 000 phytochemicals have been identified,18 but a large number still remains unknown,19 which need to be identified in order to fully understand their possible health benefits. The term “phytochemical” is now generally used to describe those specific chemicals that may affect human health.20 In fact, evidence exists showing that both essential nutrients and nonessential phytochemicals can alter the human health status.21 In addition, plants are not the only source of phytochemicals, as some chemicals arising from animal products contain compounds that may influence human health, such as chleolate (from pigs) and conjugated linoleic acid and omega-3 fatty acid (marine fish) (Table 1). Furthermore, Table 1. Nonessential Nutrients and Bioactive Components That Alter Genetic and Epigenetic Events88 nutrient group Phytochemicals Zoochemicals Fungochemicals Bacteriochemicals

example

ref.

Carotenoids, flavonoids, indoles, isothiocyanates, isoflavones, allyl sulfur Chleolate, conjugated linoleic acid, n-3 fatty acids β-glucans, lentinan, schizophyllan, compounds in mushrooms and ganoderma Equol, butyrate, compounds formed from gut microbiota fermentation

16,89−94

95,96

97

98,99

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Table 2. Partial List of Phytochemicals That May Influence Human Health class

source

possible benefits

Saponins Monoterpenes Chlorophyll

Allyl isothiocyanates, Sulforaphane Digoxin, Solanine D-limonene, D-carvone Chlorophyllin

Cruciferous vegetables (Cabbage, Broccoli, Garden cress) Herbs, Cereals, Citrus fruit oil, Caraway oil Green vegetables

Antioxidant properties, Human visual acuity maintenance Anti-inflammatory, Antitumor, Antioxidant, Lowering blood sugar, Other cardiovascular effects Antioxidants, Estrogen-like effects, Antiangiogenic effects Antioxidant, Prevention of arteriosclerosis and heart disease, Cancer prevention Prevent heart disease (atherosclerosis, high cholesterol) Anticancer, Antidiabetic, Antimicrobial effects

89,100

Caffeic acid, Ferulic acid Curcumin, Chlorogenic acid Allyl sulfur, Diallyl sulfide

Tomato, Dark green plants, Orange yellow plants (Carrot, Calabazilla) Herbs, Teas, Camellia sinensis, Cocoa, Chocolate, Grapes Fabaceae family (Soy, Red clover, Kudzu root), Herbs Herbs, Ferula, Fennel, Ginger family (Turmeric) Garlic, Onions, Leeks, Chives, Shallots

64,103,104

Capsaicinoids

Capsaicin, Dihydrocapsaicin

Capiscum (chile) pepper

Polysaccharides

Polysaccharides

Mushrooms, Ophiopogon japonicas, Astragalus membranaceus

Cardiotonic, Fungicidal and pesticidal properties Cosmetic products, Insecticide Treatment of wounds, Skin conditions (radiation burns) Topical pain relief, Cancer prevention, Cancer cell apoptosis Antitumor and immunostimulating properties

Carotenoids Flavonoids Isoflavones (Phytoestrogens) Phenolic acids Organosulfur Isothiocyanates

bioactive components Lycopene, Beta-carotene, Lutein Quercetin, Catechins, Resveratrol Genistein, Daidzein

ref.

16,90−92,100

63,100,101

100,102

93

94

105 106,107

108

22

Figure 1. Influence of phytochemicals (natural bioactive components) on genetic, epigenetic, proteomic, and metabolomic events. A host of phytochemicals are known to influence one or more stages of these processes.

Panax ginseng (Chinese ginseng), Panax notoginseng (Sanchi), Panax japonicus (Rhizoma Panacis Majoris), Panax quinquefolium L. (American ginseng), and Panax ginseng (Korean ginseng).31 PCA of the analytical data showed that the five Panax herbs could be separated into five different groups of phytochemicals. The chemical markers such as ginsenoside Rf, 20(S)-pseudoginsenoside F11, malonyl ginsenoside Rb1, and ginsenoside Rb2 accountable for the variations among groups were identified. Results from this study have demonstrated the potential of phytochemical profiling for the rapid differentiation and identification of complex plant extracts that contain similar chemical ingredients as well as the potential for the discrimination of subtle variations within the same plant species or strains due to different geographical locations, cultivation, and collection times. Dan et al. also conducted a metabolomics study to investigate the phytochemical variations in different parts of Panax notoginseng, and PCA of the UPLC− MS data showed a clear separation of compositions among the flower buds, roots and rhizomes of Panax notoginseng.42 In a recent study, an UPLC−QTOFMS-based phytoprofiling was performed on Pu-erh tea, a famous fermented tea produced mainly in the Yunnan province of China.9 The study revealed

