The Gut Microbiota

The gut microbial ecosystem is increasingly appreciated for its role in influencing intestinal and systemic diseases. The collection of microorganisms in the gastrointestinal (GI) tract is known as the gut microbiota. The collection of microbial genes is referred to as the gut microbiome. The gut microbiota consists largely of bacteria including two major phylotypes—Bacteroidetes and Firmicutes—and others such as Proteobacteria, Verrucomicrobia, and Actinobacteria (Eckburg et al., 2005). Colonization of these bacteria occurs immediately after birth and further develops within the first few years of life, contributing to the development of the host immune system. Intestinal and autoimmune diseases such as inflammatory bowel disease (IBD) and type 1 diabetes mellitus as well as other metabolic disorders are often associated with gut microbial dysbiosis. A dysbiotic microbiota is characterized by a (1) loss in microbial diversity; (2) change in composition, including blooms of pathogenic bacteria and decreases in commensal or potentially beneficial bacteria; or (3) change in metabolic function that ultimately leads to adverse consequences for the host (Schaubeck and Haller, 2015). Advances in sequencing technology have enabled researchers to interrogate the structure or relative abundance of the gut microbiota through 16s rRNA sequencing as well as their functional characteristics through metagenomic and metatranscriptomic analyses. Thus, the wealth of information regarding host–microbe interactions is rapidly increasing (Lagier et al., 2012). The human gut microbiota maintain resilience and stability over time but also shifts in response to acute changes in the environment, disease state, or diet (Berry et al., 2015). For instance, David et al. (2014) demonstrated that a diet consisting of animal products such as meat and cheese can rapidly alter microbial structure compared to a plant-based diet. However, resilience in microbial communities has also been demonstrated in studies following long-term dietary patterns (Wu et al., 2011). Due to the relationships established between gut microbes and disease, it is of particular interest to understand how modulating gut microbial communities through diet or dietary supplements such as probiotics, prebiotics, or other functional food components like dietary polyphenols reassemble the gut microbiota structure and functional characteristics to promote better health.

Gut Microbes and Intestinal Health

The GI tract is a major site of host–microbe interactions. The human gut is populated by 10^1–7 bacteria in the small intestine and 10^10–13 in the colon, constituting a larger amount than in any other part of the body (Hartstra et al., 2015). Thus, it is not surprising that communication between microbes inhabiting the gut and the host significantly contributes to the development and progression of IBD, including Crohn’s disease and ulcerative colitis. Crohn’s disease is characterized by transmural intestinal inflammation that can occur throughout the length of the GI tract, whereas colitis is characterized by more superficial inflammation specific to the colon. Typically, inflammatory states are associated with a decrease in microbial diversity or richness, meaning a decrease in the total number of bacterial species present. In IBD, these changes correspond to increases in the relative abundance of Proteobacteria and reductions in Bacteroidetes and Firmicutes, specifically Clostridium cluster XIVa and IV, including Faecalibacterium prausnitzii and other butyrate-producing bacteria (Schaubeck and Haller, 2015). The direct interaction between microbes and IBD is strongly exemplified by the finding that genetically susceptible interleukin (IL)-10^−/− mice are resistant to colitis when raised germ free. Exposure of IL10^−/− mice to specific pathogens such as Helicobacter hepaticus, Helicobacter rodentium, and Helicobacter typhlonius or other pathobionts may lead to 100% penetrance of colitis (Kaur et al., 2011). Genetically susceptible hosts have aberrant immune responses to microbial dysbiosis or even commensal bacteria that lead to chronic inflammation (Sartor, 2016). However, it is still unclear whether the inflammatory state of the host precedes microbial dysbiosis or whether the dysbiotic communities initiate inflammation in the host.

