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Gastroprotective Effects of Bioactive Foods
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Gastroprotective Effects of Bioactive Foods M. Dey, M. Thomas South Dakota State University, Brookings, SD, USA
ABBREVIATIONS ACF Aberrant crypt foci AIDS Acquired immunodeficiency syndrome CD Crohn’s disease DHNA 1,4-Dihydroxy-2-naphthoic acid GI Gastrointestinal GERD Gastric esophageal reflux disease GMP Glycomacropeptide HIV Human immunodeficiency virus IBD Inflammatory bowel disease NDM Nondialyzable material PUD Peptic ulcer disease PEITC Phenethyl isothiocyanate PEO PEITC essential oil PPI Proton-pump inhibitors UC Ulcerative colitis WHO World Health Organization
1. INTRODUCTION Gastrointestinal (GI) diseases and digestive disorders, hereafter referred to as GI diseases, affect the alimentary tract, liver, biliary system, and pancreas. Increasingly, GI-related ambulatory care visits and hospitalization were reported in 35% of the US population in 2004 (Everhart, 2008). Annual GI disorder-related healthcare expenditure was estimated at 141 billion dollars in the US for 2004 (Everhart, 2008). Digestive diseases accounted for 10% of all deaths in the United States (Everhart, 2008). GI diseases result in loss of work days, reduced quality of life, decreased life span, and also pose an economic burden to the individual as well as to the society. Chronic GI diseases have multifactorial etiology and only symptomatic treatments are available. Infectious GI diseases that are treated using antibiotics are increasingly developing resistance toward these drugs. Nutritional management offers a pragmatic alternative for prevention and treatment of GI Bioactive Food as Dietary Interventions for Liver and Gastrointestinal Disease http://dx.doi.org/10.1016/B978-0-12-397154-8.00006-3
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2013 Elsevier Inc. All rights reserved.
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diseases. But the quantity and composition of the food and frequency of intake could influence the progression or prevention of pathological conditions. A better understanding of nutrients and non-nutritional compounds in the food and knowledge about their mechanisms for biological activities in the context of health and diseases are necessary for adopting nutrition as a tool to manage health. The American Dietetic Association defines ‘biologically active’ (bioactive) food components as “physiologically active constituents in foods or dietary supplements derived from both animal and plant sources, including those needed to meet basic human nutrition needs, that have been demonstrated to have a role in health and to be safe for human consumption in intended food and dietary supplement uses.” Bioactive compounds must contribute to better health in addition to any nutritional role these components might possess. Biologically active compounds from plants are often products of a plant’s secondary metabolism. Many of these compounds have evolved over centuries as the plant’s defense mechanism against pests, pathogens, and predators (Cowan, 1999). Examples of bioactive compounds obtained from plants are polyphenols, phytosterols, carotenoids, sesquiterpene lactones, tocopherols, tocotrienols, organosulfur compounds including isothiocyanates, soluble and insoluble fibers, inulin, and oligofructosaccharides. Polyphenols are the most abundant among plant bioactive compounds. There are more than 8000 polyphenols (Opara and Rockway, 2006) of which flavonoids, isoflavones, theaflavins, and catechins are widely used for treatment of diseases. Fruits, cereals, legumes, nuts, grains, and vegetables are good sources of polyphenols (Opara and Rockway, 2006). Milk and whey protein are excellent sources of bioactive compounds that are of animal origin. Fermented dairy products contain bacteria that are beneficial to human health (Ghosh and Playford, 2003). These bacteria are designated as probiotic and are considered as bioactive food components (Ghosh and Playford, 2003). Although many of these food components have been part of human diet for ages, their use for prevention and treatment of various diseases is a relatively new concept in ‘nutrition and health’ research. Experiments on model animals and human clinical trials have demonstrated the beneficial role of bioactive compounds in managing GI health. In this chapter, scientific information evidencing GI health protection from the use of bioactive compounds is discussed. All major diseases of the GI-tract for which interventions with bioactive food components are known have been covered here. However, diseases of the associated organs such as the gallbladder and liver have not been discussed here, in an attempt to stay within the word limit.