(liquid chromatography or gas chromatography−MS, NMR, etc.), resulting in total phytochemical profiles. Phytoprofiling has now been performed on a diverse array of plant species, including but not limited to tea,9 ginseng,31 Arabidopsis,32 tomato,33 potato,34 rice,35 wheat,36 strawberry,37 Medicago,38 cucumber,39 and tobacco.40 Chan et al. have applied ultraperformance liquid chromatography−quadrupole time-of-flight mass spectrometry (UPLC− QTOFMS)-based metabonomics approach to discriminate differentially processed herbs such as raw and steamed Panax notoginseng.41 The unsupervised principal component analysis (PCA) score plot reveals clear separation between raw and steamed Panax notoginseng, and the concentration of notoginsenoside R1, ginsenosides Rg1, Re, Rb1, Rc and Rd was found to decrease upon steaming. It was demonstrated that the UPLC−TOFMS-based metabonomics approach is promising for the quality control of herbs subjected to internal (genetic, diurnal, seasonal) and external (climate, processing, and cultivation practice) variations and the holistic standardization of herbal extracts for clinical studies. Xie et al. have performed an UPLC−QTOFMS-based phytoprofiling study of five medicinal Panax herbs including 1549



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Figure 2. Application of nutrigenomics and systems biology together with new bioinformatics tools to unravel disease mechanisms, define biomarkers or apply personalized nutrition. The nutrigenomics approach extracts relevant differences, which become leads for further mechanistic research, while the nutritional systems biology approach aims at a complete description of the physiologic response by exploiting the complete data sets, thus targeting a new concept of biomarker.

lactif lora in certain constituents, such as phenolic acids, thereby leading to different bioefficacy and quality of the two species.

that unfermented green tea (Chinese Longjing) was rich in polyphenols and theanine, and Lipton black tea contained more thearubigin (TR) and theaflavic acid, while Pu-erh tea possessed characteristic phytochemicals such as theabrownin (TB, a group of brown color polyphenols) and gallic acid (GA). Bradish et al. applied a targeted phytoprofiling approach for the investigation of metabolic variations among three fallfruiting red raspberry cultivars (‘Autumn Britten’, ‘Caroline’, ‘Nantahala’) grown at three North Carolina locations differing in elevation and average day/night temperatures, which has significant antioxidant activities.43 LC−TOF-MS analysis revealed that variation in flavonoid composition including cyanidin-3-glucoside, cyanidin-3-sophoroside, cyanidin-3-rutinoside, cyanidin-3-sambubioside, and quercetin-3-glucoside was primarily attributed to genotypes and associated with night temperature and hours exposed to temperatures over 29 °C. A similar study was done by Ioset et al. using 1H NMR spectroscopy for the analysis of Rhodiola rosea rhizome extracts, which identified the secondary metabolites responsible for phytochemical variations among the plants from three different geographic areas.44 Kim et al. have reported NMR spectroscopy-based phytoprofiling applied to the classification of 11 South American Ilex species.45 PCA, partial least squares-discriminant analysis (PLS-DA) and hierarchical cluster analysis (HCA) of the NMR spectral data were able to differentiate and group the species based on metabolic similarities. Xu et al. have applied HPLC based phytoprofiling to investigate the differences between two species of Radix Paeoniae Rubrae (“Chi-shao” in Chinese)Paeonia lactif lora Pallas and Paeonia veitchii Lynch, which have different pharmacological effects due to different species and growing conditions.46 The study revealed that there exist significant differences between the roots of Paeonia veitchii and Paeonia

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METABOLIC ASSESSMENT OF PHYTOCHEMICALS INTERVENTIONSMETABOTYPING Over the past three decades, nutritional research has undergone an important shift in focus from physiology and epidemiology to genetics and molecular biology. Meanwhile, genomics, transcriptomics, and proteomics, together with metabolomics, made the systems biology approach possible for nutrition research.47 Successful generation of findings to further the progress in this field is promising, through a systematic inventory of all relevant parameters by using different “-omics” technologies and applying new bioinformatics tools together with extensive data warehousing to unravel disease mechanisms, define biomarkers or apply personalized nutrition (Figure 2). The human metabolic system is highly extensive and sophisticated, and the functional integrity of human physiology (homeostasis) ultimately reflected in the phenotype depends not only on nucleotide polymorphism,48 but also on external factors such as environmental and behavioral influence, and even other genomes from symbiotic organisms such as gut microbiota.49 In the context of nutrition science, gene expression and proteomic data might only indicate the potential for physiological and pathological changes, as pathway feedback mechanisms are simply not reflected in gene expression level and protein concentration. The metabolome, or the complete metabolite composition of a system such as a cell or organism, is the end product not only of the genetic blueprint of an organism, but also all influential factors to which the organism is exposed, such as nutrition, environmental factors, or treatments. Changes in an individual’s metabolome occur immediately or on a more gradual basis, partially due to the 1550


H NMR

1

1551

6 female pigs (plasma and urine)

21 healthy women (n = 12) and men (n = 9) (spot urine)

6 groups of 8 male Wistar rats (urine)

Noncontrolled human study (parallel design): low-phytochemical diet for 2 days followed by a standard phytochemical diet for 2 days (apple, carrot, strawberry drinks)