Gut Microbes and Systemic Health

Microbes residing in the gut influence host metabolism and have been linked to obesity, nonalcoholic fatty liver disease, diabetes, and metabolic syndrome. Obesity afflicts more than one-third of the adult population (Flegal et al., 2010) and is often thought to result from sedentary lifestyles and consumption of Western diets, which are high in saturated fats and simple sugars. However, advancing research on the gut microbiota has convincingly established host–microbe interactions in the development of obesity and associated disorders (Ojeda et al., 2016). Obese humans and mice exhibit altered community structure such as decreased abundance of Bacteroidetes and increased abundance of Firmicutes compared to lean subjects (Ley et al., 2005, 2006). Transfer of obese microbiota to germ-free (GF) mice leads to increased adiposity, suggesting that microbiota alone can induce transferability of an obeselike phenotype (Turnbaugh et al., 2008). The inverse scenario has also been demonstrated because fecal transplantations of lean donor stool have shown improved insulin sensitivity in patients with metabolic syndrome (Vrieze et al., 2012). Furthermore, Roux-en-Y gastric bypass surgery, which dramatically improves glucose homeostasis and results in the rapid loss of 65–75% of body weight and fat mass, distinctly alters the community structure of intestinal microbiota in humans and rodents, namely by increasing the abundance of Gammaproteobacteria and Verrucomicrobia. In addition, fecal transplants from Roux-en-Y-treated mice cause decreased weight and fat mass in GF recipient mice (Liou et al., 2013). Taken together, gut microbes may directly improve the state of obesity and associated comorbidities. It is expected that therapeutic approaches such as the use of prebiotics, probiotics, and fecal microbiota transplantation (FMT) can be employed to promote restructuring of microbial communities leading to improved intestinal and systemic health for those suffering from IBD or systemic metabolic disease.

Therapies Targeting Gut Microbiota in Intestinal and Metabolic Disease

Current therapies targeting the gut microbiota to combat IBD and metabolic disease include antibiotics, probiotics, prebiotics, and FMT. These therapies directly target the GI microorganisms, the host, or both. These therapies are discussed in the following sections.

Phytochemicals

Phytochemicals or chemicals in plants play important roles in their growth and development. They protect plants from harmful agents such as insects and microbes as well as stressful events such as ultraviolet (UV) irradiation and extreme temperatures. They also attract beneficial birds and insects that promote pollination, germination, and seed dispersal. Phytochemicals provide colors to plants and an array of flavors both pleasant and unpleasant when consumed. They are unique to specific plants and parts of plants, and they usually increase in abundance during stressful events. Phytochemicals also provide health benefits when consumed. They consist of nutrients essential for optimal health (e.g., proteins, carbohydrates, vitamins, and minerals) and other chemicals (e.g., phenolic acids, flavonoids, and other phenolics) (Fig. 18.1) (Bohn, 2014) with lesser known roles in health promotion or disease prevention. A number of these phytochemicals are recognized as bioactive components in traditional herbal medicines (e.g., salicylates (aspirin) found in willow bark used to reduce inflammation, quinine in cinchona bark used to treat malaria, and proanthocyanidins in cranberries used to treat urinary tract infections). Polyphenols represent the largest category of phytochemicals and serve as powerful antioxidants due to their multiple hydroxyl groups (Pietta, 2000), so they will be the focus of this chapter.

Phenolic Phytochemicals

Polyphenols or compounds containing multiple phenol ring structures represent at least 4000 known plant chemicals that are particularly abundant in fruits, vegetables, and beverages made from fruits (Cao et al., 1997). They are defined based on the nature of their carbon skeletons, patterns of hydroxylations, existence of stereoisomers, and states of oxidation, glycosylation (of flavonoids), and acylation (of phenolic acids) of heterocyclic rings. The polyphenol content in plants varies between 1 and 3 mg/kg and is influenced by cultivar, maturity, part of the plant, growing conditions, processing, and storage. There are three main classes of polyphenols: (1) phenolic acids (i.e., hydroxybenzoic and hydoxycinnamic acids), (2) flavonoids (e.g., flavones, flavonols, flavan-3-ols, isoflavones, flavanones, and anthocyanidins or anthocyanins), and (3) other phenolics (e.g., stibenes, lignans, tannins, xanthones, lignins, chromones, and anthraquinones) (Fig. 18.1).