2. ORAL DISEASES The mouth or oral cavity is the anterior opening of the digestive tract (Martini, 2006). It is bound by the lips anteriorly, hard and soft palate dorsally, and tongue ventrally. The oral cavity contains two layers, each of teeth and alveolar ridge or gum. The inside of the mouth is lined by mucus membrane. Salivary glands open into the oral cavity and
Gastroprotective Effects of Bioactive Foods
secrete saliva. The normal functioning of these body parts is important in initiating the digestion of food. Oral diseases are prevalent among all populations and affect general health and quality of life. The most common conditions are dental caries and periodontal diseases. Globally, 5–15% of the population has severe periodontal diseases and signs of gingivitis. According to World Health Organization, 60–90% of school children and a majority of adults have dental caries (Petersen et al., 2003). Common symptoms include halitosis, orofacial pain, reduced salivary flow, loose teeth, and altered sense of taste and smell. It has been demonstrated that oral lesions are associated with cardiovascular diseases, diabetes mellitus, cancer, chronic obstructive pulmonary disease, and human immunodeficiency virus/ acquired immunodeficiency syndrome (Petersen et al., 2003). Biofilm formation in the mouth is critical in developing dental caries and periodontal diseases. Biofilm is a complex arrangement of multiple communal bacteria and can lead to plaque formation that remains adherent to the teeth. Toxic products and virulent factors from plaques can elicit inflammatory responses in the host and damage soft tissues and bones leading to gingivitis and periodontal diseases. Bacteria in the biofilm ferment the sugars in the food producing organic acids, which will reduce the pH, and leads to dental caries (Marsh, 2005). Thus reducing biofilm formation is critical to prevent dental caries and periodontal diseases. The inhibitory effect of food-based bioactive compounds on biofilm formation is well documented.
2.1 Oral Health Benefits of Bioactive Compounds Dried fruits and cranberry: Dried fruits, especially raisins, contain phytochemicals known for their antibacterial actions. Raisins contain oleanolic acid, oleanolic aldehyde, linoleic acid, linolenic acid, betulin, betulinic acid, 5-(hydroxymethyl)-2-furfural, rutin, and their derivatives. These agents can inhibit S. mutans (cariogenic) and Porphyromonas gingivalis (periodontopathic; Wu, 2009). The nondialyzable material (NDM) in cranberries has a potent anti-adhesion property that prevents biofilm formation. The NDM contains 65% proanthocyanidin-like compounds, which accounts for anti-adhesive property. The biofilm formation was inhibited by cranberry polyphenol fraction. Also mouthwash supplemented with NDM decreased total bacterial count and S. mutans count. The NDM also inhibited the adhesion of S. sobrinus to saliva-coated hydroxyapatite. These experiments indicate that the polyphenol fraction or NDM in cranberry can prevent or reduce the biofilm formation mostly by counteracting the bacterial adhesion to dental enamel (Petti and Scully, 2009). Cranberry NDM can also inhibit periodontal diseases because of its anti-inflammatory properties. The experiments conducted by Bodet and coworkers suggested that NDM fraction inhibits the production of proinflammatory cytokines by macrophages stimulated with lipopolysaccharides (Bodet et al., 2008). Cranberry polyphenols are suggested to play a role in reducing the release of bacterial toxic products.