Animal study: normo-(5%) or hyperlipidic (15 and 25%) diets supplemented or not with (+)-catechin (0.2% diet) for 6 weeks

12 healthy men (24 h urine)

Animal study: Comparison of a rye-based diet (whole grain) and a wheat-based diet (nonwhole grain), each diet for one week

Randomized crossover study: Comparison of vegetarian (420 g/day), low-meat (60 g/ day), high-meat (420 g/day) diets for 15 days

H NMR LC−TOF

1

LC−TOF

H NMR LC−MS

1

H NMR

H NMR

1

14 healthy women (n = 7) and men (n = 7) (spot urine) 17 healthy men (plasma and 24 h urine)

1

H NMR

1

Healthy nonvegetarian women (urine)

Human study: textured vegetable protein/day (60 g/day (dry weight), (n = 6) or 50 g of miso (an unconjugated form of aglycone isoflavones)/day (n = 3) Controlled study: chamomile tea intervention (200 mL/day, 25 mg/mL of chamomile flowers) for 2 weeks Randomized crossover study: Consumption of black tea (6 g/day), green tea (6 g/day) or caffeine (control) for 2 days

H NMR

5 healthy premenopausal women (plasma)

Controlled study: soy protein intervention for 1 month (60 g/day containing 45 mg of isoflavones)

1

10 Sprague−Dawley rats (spot urine)

H NMR

analytical technique 1

subjects (samples)

Animal study: single dose of epicatechin (22 mg)

intervention

Perturbation of the gut microflora activity High intrinsic physiological variations Intestinal bacterial metabolism of tea flavanols Stimulation of oxidative energy metabolism Liver ketogenesis/Fatty acid oxidation Reduction in anaerobic glycolysis Enhanced insulin activity

↑ Hippurate, ↑ Glycine, ↓ Creatinine (after chamomile intake) ↑ Citrate and ↑ Glycine in women, ↑ Creatinine in men Urine: ↑ Hippurate, ↑ 1,3-Dihydroxyphenyl-2-osulphate

↑ Hippuric acid, ↑ Hydroxyhippuric acid, ↑ Catechin (glucuronide and aglycone), ↑ Methylcatechin (glucuronide and aglycone), ↑ Dihydroxyphenylvalerolactone glucuronide, ↑ Methoxyhydroxyphenylvalerolactone (glucuronide, aglycone, and sulfate)

↑ Dihydroxyquinoline, ↑ Pipecolinic acid

↑ Deoxycytidine, ↑ Nicotinic acid,

↑ Hippurate

↑ Creatinine, ↑ 3-Methylhistidine

↑ Carnitine after the high meat diet ↑ p-Hydroxyphenylacetate after vegetarian diet, ↑ N-Acetyl-5-hydroxytryptamine after high meat diet ↑ Betaine, ↑ Hippurate after the whole-grain diet (rye), ↑ Creatinine after the nonwhole grain diet (wheat)

Intestinal bacterial metabolism of phytochemicals Possible increase in DNA breakdown, chronic liver dysfunction or peroxisomal disorders Possible microbiota growth inhibition by catechin Catechin metabolites

Further studies needed to elucidate the role of betaine and its potential connection with creatinine excretion in the healthpromoting effect of whole grain cereals Possible changes in energy metabolism and muscle proteolysis

Microbial metabolism of plant foods Changes in tryptophan metabolism

Biomarkers of meat consumption, Changes in energy metabolism

Increase in anaerobic metabolism Osmolyte modulation; altered energy metabolism

↑ Lactate, ↓ Carbohydrates ↑ TMAO, ↑ Choline, ↓ Creatinine, ↑ Glutamate, ↑ Glutamine, ↓ Citrate

Urine: ↑ Citrate, ↑ Succinate, ↑ Oxaloacetate, ↑ 2-Oxoglutarate Urine: ↑ β-Hydroxybutyrate (only after black tea) Plasma: ↓ Lactate, ↓ Alanine (only after green tea) Plasma: ↓ Glucose ↑ Creatinine, ↑ Taurine, ↑ TMAO, ↑ Methylhistidine after the high meat diet

Changes in liver and kidney functions Changes in carbohydrate/energy metabolism

↓ Creatinine, ↓ Taurine ↑ 3-Hydroxybutyrate, ↑ N-acetyl Glycoproteins

biological hypotheses Modification in carbohydrate metabolism

↓ Citrate, ↓ 2-Oxoglutarate, ↓ Dimethylamine,

modified endogenous metabolites

Table 3. Reported Endogenous Metabolite Modifications Resulting from Dietary Phytochemical Intervention by Metabolomics Approach

112

111

110

109

90

60

63

101

92

ref.