Phenolic Acids

These aromatic acids represent approximately 30% of all dietary polyphenols, depending on the geographical location, food-harvesting techniques, processing practices, and cultural considerations inherent to the region of origin. The two major subclasses of phenolic acids are listed in the following sections, and their structures are shown in Fig. 18.2.

Flavonoids

Flavonoids represent approximately 60% of all dietary polyphenols. They share a common chemical structure (e.g., C6–C3–C6) having at least 15 carbons with two benzene rings (A and B) and a heterocylic ring (C). Classifications are based on variations in the heterocyclic (C) ring. Major subclasses and structures of flavonoids are described in the following sections and shown in Fig. 18.3.

Other Phenolics

Stilbenes

Stilbenes have classical C6–C2–C6 structures with two hydroxyl groups on the A ring and one on the B ring (Fig. 18.4). They exist in plants as aglycones or glycosides, providing protection against bacterial, mold, or fungal invasion. Examples of stilbenes are the phytoalexins resveratrol and piceatannol, a resveratrol metabolite. They are found in grapes (skin), mulberries, peanuts, and red wine (Selma et al., 2009).

Antioxidant Properties of Polyphenols

Electrophiles or free radicals are generated from pollution, ozone, UV light, radiation, cigarette and cigar smoke, chemicals, drugs, pesticides, enzymes (e.g., nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, P450s, immune cells (e.g., phagocytes)), and cellular respiration. Examples of free radicals include superoxide (O₂), hydroxyl (OH), peroxyl (LOO), alkoxyl (LO), hydroperoxyl (HO₂), nitric oxide (NO), nitric dioxide (NO₂), peroxynitrite (ONOO), and nonlipid (ROO, R) radicals (Gropper and Smith, 2013). Free radicals can directly or indirectly cause oxidative damage to DNA, proteins, and polyunsaturated fatty acids, leading to cell mutations, toxicity, and inflammation with dire physiological consequences, including death.

Polyphenols neutralize or scavenge free radicals by electron transfer due to the hydroxyl group(s) associated with their phenol ring structure (C6) (Pietta, 2000). As the number of hydroxyl groups increases, so does the antioxidant potential of the polyphenol (Cao et al., 1997). Polyphenols also decrease free radical concentrations by inducing genes encoding antioxidant enzymes such as heme oxygenase-1, glutathione peroxidase, superoxide dismutase–1/2, catalase, and γ-glutamate-cysteine ligase catalytic subunit by activating the transcription factor nuclear factor–erythroid 2 (NF–E2)-related factor 2 (Nrf2) (Chuang and McIntosh, 2011). Collectively, these antioxidant actions of polyphenols provide a means of preventing oxidative damage mediated by free radicals, a notorious contributor to chronic disease risk.

Antiinflammatory Properties of Polyphenols

Free radicals activate enzymes such as NAPDH oxidase and NO synthase that generate reactive oxygen species and nitric oxide species, respectively. These radicals, in turn, trigger the inflammatory mitogen-activated protein kinases (MAPKs), apoptosis signal-related kinase-1, c-Jun N-terminal kinase, p38, and extracellular signal-related kinase, and the transcription factors nuclear factor kappa B (NFκB), and activator protein-1 (AP-1) that induce inflammatory gene expression. Increased inflammatory gene expression, in turn, leads to the synthesis and release of inflammatory cytokines and chemokines that activate or recruit immune cells to target tissues, which results in tissue inflammation (Chuang and McIntosh, 2011). Proinflammatory species also trigger the synthesis of proinflammatory eicosanoids via activation of phospholipases, cyclooxygenases, lipooxygenases, or P450 enzymes.