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Figure 30.1 illustrates the mechanisms by which cranberry prevents periodontitis (Bodet et al., 2008). Milk and milk products: Bioactive peptides are embedded in milk protein, especially in the casein fraction, which are capable of inhibiting bacterial growth (Guggenheim et al., 1999). The diets containing casein could inhibit the growth of S. sobrinus and alter overall bacterial composition of plaque in rats (Guggenheim et al., 1999). Glycomacropeptide (GMP), a major component of cheese whey protein, can prevent the adhesion of carcinogenic bacteria and also alter the microbiota of plaque favorably. Other milk proteins such as lactoferrin, lactoperoxidase, and lysozyme also have antibacterial properties. Also, casein phosphopeptide can reduce enamel demineralization and promote remineralization by stabilizing the calcium phosphates in the plaque (Reynolds, 1997). Tea: Black tea contains theaflavin that is produced by the oxidation of catechins during the manufacturing process. In vitro and in vivo experiments have shown that catechins have an inhibitory effect on bacterial enzymes such as amylase and glucosyl transferase and thus prevent bacterial propagation and adhesion. Although human studies have remained inconclusive, some of those studies have exhibited a correlation between tea drinking and reduced plaque scores (Petti and Scully, 2009). Honey (Molan, 2001): Honey has been used for the treatment of skin wounds, ulcers, and burns throughout the ages. Hydrogen peroxide in honey is responsible for the
Streptococci adhesion to enamel ·Inhibits bacterial enzymes and
Bacterial multiplication and tissue distruction ·Inhibits bacterial proteolytic
glucan binding protein activity
enzymes – gingipain, dipeptidyl peptidase IV, trypsin, and chymotrypsin like enzymes
·Reduces the hydrophobicity of oral streptococci ·Partially inhibits acid production
Prevents dental caries
Coaggregation of streptococci ·Inhibits bacterial pairs in which one or both are Gram-negative anaerobic bacteria
Cranberry polyphenols
Prevents periodontal diseases
Modify host responses ·Reduces pro-inflammatory cytokines, nitric oxide, and reactive oxygen species production ·Inhibits production and activity of matrix metalloproteinases
Figure 30.1 Scheme showing proposed mechanisms by which bioactive compounds in cranberry inhibit localization of pathogens involved in the initiation and development of periodontitis. Modified from Figure 2 in Bodet, C., Grenier, D., Chandad, F., et al., 2008. Potential oral health benefits of cranberry. Critical Reviews in Food Science and Nutrition 48, 672–860, Taylor and Francis Group, LLC.
Gastroprotective Effects of Bioactive Foods
antibacterial activity. Honey also has antioxidants that could reduce the damage due to free oxygen radicals during periodontitis. Probiotics: These are the bacteria that potentially benefit human health on ingestion. Several species under genus Lactobacillus as well as other genera have been studied in context of oral health. Some examples are L. paracasei, L. rhamnosus, L. lactis, L. reuteri, L. brevis, L. helveticus, Weissella cibaria, and Streptococcus thermophilus. Probiotic organisms inhibit the growth of pathogenic organisms, by competing and displacing them from biofilms and thus prevent their adhesion. L. reuteri can prevent gingivitis and gum bleeding (Krasse et al., 2006). Probiotic strains could also prevent periodontal, halitosis, or oral malodor and inhibit the production of toxins by pathogenic strains of bacteria.
3. ESOPHAGEAL AND GASTRIC DISEASES The esophagus (Martini, 2006) is a flattened muscular tube that connects the pharynx to the stomach. It is lined by mucosal membrane that secretes mucus to lubricate and move the food bolus. The peristaltic movement of the esophagus propels the food to the stomach. The lower and upper sphincters in the esophagus prevent retrograde movement of food. The stomach (Martini, 2006) is the muscular sac lying between the esophagus and small intestine. Glands in the stomach wall secrete mucus, enzymes, and hydrochloric acid, which help in the digestion of food. The muscular wall of the stomach aids in churning and evacuating its contents into the small intestine.
3.1 Gastric Esophageal Reflux Disease and Barret's Esophagus Reflux of gastric contents into the esophagus (esophagitis) develops from either dysfunctional esophageal motility or improper functioning of lower esophageal sphincter or both (Herbella and Patti, 2010). Common symptom of gastric esophageal reflux disease (GERD) is heartburn. The incidence of GERD is 10–20% among Western population (Dent et al., 2005). In Asian population, the rate was less than 5% in 2005, but has reached 8.5% by 2010 (Jung, 2011). This increase could be a reflection of changes in lifestyle and eating habits in recent years due to changing socio-economic structure or due to improvement in reporting and record keeping or both. Occurrence of GERD is highly correlated to obesity and diabetes mellitus, which are on rise globally (Dent et al., 2005). Complications of GERD include stomach and esophageal ulcers and Barrett’s esophagus. Gastric and esophageal ulcers are discussed later under the Section 4.1. Barrett’s esophagus is an abnormal benign change in the epithelial cell morphology (metaplasia) of the lower esophagus typically in response to chronic acid exposure in GERD. Metaplastic cells can potentially progress to develop dysplasia, and then malignant neoplasia (cancer). About 10–15% of GERD patients develop Barrett’s disease and are, therefore, at an increased risk for developing esophageal adenocarcinoma, a particularly lethal cancer
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(Oh and Demeester, 2010). Current treatment options for Barrett’s and GERD include antacids, H2 blockers, and proton-pump inhibitors (PPIs). The disease could be better managed by life style and dietary changes such as reducing body weight, carbonated drinks, citrus fruits, and smoking. Surgery could be beneficial if other treatments fail (Oh and Demeester, 2010).