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Gut microbial and phase II metabolism of polyphenols Gut microbiota metabolism of polyphenols

↑ fatty acid conjugated metabolites, ↑ phenolic metabolites, ↑ serotonin metabolites ↑ Valine, ↓ 4-Hydroxy-3-methoxyphenylacetic acid, ↓ Ornithine, ↓ 2-Methoxyphenol, ↑ 4-Aminobutanoic acid, ↑ Aminomalonic acid, ↑ Phenol

LC− QTOFMS HPLC− QTOFMS UPLC− QTOFMS GC− TOFMS

24 human subjects (urine)

42 human subjects, Nuts group (n = 22), control group (n = 20) (urine) 20 healthy men (n = 10) and women (n = 10) (urine)

Human study: ingested 10 capsules containing almond skin extract (3.5 g of almond extract and 0.5 g of microcrystalline cellulose) Human study: mixed nuts (15 g of walnuts, 7.5 g of almonds and 7.5 g of hazelnuts) intervention 30 g/day up to 12 weeks Human study: Pu-erh tea intervention, 200 mL of tea infusion/day (10 g of tea powder)

biological hypotheses

↑ trans-aconitate, ↓ Hippurate, ↑ p-cresol sulfate (after chocolate consumption) ↑ (Epi)catechin sulfate, ↑ O-methyl-(epi)catechin sulfates, ↑ Narigenin-O-glucuronide,

Normalized stress-related differences in energy metabolism and gut microbial activities Gut microbiota metabolism of polyphenols

↓ Glycine, ↑ 4-Methyl-phenol, ↓ Glutamine, ↓ Isocitrate, ↓ Aconitate, ↑ Nicotinate, ↑ Aspartate, ↓ 4-Hydroxyphenylacetate, ↓ Citrate, ↑ Glutamate, ↓ Hippurate, ↑ Homovanillate, ↓ Dopamine, ↑ 5-Hydroxy-indole-3-acetate, ↓ Tyrosine, ↓ Tryptophan (in control group) ↓ Cortisol, ↓ Catecholamines, ↓ Glycine, ↓ Citrate,

GC−MS

H NMR, LC−MS, LC−MS/ MS

↑ 5-Hydroxytryptophan, ↑ Inositol, ↑ 4-Methoxyphenylacetic acid, ↓ 3-Chlorotyrosine, ↓ Creatinine

UPLC− QTOFMS

1

Alterations of metabolites in metabolic pathways of catecholamines, glucocorticoids, the tricarboxylic acid cycle, tryptophan, and gut microbiota Reduced urinary excretion of the stress hormone cortisol and catecholamines

Hippuric acid, 4-Hydroxyhippuric acid and 1,3-Dihydroxyphenyl-2-O-sulfate

H NMR

Microbial fermentation of polyphenols in the gut Alteration of gut microbial populations by Pu-erh tea

30 human subjects, low anxiety traits (n = 17) and high anxiety traits (n = 13) (urine, plasma)

modified endogenous metabolites

Human study: dark chocolate intervention 40 g/day for up to 14 days

1

20 healthy nonsmoking males (urine) 20 healthy volunteers (10 male and 10 female) (urine) 14 Sprague−Dawley rats (urine)

Human study: black tea (2500 mg of dried black tea extract powder/day) Human study: Pu-erh tea intervention, 50 mg/mL of Pu-erh tea, 200 mL/day for 2 weeks Animal study: ginsenosides intervention: 100 mg/kg per day for 2 weeks

analytical technique

subjects (samples)

intervention

Table 3. continued

65

115

114

16

64

9

113

ref.

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In a metabonomics study, chamomile, an important alternative and functional food, was employed to study the human metabolic response to nutritional intervention by Wang et al.60 The results showed a clear clustering of the subjects as a function of chamomile tea intake characterized by a decrease in urinary excretion of creatinine, and an increase in glycine and hippurate. Samples obtained two weeks after daily chamomile intake formed an isolated cluster in the discriminant analysis map, which was partially ascribed to chamomile-induced changes in gut microbial metabolism. The interesting observations and results of this study highlight the diversity of physiological variations of human metabolism and emphasize the effect of nutritional phytochemicals in modulating human metabolism and maintaining homeostasis of human gut ecosystem. Llorach et al.61 have applied an LC−MS-based metabonomics approach for exploring urinary metabolic modifications after cocoa consumption. After overnight fasting, 10 subjects consumed randomly either a single dose of cocoa powder with milk or water, or milk without cocoa. Urine samples collected at baseline and at 0−6, 6−12, and 12−24-h postcocoa-consumption were analyzed, which revealed an important effect of cocoa intake on urinary metabolome. The metabolomic changes are characterized by 27 metabolites including alkaloid derivatives, both host and microbial metabolites polyphenols and processing-derived products such as diketopiperazines. Van Dorsten et al. have performed a study on 17 healthy male volunteers, who consumed black tea, green tea, or caffeine taken as a control in a randomized crossover study to compare the effects of black and green tea consumption on human metabolism.62 Participants were received a daily intake of 1 g of tea solids and 360 mg of caffeine for the control group. Twentyfour-hour urine and blood plasma samples were profiled by NMR-based metabonomics. Green and black tea consumption resulted in similar increases in urinary hippuric acid and 1,3dihydroxyphenyl-2-O-sulfate levels. Interestingly, green and black tea consumption had different impacts on endogenous metabolites in urine and plasma. Green tea intake caused a greater increase in urinary excretion of several citric acid cycle intermediates such as pyruvate, oxaloacetate, and citrate, while black tea consumption caused a shift in the plasma lipoprotein distribution and a reduction of glucose and acetate. Even if the metabolic effects in plasma of both teas could not be statistically differentiated in a robust fashion, green tea intake was associated with lower plasma levels of lactate and alanine and higher levels of acetate and β-hydroxybutyrate. This study demonstrated that consumption of different tea products might have different effects on human oxidative energy metabolism and biosynthetic pathways. Solanky et al.63 applied NMR-based metabonomics to the study of healthy nonvegetarian women’s metabolic response to isoflavones, a nutritional phytochemical rich in soy and beans. The metabolic changes observed in the study suggest that isoflavone intake had significant effects on several metabolic pathways, such as trimethylamine N-oxide, betaine, choline and creatinine involved in osmolyte modulation and glutamate, glutamine and citrate involved in energy metabolism. These metabolic perturbations were even more significant following intake of unconjugated soy isoflavone diet. This study demonstrated how urine metabonomics can provide invaluable information on the subtle biochemical effects of dietary components in complex human metabolic regulatory system.