Polyphenols have been reported to activate specific transcription factors that antagonize NFκB or AP-1 (Chuang and McIntosh, 2011). For example, enhancing peroxisome proliferator activator receptor-γ (PPARγ) activation antagonizes NFκB and AP-1-mediated inflammatory gene expression, thereby reducing inflammation (Ricote and Glass, 2007). In addition, antiinflammatory, alternatively activated macrophages (i.e., M2s) require PPARγ for their activation (Bouhiel et al., 2007; Odegaard et al., 2007). Furthermore, feeding polyphenol-rich grapes to rats (1) increased cardiac PPARγ and δ mRNA levels and DNA binding activity, (2) decreased cardiac NFκB activity, and (3) decreased systemic markers of inflammation (Seymour et al., 2010). Supplementing high-fat-fed Zucker rats with grape seed procyanidins decreased white adipose tissue (WAT) mRNA levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and C-reactive protein (CRP) and attenuated plasma levels of CRP (Terra et al., 2009).

Consistent with these data, we demonstrated that a polyphenol-rich grape extract or quercetin supplementation of primary cultures of human adipocytes treated with TNF-α (1) increased the activity of PPARγ, (2) increased the mRNA levels of several PPARγ target genes, or (3) decreased inflammatory signaling and insulin resistance (Chuang et al., 2010a,b). We also showed that a polyphenol-rich grape extract or quercetin-attenuated inflammatory signaling in human macrophages and in human primary adipocytes treated with conditioned media obtained from human macrophages (Overman et al., 2010, 2011). Similarly, quercetin and kaempferol increased PPARγ activity and decreased NO levels mediated by lipopolysaccharide (LPS) and insulin resistance in murine 3T3-L1 (pre)adipocytes (Fang et al., 2008). We further demonstrated that polyphenol-rich grape powder improved glucose tolerance acutely and decreased markers of inflammation in blood and WAT chronically in high-fat-fed mice (Chuang et al., 2012). Finally, we demonstrated that the xanthone α-mangostin, a polyphenol derived from Garcinia mangostana in Southeast Asia and used as a traditional medicine for skin infections, wounds, and diarrhea, prevented LPS-mediated inflammation or insulin resistance in human adipocytes and macrophages (Bumrungpert et al., 2009, 2010).

Notably, quercetin and trans-resveratrol activated the histone deacetylase sirtuin 1 (SIRT-1), causing NFκB deacetylation and thereby attenuating NFκB activity and inflammatory signaling (Howitz et al., 2003). Similarly, resveratrol reduced inflammatory signaling and improved insulin sensitivity in an SIRT-1–dependent manner by deacetylating NFκB (Fischer-Posovszky et al., 2010; Olholm et al., 2010; Yang et al., 2010; Zhu et al., 2008) and PGC1α (Lagouge et al., 2006; Sun et al., 2007), thereby enhancing mitochondrial biogenesis, oxidative phosphorylation, and aerobic capacity (Lagouge et al., 2006). Taken together, these antioxidant and antiinflammatory actions of polyphenols (Chuang and McIntosh, 2011) provide a means of preventing inflammation, a notorious risk factor for chronic disease.

Before discussing the intestinal health benefits of polyphenols, the next sections will examine (1) the influence of polyphenols on nutrient bioavailability, (2) how polyphenols are digested and absorbed, and (3) their interactions with gut microbes.

Polyphenol Bioaccessibility and Bioavailability

The amount of polyphenol available for absorption (i.e., bioaccessibility) and the rate and extent of absorption and availability for metabolism (i.e., bioavailability) are impacted by their structure, degree of polymerization, types of interactions with food matrices, dietary status, diet composition, intestinal pH, and abundance of digestive enzymes (Lila et al., 2012; Bohn, 2014; Neilson and Ferruzzi, 2013). For example, conjugated polyphenols require deconjugation in order to diffuse into the enterocyte (Rein et al., 2013). The brush border of the small intestine contains membrane bound β-glucosidases that hydrolyze gluconated polyphenols into more readily absorbable aglycones (Van Duynhoven et al., 2011) (Fig. 18.5). Subsequently, the aglycone will undergo Phase I (e.g., reduction, oxidation, or hydrolysis) or Phase II (e.g., conjugation) metabolism in the enterocyte, converting it into a methyl ester, a glucuronide, or sulfate or be transported as an aglycone to the liver for similar metabolism (Chiou et al., 2014). Conjugating aglycones reduces their potential microbial toxicity and makes them easier to transport as biotransformed polyphenols. Furthermore, dietary macronutrients can alter the composition of intestinal microbes, which in turn influences polyphenol biotransformation in the GI tract (Fava et al., 2012). For instance, a high-fat meal increases the bioaccessibility of anthocyanins, whereas protein-rich matrices protect anthocyanins from degradation in the small intestine, thus making them available for colonic microbial biotransformation (Ribnicky et al., 2014).