3.2 Bioactive Foods for Esophageal and Gastric Diseases Neem (Azadiracta indica): Neem bark extract has shown potent antisecretory and antiulcer properties in animals and human (Bandyopadhyay et al., 2004; Maity et al., 2009; Malfertheiner et al., 2009). Lyophilized bark extract at 30-mg daily oral dose for 10 days significantly reduced gastric acid secretion in patients with chronic acid reflux and gastric ulcers. Further experiments are required to identify the bioactive compounds in neem bark extract. Morinda citrifolia aqueous fruit extract: Morinda fruit (Noni fruit) extract containing the bioactive compound scopoletin showed antisecretory and antiulcer properties in rats (Mahattanadul et al., 2010). Asparagus racemosus: Crude extract derived from Asparagus racemosus administered orally at 100 mg kg1 reduced ulcers in rats that compared with the effects of Ranitidine, a current prescription drug. The extract also decreased gastric acid secretion (Bhatnagar and Sisodia, 2006).
3.3 Helicobacter pylori Infection H. pylori colonize gastric mucosa. These organisms enzymatically metabolize urea into ammonia, thereby neutralizing the acidic environment in the stomach (Wroblewski et al., 2010). The infection is prevalent in 50% of the world population but often do not produce apparent symptoms. Among long-term carriers, 10% develop peptic ulcers and 1–3% may develop gastric adenocarcinoma (Uemura et al., 2001). Although the symptoms are not specific to H. pylori infection, the disease could be suspected if there is severe abdominal pain, nausea, vomiting, weight loss, and bloating. Treatment for H. pylori infection is indicated for gastric and duodenal ulcer, dyspepsia, patients on long-term nonsteroidal anti-inflammatory drug (NSAID) therapy, atropic gastritis, gastric cancer, unexplained iron-deficiency anemia, and gastric mucosa-associated lymphoid tissue lymphoma. Antimicrobial agents in combination with PPIs are used successfully to treat H. pylori infection. However, resistance to these drugs is increasing and alternate antimicrobial and gastroprotective agents are being developed.
3.4 Bioactive Foods Against H. pylori Infection Bioactive components do not eradicate the bacteria, but are useful when used in combination with antibiotics. Bioactive foods provide an alternate solution for the growing
Gastroprotective Effects of Bioactive Foods
antibiotic resistance. The major bioactive foods against H. pylori infection as substantiated by research are as follows: Cranberry and grape extracts: The NDM fraction of cranberry extract rich in plant polyphenols inhibits H. pylori adhesion to gastric mucosa in vitro (Burger et al., 2000) in an NDM-concentration-dependent and bacterial strain specific manner. It was observed that the bacteria went into a coccoid form after NDM treatment and were unable to proliferate likely due to this morphological change (Matsushima et al., 2008). The polyphenolic extracts from grapes containing resveratrol also showed inhibitory effect on H. pylori growth (Brown et al., 2009). Probiotics: Probiotics inhibit the growth of H. pylori by multiple mechanisms (Lesbros-Pantoflickova et al., 2007). Some of the probiotic organisms synthesize antibacterial compounds such as bacteriocin, which is capable of inhibiting H. pylori growth. Also the end products of bacterial fermentation, especially lactic acid, inhibits H. pylori urease enzyme, lowers pH, and creates unfavorable environment for H. pylori growth. Another proposed mechanism is that probiotics such as L. johnsonii La1, L. salivarius, L. acidophilus, and W. confuse compete with H. pylori for adhesion to gastric epithelium (Lesbros-Pantoflickova et al., 2007). Probiotic bacteria also increase the mucin production in stomach. This thickens the gastric mucosal layer, which acts as a physical barrier against H. pylori colonization (Lesbros-Pantoflickova et al., 2007). The summary of clinical trials that used probiotics in combination with antibiotics is given in Table 30.1. (Gotteland et al., 2006). In a separate study where probiotics were supplemented to a standard triple therapy (two antibiotics and a PPI), supplementation improved H. pylori eradication rate, and lowered side effects such as nausea, diarrhea, and taste disturbance that are generally associated with the triple therapy (Song et al., 2010). Dairy products: Human trials have demonstrated that bovine lactoferrin has beneficial effect on H. pylori eradication. Whey protein isolates such as GMP, a-lactalbumin, and lactoperoxidase could also inhibit H pylori growth, but further research is warranted to obtain conclusive results. Kefir, a fermented milk product, is proposed to have antimicrobial, antimutagenic, and anticarcinogenic properties (Bekar et al., 2011) but further research is needed to establish the dose range and mechanism of such biological activities.