constancy of an individual’s genetic makeup and lifestyle/ environment. Holmes et al. suggest that common diets, gut microbes, medicinal practices, genetics and other lifestyle and environmental factors give rise to regional metabolomic phenotypes.50 Metabolite concentrations and their kinetic changes in cells, tissues and even the organism represent the real endpoints of physiological or pathological regulatory processes.51 In this sense, the depiction of metabolite concentration change may be the optimal indication of human homeostasis. It has long been understood that nutrition plays a role in human health. However, many of the links between an individual’s diet and specific health outcomes are still not completely understood; for example, why does one person easily develop obesity and another, with the same diet, does not (responders and nonresponders). Metabonomics employs 1H NMR and MS-based techniques to generate profiles of metabolites in biofluids, including urine, plasma and fecal water. It provides a systems approach to understanding global metabolic regulation of an organism and its commensal and symbiotic partners. In particular, it focuses on the measurements of metabolite concentrations, fluxes and secretions in cells and tissues in which there is a direct connection between gene expression, protein activity and metabolic activity.52 Metabonomic strategies together with advanced chemometric and bioinformatic tools53−55 can help track the interaction between phytochemicals and human metabolism, as well as the involvement of the genome and the gut microbiome, in overall human health, and can be considered critical measures of function or phenotype.56 A depletion−repletion study of choline conducted by Dr. Zeisel’s group showed that an individual’s metabolomics profile at baseline could predict whether or not the individual would develop liver dysfunction as a result of inadequate choline intake.57 Given the integral nature of a specific gut microbiome and metabolome, any differences in the microbial communities could result in significant alterations in the extracellular metabolome. Gut microbiota structure and composition reflects this symbiotic relationship, with only the bacterial populations beneficial to the host predominating in the human microbiota in health and contributing to co-metabolism of a range of dietary components and xenobiotic compounds. This relationship is the basis behind the concept of host−gut microbiota cometabolism put forward by Nicholson et al.58 The human metabolome thus comprises the metabolites derived from human encoded genetic determinants, metabolites of microbiotal origin, and the flux in these combined metabolite profiles under different perturbations, e.g., consumption of different foods or drugs, carriage of parasites, and chronic disorders such as cardiovascular disease.59 Metabonomics/metabolomics has been identified as a promising approach to assess nutrients and functional phytochemicals via simultaneous detection of multiple metabolic endpoints in the complex metabolic regulatory system. Over the past decades, numerous studies have discussed the potential to generate novel insights for the understanding of the intrinsic relationships between organism metabolism and nutrients, especially phytochemicals (Table 3). Nutritional science might benefit from metabonomics-based technology to decipher the mechanism of bioactive phytochemical effects, and ultimately, to maintain homeostasis and promote human health. 1553