Bacterial Metabolism of Polyphenols

Dietary polyphenols that reach the colon are metabolized by microbes and intestinal enzymes (Fig. 18.5). Biotransformation of polyphenols (e.g., deconjugated, cleaved, or hydrolyzed) to more or less bioaccessible and bioactive metabolites influences microbial growth and metabolism (Selma et al., 2009; Kemperman et al., 2010). Alternatively, biotransformed polyphenols (e.g., aglycones, monomeric proanthocyanidins, and phenolic acids) may be absorbed into the mucosa or bloodstream, where they can activate local or systemic receptors or transporters, respectively, that impact metabolism (Neilson and Ferruzzi, 2013). For the most part, microbial enzymes (e.g., dehydroxylases, decarboxylases, demethylases, esterases, glucosidases, glucuronidasases, hydrogenases, and isomerases) convert a diverse group of dietary polyphenols into a relatively small group of aromatic metabolites (Selma et al., 2009; Van Duynhoven et al., 2011). For example, benzoic, hippuric, and vanillic acids are the main microbial metabolites of green tea polyphenols (Fang et al., 2008). Those that are absorbed into the portal blood and reach the liver undergo sulfation, glucuronidation, methylation, or acetylation by Phase II enzymes (Neilson and Ferruzzi, 2013). These hepatic polyphenol metabolites, in turn, enter the bloodstream or bile acid pool.

Microbial Fermentation Products That Influence Intestinal Health

Polyphenols alter the production of the microbial SCFAs acetate, propionate, and butyrate, which are normally at molar ratios of 60:23:17 (Blaut, 2014). SCFAs contribute approximately 10% of the total daily kcal intake (Bergman, 1990) and can regulate energy harvest. For example, (1) propionate is a precursor for hepatic gluconeogenesis, (2) propionate and acetate are precursors of cholesterol synthesis, and (3) acetate and butyrate are substrates for hepatic and WAT triglyceride (TG) synthesis. In addition, butyrate is the preferred energy substrate for colonocyte growth and differentiation (Roediger, 1980). Butyrate reduces the growth of colorectal cancer cells via upregulation of Wnt–beta-catenin signaling (Lazarova et al., 2014). Butyrate also increases the localization of tight junction proteins on the apical surface of epithelial cells, improving gut barrier function and preventing translocation of endotoxins into the systemic circulation (Cox and Blaser, 2013). Butyrate-inhibits NFκB signaling, thereby reducing inflammatory cytokine synthesis associated with GI inflammatory disease (Segain et al., 2000; Lührs et al., 2002). The acidic nature of SCFAs reduces luminal pH throughout the colon, preventing the growth of certain pathogenic bacteria (e.g., Enterobacteriaceae) (Roe et al., 2002; Hirshfield et al., 2003). This effect on pH may also be a determining factor on which class of fermenters predominates. At more neutral pH (6.5), acetate producers predominate; in contrast, in a more acidic environment (pH 5.5), butyrate producers predominate (Walker et al., 2005).

Activation of Endocrine Cell Signals

Polyphenols, their metabolites, or SCFAs activate G protein receptors (GPRs) on gut endocrine cells (e.g., GPR 41, 43, or 119) that secrete peptides that influence the host. For instance, butyrate increased GLP-1 secretion (Samuel et al., 2008), and GRP-mediated secretion of GLP-1 and -2 inhibited gastric emptying, elevated insulin secretion and sensitivity, and stimulated satiety (Holst, 2007; Wichmann et al., 2013). Similarly, GPR-mediated PYY secretion prevented obesity by increasing satiety, energy expenditure, or sympathetic-mediated thermogenesis in adipose tissue (Mestdagh et al., 2012). Therefore, polyphenol-mediated changes in fermentation products influence intestinal and systemic metabolisms.

Altering the Gut Microbiome and Improving Barrier Function

Dietary polyphenols increase the abundance and diversity of microbial populations (Tuohy et al., 2012). For example, a decreased ratio of Firmicutes to Bacteroidetes and increased Lactobacilli, Bifidobacteria, Akkermansia muciniphila, Roseburia spp., Bacteroides, and Prevotella spp. attenuates gut dysbiosis and accompanying metabolic complications (Selma et al., 2009; Roopchand et al., 2013; Neyrinck et al., 2013; Anhe et al., 2014). High-fat-fed mice consuming Concord grape polyphenols had a robust increase in fecal A. muciniphila abundance, which is associated with improved gut barrier function (Roopchand et al., 2015). Mice fed high levels of fat and sugar but supplemented with proanthocyanidin-rich cranberry extract had an increased abundance of fecal A. muciniphila (Anhe et al., 2014), a commensal, mucin-degrading bacteria that play a key role in enhancing gut barrier function and reducing inflammation, insulin resistance, and adiposity (Everard et al., 2013).

Polyphenol-rich grape juice increased the growth of the probiotics L. acidophilus and Lactobacillus delbruekii, and decreased the growth of Escherichia coli in vivo (Agte et al., 2010). Resveratrol supplementation of rats treated with dextran sulfate sodium (DSS) saw increased the levels of Lactobacilli and Bifidobacteria and improved colon mucosa architecture and inflammatory profile compared to controls (Larrosa et al., 2009b). Quercetin supplementation increased the growth of the probiotics L. acidophilus and L. plantarum (Yadav et al., 2011). Malvindin-3-glucoside increased the growth of Bifidobacterium and bacteria from the genuses Lactobacillus and Enterococcus (Hidalgo et al., 2012). Rats consuming polyphenol-rich grape fiber had increased cecum levels of Lactobacillus spp. (Pozuelo et al., 2012). Rats fed polyphenol-rich grape pomace juice had increased abundance of Lactobacillus and Bifidobacterium and decreased levels of secondary bile acids in their feces (Sembries et al., 2006). A reduction in secondary bile acids is positively associated with a reduced risk of GI cancers. Similarly, rats consuming red wine polyphenols had lower levels of Clostridium spp. and higher levels of Lactobacillus spp. (Dolara et al., 2005). In addition, adults consuming red wine had an increased abundance of Enterococcus, Prevotella, Bacteroides, Bifidobacterium, Bacteroides uniformis, Eggerthella lenta, Blautia coccoides, and Eubacterium rectale groups compared to a baseline. The wine consumers had lower blood pressure, blood cholesterol, and CRP levels, which were positively correlated with Bifidobacteria (Queipo-Ortuño et al., 2012). Wine polyphenols increased the growth of the probiotic L. plantarum (Barrosa et al., 2014). Adult males given a proanthocyanin-rich extract had reduced fecal microbial populations of Bacteriodes, Clostridium, and Propionibacterium genuses and higher levels of the probiotics Bacteriodes, Lactobacillus, and Bifidobacterium (Cardona et al., 2013).

High-fat diets cause gut dysbiosis, including increasing the abundance of deleterious sulfidogenic bacteria (Zhang et al., 2010; Shen et al., 2013, 2014) that produce hydrogen sulfide, a toxic gas that damages intestinal cells (Carbonero et al., 2012; Devkota et al., 2012). We demonstrated in butter-fed mice that table grape powder reduced adiposity, improved hepatic TG levels, modestly reduced WAT inflammatory gene expression, and lowered the cecum levels of deleterious sulfidogenic bacteria while tending to increase the abundance of A. muciniphila and Allobaculum in the proximal colon and cecum (Baldwin et al., 2016). In a follow-up study, we examined the impact of a polyphenol-rich, extractable fraction from table grape powder in mice fed a high-fat, American-type diet. The extractable fraction was rich in polyphenols, particularly anthocyanins and proanthocyanidins. The polyphenol-rich fraction attenuated diet-induced obesity, insulin resistance, steatosis, and chronic inflammation in WAT while improving gut barrier function and altering the bacterial structure of the cecum mucosa (Collins et al., 2016).