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great importance for scientists to understand and characterize the interactive processes between host and its microbiome. Metagenomics is defined as “the application of modern genomics techniques to the study of communities of microbial organisms directly in their natural environments, bypassing the need for isolation and lab cultivation of individual species.” This rapidly developing field focuses on the application of cultureindependent techniques to understand the structures and functions of microbial communities and their interactions with the habitats they occupy.69 Our recent study of human gut microbiota using metabolic profiling coupled with metagenomic sequencing provided a basis for understanding the “microbial-mammalian metabolic axis,” which led to the concept of “functional metagenomics,” defined as “the characterization of key functional members of the microbiome that most influence host metabolism and hence health.”70 Phytochemicals are bioactive plant compounds with potential health beneficial effects, including antioxidant, antiestrogenic, anti-inflammatory, immunomodulatory, and anticarcinogenic activities.71 However, the bioavailability and effects of some phytochemicals (e.g., polyphenols) greatly depend on their transformation under the occurrence of gut microbiota. Phytochemicals and their metabolic products may also inhibit pathogenic bacteria while stimulating the growth of beneficial bacteria, exerting prebiotic-like effects.72 Gut microbiota influences the development and maturation of the digestive and immune systems and is a source of regulatory signals, some of which may be suitable for exploitation for therapeutic purposes. In reality, most human diseases are polygenic in origin and linked to numerous environmental factors, such as nutrient or phytochemical intervention. Therefore, there will be complex metabolic profiling markers associated with human homeostasis/disease status. There is a recent increasing awareness of the importance of variation in the gut microbiota, as a nutrient associated factor, that influences human health, and gut microbiota dysbiosis is known to be related to a wide range of disease processes.67,73−76 The effects of gut microbiota on modulating drug, nutrient, and phytochemical metabolism are well-known. Microbiota are responsible for the hydrolysis of biliary excreted xenobiotic conjugates (glucuronide and sulfate conjugates) into their corresponding aglycones.77−79 The deconjugated aglycones are then available for reabsorption through enterohepatic recycling, which results in the extension of pharmacological or nutritional action. The contribution of gut microbiota to some of these processes has been studied in germ-free rats.80 In the case of flavone glucuronide baicalin, found in Scutellariae radix, the appearance of baicalin in rat plasma after oral administration required a microbially dependent hydrolysis process to generate the aglycone baicalein, followed by absorption and conjugation back to baicalin. However, in the germ-free rat model, much lower concentrations of baicalin were detected in the circulation following oral administration as compared with normal rats. Polyphenols, a ubiquitous group of secondary plant metabolites originating from the shikimate pathway and sharing at least one aromatic ring structure with one or more hydroxyl groups, represent a large group of natural antioxidants abundant in fruits, vegetables, and beverages.81,82 The intact forms of complex dietary polyphenols have limited bioavailability, and this bioavailability is highly variable among individuals and generally far too low to explain the direct antioxidant effects in vivo.81 A large portion of the polyphenols

In addition, it also provides novel insight in the mechanisms of the unconjugated and conjugated isoflavones in modulating women’s metabolic homeostasis. Wang et al.64 reported a urinary metabolic profiling study of Sprague−Dawley rats exposed to freezing temperature (−10 °C) to mimic the acute cold stress. Gas chromatography−mass spectrometry (GC−MS) in conjunction with multivariate statistical techniques was used, which revealed significant changes of urinary metabolites, and demonstrated the beneficial protective effect of total ginsenosides (a group of saponin phytochemicals existing in Panax ginseng) on cold stressed rats. The study showed that pretreatment and long-term nutritional fortification with total ginsenosides may strengthen the mammalian’s physical capability of resisting the sudden environment changes such as acute cold stress and thus maintain the homeostasis of human metabolic regulatory system. We recently performed a study on 20 volunteers to investigate the human metabolic response to drinking Pu-erh tea over a six-week period, using a UPLC−QTOFMS-based metabonomics approach.9 The final metabolic profile was greatly altered by Pu-erh tea consumption, with an observed depletion of creatinine and elevation of 4-methoxyphenylacetic acid, inositol, myristic acid, and 5-hydroxytryptophan. The trajectory of the PCA scores plot based on urine data revealed a clear separation tendency of samples obtained before (days 1 and 7), during (days 16, 21 and 28) and after tea ingestion (wash-out period; days 30, 36, 42). The metabolic patterns of objects deviate from baseline during the Pu-erh tea intake, and approach the baseline during the wash-out period, although the postdose metabolic pattern is still distinct from the predose pattern, probably due to the possibility that Pu-erh tea may change the structure of the resident gut microbiota. Following the metabonomic study of Pu-erh tea, we conducted another study to determine the metabolic fate of polyphenolic components in Pu-erh tea in human subjects.65 Urine samples were collected at 0, 1, 3, 6, 9, 12, and 24 h within the first 24 h of tea intake and once a day during a 2-week daily Pu-erh tea ingestion phase and a two-week “wash-out” phase. The dynamic concentration profile of bioavailable plant molecules (due to in vivo absorption and the hepatic and gut bacterial metabolism) and the human metabolic response profile were identified and correlated with each other, highlighting the great potential of metabonomic strategy to unravel the complex interactions between multicomponent nutraceuticals and human metabolic system in nutritional studies.

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FUTURE PERSPECTIVES

Gut Microbiota and Phytochemicals in the Context of Nutritional Science

The homeostasis and the metabolome of an organism are dependent upon not only the host but also the interaction between host and its microfloral complement or cometabolome. Studies have demonstrated the importance of the interaction between gut microbiota and host metabolism.66,67 The influence of the gut microbiota and its interaction with the host is pivotal to understanding nutrition and metabolism. Modulation of the gut microbiota composition by alteration of food habits has potential effects on health improvement or even disease prevention.68 It is therefore of 1554



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Figure 3. Interactions between phytochemicals, gut microbiota and host as a combined contribution to human metabolism. The interplay between gut microbiota and host, and its modulation by nutrition, will benefit from the integration of information on a systems biology-wide approach.68

undergoes extensive phase II biotransformation (covalent attachment of a small polar endogenous molecule, such as glucuronic acid, sulfate, or glycine, to form water-soluble compounds) in the small intestine and liver, at which point the polyphenol aglycones are conjugated to glucuronide, sulfate and/or methyl-moieties to facilitate their elimination from the body.82 Dietary polyphenols are transformed into deglycosylated forms by mammalian β-glucosidases in the gastrointestinal tract before reaching the systemic circulation system.83 The polyphenol-derived metabolites, such as derivatives of phenylpropionic, phenylacetic and benzoic acids, with different hydroxylation patterns generated by the action of intestinal microbiota are easily absorbed through the colonic barrier and can be further transformed in tissues by conjugation with glycine, glucuronic acid or sulfate groups.84 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 3). Integration of gene sequence of the microbiome, proteomics, transcriptomics, and metabolomics will pave the way toward a better molecular understanding of the complex mammalian superorganism.

Figure 4. Conceptualization of nutritional metabonomics/nutrimetabolomics for health and risk management. Integration of nutritional metabonomics/nutrimetabolomics and systems biology at the population scale may lead to enhanced use of nutrients to prevent or delay the onset of disease and to optimize human health at an extensive scale. The metabotypes of individuals result from gene, environment, lifestyle, food, and host−gut microbiota interactions. Different metabotypes (represented by green, blue and red lines/ ellipse) are under homeostasis, which aims to maintain metabolic fluctuations within a healthy range (green ellipse). Metabonomicsgenerated prognostic biomarkers can be used to assess homeostasis loss and likelihood for future diseases. Nutritional metabolomics/ nutrimetabonomics aims at optimizing nutrition for health maintenance and to restore homeostasis as illustrated by the blue line/ ellipse. Adapted from refs. 85 and 87.

Nutrimetabolomics and Personalized Nutrition

The goal of nutrition has extended beyond just ameliorating or curing diseases, and now aims to achieve an overall objective in preventing diseases and improving health. Therefore, the pivotal scientific objective has become understanding the relationship between diet (both macro- and micronutrients) and health/diseases. The comprehensive analysis of the metabolome via metabolomics/metabonomics will serve as the bioinformation base for modern nutritional science. Biomarkers and/or patterns of expression will undoubtedly have the potential to be used for human health assessment (Figure 4). Together this indicates that the future goal of nutritional research will be to predict the likelihood of future diseases within the context of an individual’s overall heath and identify causal risk factors, leading to recommendations for appropriate intervention, such as dietary habit changes, to avoid homeostasis loss and maintain healthy status.

In order to accomplish this mission, a deeper insight into the role of diet (particularly phytochemicals) in the development of human disease and providing crucial bioinformation for personalized nutrition is undoubtedly necessary. Personalized nutrition is the outcome for individuals who will adapt their diet and lifestyle according to knowledge about their current or future healthy status, and their subsequent nutritional requirements.85 The knowledge could be built around the characterization of different metabolic phenotypes in human population. Clayton and his colleagues have described a novel “pharmaco1555



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metabonomics” concept of personalized drug treatment,86 which applies a combination of predose metabolic profiling and bioinformatic tools to model and predict the response of individual subjects. The concept of pharmaco-metabonomics is sensitive to both genetic and environmental influences and addresses the metabolic response at the individual level. This concept could be alternatively applied to nutritional research as a means of assessing individual response to diets or phytochemicals. In the future, researchers could use such metabolic profiling to measure, predict and optimize the metabolic response of individual response to dietary interventions or modulations. Likely, in cases of impairment of human homeostasis, the patients would thus develop a coordinated approach to reestablish a metabolic trajectory for the individual consistent with their metabolic phenotype.