Quercetin or trans-resveratrol supplementation of mice consuming a high-fat, high-sugar diet decreased body weights and insulin resistance compared to control mice (Etxeberria et al., 2015). Notably, quercetin-mediated improvements in systemic health were positively correlated with a decreased ratio of Firmicutes and Bacteroidetes and an abundance of deleterious bacteria (e.g., Erysipelotrichaceae, Bacillus, and Enubacterium cylindroides), thereby reducing diet-induced dysbiosis. Quercetin-mediated increases in the Bacteroidetes phylum were accompanied by increases in the Bacteriodaceae and Prevotellaceae families (Etxeberria et al., 2015), which have been previously reported to be decreased in high-fat-fed mice (Hildebrandt et al., 2009). Trans-resveratrol–fed mice had suppressed intestinal markers of inflammation and enhanced markers of barrier function but only alterations in gut microbial profiles.

Antimicrobial Properties

Polyphenols have bacteriostatic, bactericidal, or adhesion-preventing properties against disease-causing bacteria (Selma et al., 2009). They have also been shown to inhibit quorum sensing (Gonzalez and Keshavan 2006), disrupt lipid membrane integrity (Kemperman et al., 2010), and DNA polymerase activity of bacteria (Cushnie and Lamb, 2005). For instance, anthocyanin-rich extracts from varieties of vegetables, juices, and tea inhibited the growth of infectious strains of bacteria (Lee et al., 2003, 2006). Polyphenols from tea attenuated the growth of Candida albicans (Evensen and Braun, 2009). Microbial metabolites of berries decreased the growth of salmonella (Alakomi et al., 2007). Gallic acid reduced the growth of potential respiratory pathogens, particularly the gram-negative bacteria Moraxella catarrhalis and the gram-positive Staphylococcus aureus (Cueva et al., 2012). Flavon-3-ol diminished the growth of the Staphylococcus genus and several E. coli strains in human fecal samples (Cueva et al., 2015). Finally, resveratrol mitigated the growth of drug-resistant strains of Myobacterium smegmatis (Lechner et al., 2008).

Suppressing Immune Cell Infiltration or Inflammatory Signaling in the GI Tract

Several intestinally derived polyphenol metabolites (i.e., dihydro-oxyphenylacetic, hydrocaffeic, and hydroferulic acids) suppressed inflammatory prostaglandin production in colon cancer cells and in rodents (Larrosa et al., 2009a). Hydrocaffeic acid reduced inflammation and DNA damage in a DSS-induced model of ulcerative colitis (Larrosa et al., 2009a). Similarly, a microbial metabolite of curcumin (i.e., ferualdehyde) reduced inflammation and extended life span in endotoxin-treated rodents (Radnai et al., 2009). Cranberry products reduced intestinal disease activity indices and markers of inflammation in experimentally induced colitis in mice (Xiao et al., 2015; Popov et al., 2010). Cranberry-derived flavonoids, and procyanidin dimers and oligomers were responsible for preventing lipid peroxidation and inflammatory signaling in intestinal Caco-2 cells treated with prooxidants or LPS (Denis et al., 2015). Rutin, quercetin glycosides, and resveratrol attenuated intestinal inflammation in rodents (Galvez et al., 1997; Kwon et al., 2005; Martin et al., 2004, 2006; Ergun et al., 2007). Polyphenol-rich grape seed extract reduced IBD markers, increased goblet cell number, and decreased myeloperoxidase activity, a constituently expressed enzyme in neutrophils that is positively associated with GI inflammation, in IL-10–deficient mice (Suwannaphet et al., 2010). Consistent with these data, resveratrol decreased nitric oxide synthase activity and mucosal damage in an enterocolitis rat model (Ergun et al., 2007). Intestinal colitis in Wistar rats was suppressed by grape juice flavonoids (Paiotti et al., 2013). Collectively, these data demonstrated the antiinflammatory properties of polyphenols.

Preventing or Treating Peptic Ulcers and Colitis

Two recent reviews describe literature supporting a positive role for dietary polyphenols found in Piper betel, apples, curcumin, green tea, grapes, pomegranate, bilberry, olive oil, and citrus fruits for the management of peptic ulcers (Farzaei et al., 2015a) and IBDs (Farzaei et al., 2015b). Mechanisms cited in these reviews for the beneficial effects of these polyphenols include (1) decreasing proinflammatory signaling cascades or enzymes, (2) increasing antioxidant compounds or enzymes, (3) increasing angiogenesis and growth factors, and (4) increasing populations of commensal and decreasing populations of disease-causing gut microbes. For example, apple polyphenols protected against aspirin-induced gastric ulcer (Paturi et al., 2014; D’Argenio et al., 2008; Graziani et al., 2005) in part by increasing the antioxidant status of the gastric mucosa and upregulating genes encoding proteins that defend gastric mucosa from insult. Apple polyphenols also reduced the incidence of colitis in a DSS mouse model of colitis via downregulating MAPKs and the induction of downstream inflammatory genes they regulate (Skyberg et al., 2011). Resveratrol decreased the activity of intestinal myeloperoxidase and improved the antioxidant status and degree of damage of the gastric mucosa in a murine model of acetic acid–induced gastric ulcers (Solmaz et al., 2009). Resveratrol also decreased DSS-mediated injury to colonic mucosa, which was associated with diminished NFκB and MAPK signaling in a mouse model of colitis (Youn et al., 2009). Ellagic acid, a pomegranate metabolite from intestinal bacteria, protected rats against gastric ulcer development in part by suppressing the activation of inflammatory cytokine production and increasing antioxidant activities (Beserra et al., 2011). Ellagic acid decreased trinitrobenzenesulfonic acid–mediated colitis in rats, which was associated with decreased activation of cyclooxygenase-2, iNOS, MAPK, and NFκB pathways that trigger inflammatory gene expression and the recruitment of immune cells into the GI mucosa (Rosillo et al., 2011). Tea polyphenols decreased the abundance of Helicobacter pylori, a GI bacterium associated with gastritis, by decreasing LPS-mediated activation of toll-like receptor 4 (Ankolekar et al., 2011). Tea polyphenols also decreased DSS-mediated colitis in mice by attenuating inflammatory gene expression and increasing antioxidant status (Oz et al., 2013).

Reducing GI Cancer Risk

Dietary phytochemicals and other natural products have anticancer properties (Singh et al., 2016a) that target cancer stem cells (Singh et al., 2016b) or the arachidonic acid pathway (Yarla et al., 2016). For instance, rats fed wine polyphenols for 16 weeks had a reduced incidence of colon carcinogenesis, which was positively associated with lower intestinal indicators of oxidative stress and populations of Bacteriodes, Clostridium, and Propionibacterium spp. (Dolara et al., 2005). Rats treated with the colon carcinogen 1,2-dimethylhydrazine (DMH) and supplemented with resveratrol had a lower colonic tumor burden, which was positively correlated with decreases in microbial biotransforming enzymes (e.g., β-glucuronidase, β-glucosidase, β-galactosidase, mucinase, nitroreductase, and sulfatase) linked with the development of cancer (Sengottuvelan and Nalini, 2006). Consistent with these data, DMH-treated rats consuming resveratrol had reduced colonic DNA damage that was positively associated with increased activities of superoxide dismutase, catalase, and glutathione peroxidase, reductase, and S-transferase and higher levels of glutathione, vitamins and E, and beta-carotene. The resveratrol-mediated enhancement of antioxidant status was accompanied by decreased markers of lipid peroxidation compared to nonresveratrol-supplemented mice (Sengottuvelan and Nalini, 2009).