American Society for Clinical Nutrition. Am. J. Clin. Nutr. 1997, 66 (3), 683−706. (2) Grusak, M. A.; DellaPenna, D. Improving the nutrient composition of plants to enhance human nutrition and health. Annu. Rev. Plant Physiol. Plant Mol. Biol. 1999, 50, 133−61. (3) Godfrey, K. M.; Barker, D. J. Fetal nutrition and adult disease. Am. J. Clin. Nutr. 2000, 71 (5 Suppl), 1344S−52S. (4) Nicholson, J. K.; Holmes, E.; Wilson, I. D. Gut microorganisms, mammalian metabolism and personalized health care. Nat. Rev. Microbiol. 2005, 3 (5), 431−8. (5) Jia, W.; Li, H.; Zhao, L.; Nicholson, J. K. Gut microbiota: a potential new territory for drug targeting. Nat. Rev. Drug Discovery 2008, 7 (2), 123−9. (6) Desiere, F. Towards a systems biology understanding of human health: interplay between genotype, environment and nutrition. Biotechnol. Annu. Rev. 2004, 10, 51−84. (7) Chandra, R. K. Nutrition and the immune system: an introduction. Am. J. Clin. Nutr. 1997, 66 (2), 460S−3S. (8) Zhang, X.; Yap, Y.; Wei, D.; Chen, G.; Chen, F. Novel omics technologies in nutrition research. Biotechnol. Adv. 2008, 26 (2), 169− 76. (9) Xie, G.; Ye, M.; Wang, Y.; Ni, Y.; Su, M.; Huang, H.; Qiu, M.; Zhao, A.; Zheng, X.; Chen, T.; Jia, W. Characterization of pu-erh tea using chemical and metabolic profiling approaches. J. Agric. Food Chem. 2009, 57 (8), 3046−54. (10) Cencic, A.; Chingwaru, W. The role of functional foods, nutraceuticals, and food supplements in intestinal health. Nutrients 2010, 2 (6), 611−25. (11) Nicholson, J. K.; Lindon, J. C.; Holmes, E. ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 1999, 29 (11), 1181−9. (12) Fiehn, O. Metabolomicsthe link between genotypes and phenotypes. Plant Mol. Biol. 2002, 48 (1−2), 155−71. (13) Nicholson, J. K.; Lindon, J. C. Systems biology: Metabonomics. Nature 2008, 455 (7216), 1054−6. (14) German, J. B.; Roberts, M. A.; Watkins, S. M. Personal metabolomics as a next generation nutritional assessment. J. Nutr. 2003, 133 (12), 4260−6. (15) Scalbert, A.; Brennan, L.; Fiehn, O.; Hankemeier, T.; Kristal, B. S.; van Ommen, B.; Pujos-Guillot, E.; Verheij, E.; Wishart, D.; Wopereis, S. Mass-spectrometry-based metabolomics: limitations and recommendations for future progress with particular focus on nutrition research. Metabolomics 2009, 5 (4), 435−58. (16) Martin, F.-P. J.; Rezzi, S.; Pere-Trepat, E.; Kamlage, B.; Collino, S.; Leibold, E.; Kastler, J.; Rein, D.; Fay, L. B.; Kochhar, S. Metabolic effects of dark chocolate consumption on energy, gut microbiota, and stress-related metabolism in free-living subjects. J. Proteome Res. 2009, 8 (12), 5568−79. (17) Gavaghan, C. L.; Holmes, E.; Lenz, E.; Wilson, I. D.; Nicholson, J. K. An NMR-based metabonomic approach to investigate the biochemical consequences of genetic strain differences: application to the C57BL10J and Alpk:ApfCD mouse. FEBS Lett. 2000, 484 (3), 169−74. (18) Saeed, S. A.; Manzoor, I.; Quadri, J.; Tasneem, S.; Simjee, S. U. Demystifying phytochemicals: an insight. Int. J. Pharmacol. 2005, 1 (3), 234−8. (19) Liu, R. H. Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals. Am. J. Clin. Nutr. 2003, 78 (3 Suppl), 517S−20S. (20) Ovesna, J.; Slaby, O.; Toussaint, O.; Kodicek, M.; Marsik, P.; Pouchova, V.; Vanek, T. High throughput ‘omics’ approaches to assess the effects of phytochemicals in human health studies. Br. J. Nutr. 2008, 99 (E Suppl 1), ES127−34. (21) Milner, J. A. Functional foods: the US perspective. Am. J. Clin. Nutr. 2000, 71 (6 Suppl), 1654S−9S discussion 1674S−5S.

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CONCLUSION With the advent of the postgenomic era, nutrition science has witnessed an explosion in methodology that could be used for understanding the complex relationship between human metabolic homeostasis and phytochemicals. The application of “-omics” technology, such as nutritional metabonomics or nutrimetabolomics, has already demonstrated the potentiality for the quantitative measurement of the dynamic metabolic response of organism to nutritional intervention. The NMRand MS-based metabonomics/metabolomics approach ensures the identification of a variety of metabolites that are the end point of physiological processes, nutrient intervention, gut microbiota metabolism and xenobiotic factors are highlighted in field of systems biology. However, despite significant advances in this field, some challenges still remain in nutritional science. For example, metabolic profiling strategies, in many respects, only provide a “snapshot” of the metabolic status of a cell, tissue or organism. Furthermore, determination of the structures of the exogenous metabolites is still a challenge in biomarker discovery especially when using LC−MS approaches. Improved technologies for metabolite analysis and better bioinformatics tools for data handling will need to be established for realization of the full potential of metabonomics/metabolomics in the realm of nutrition science. The use of metabolomics data in nutritional research also faces the challenge that changes in the metabolic profiling of biologically complex organisms, like humans, in response to special diet or food components may be difficult to distinguish from normal physiological variation. In addition, fully understanding the relationships among human genetic susceptibilities, nutrients, phytochemicals, xenobiotics and gut microbiota metabolism remain a puzzling challenge in nutritional science.

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AUTHOR INFORMATION

Corresponding Author

*Phone: 808-564-5823. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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REFERENCES

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