4. INTESTINAL DISEASES The small intestine is divided into three parts: duodenum, jejunum, and ileum (Martini, 2006). Mucosal layer of small intestine is modified into villi, finger-like projections, which increases the surface area for absorption of nutrients. The mucus from the goblet cells in the mucosa protects the intestine from acid in the chime (digesta from the stomach). Digestion of food is completed in the small intestine and the digested wastes are moved into the large intestine. Large intestine has three parts: cecum, colon, and rectum. Illeocecal valve at the juncture of the two intestines prevents the retrograde flow of chime from cecum to ileum.
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Table 30.1 Summary of Clinical Trials that used Probiotics in Association with Antibiotics for the Treatment of H. pylori Colonization Study design Subjects Eradication therapy Probiotic Results
RCT
Dyspeptic adults
Rabeprazole, clarithromycin, amoxicillin
Lactobacillus acidophilus LB for 10 days
RCT
Asymptomatic adults
Pantoprazole, clarithromycin, tinidazole
L. rhamnosus GG for 10 days
RCT
Dyspeptic adults
DBPC
Asymptomatic adults
Lansoprazole, clarithromycin, amoxicillin Rabeprazole, clarithromycin, tinidazole
DBPC
Asymptomatic adults
Clarithromycin
RCT
Dyspeptic patients with resistant H. pylori infection H. pylori positive
Esomeprazole or pantoprazole, ranitidine bismuth citrate, amoxicillin and tinidazole Esomeprazole Clarithromycin Amoxycillin Pantoprazole, clarithromycin, Amoxycillin Amoxycillin, Clarithromycin, Omeprazole
L. acidophilus LA5 þ B. lactis for 4 weeks L. rhamnosus, Saccharomyces boulardii Lactobacillus þ B. lactis for 2 weeks L. johnsonii LA1 acidified milk for 3 weeks L. casei DG for 10 days
DBPC
RCT
Symptomatic children
RCT
H. pylori symptomatic
L. casei for 4 weeks
L. acidophilus, L. rhamnosus BID for 20 days S. boulardii for 4 weeks
E.R.: increased A. E.: no effect E.R.: no effect A:E.: decreased E.R.: increased E.R.: no effect A:E.: decreased E.R.: no effect E.R.: no effect A:E.: decreased E. R: no effect E.R: increased E.R.: increased A.E.: decreased
Abbreviations: E.R., eradication rate; A.E., adverse effects; RCT, randomized clinical trial; DBPC, double-blind placebo controlled. Information for the table is obtained from Gotteland et al. (2006), Song et al. (2010), and Zou et al. (2009).
Most of the water in the digesta is absorbed in the large intestine, although a small amount of water is absorbed in the small intestine. Large intestine harbors bacteria that can ferment carbohydrates and fiber that are not digested in the small intestine.
4.1 Peptic Ulcer Disease Peptic ulcer disease (PUD) includes esophageal, gastric, and duodenal ulcers. Among these, esophageal ulcers are least common and are mostly associated with GERD.
Gastroprotective Effects of Bioactive Foods
Common cause for gastric ulcers and proximal duodenal ulcers is H. pylori infection (Malfertheiner et al., 2009). General causes of all types of ulcers include side effects of drugs (NSAIDs, some antibiotics, and metronidazole), chronic vomiting, infections, and idiopathic origin. In the elderly, 70% of PUD patients are H. pylori positive and 40% of peptic ulcers are caused by NSAID or other drugs. About 20–25% of PUD incidences are idiopathic of origin (Pilotto et al., 2010).The annual incidence of physician-diagnosed cases of PUD range from 0.1 to 0.19% of the global population (Sung et al., 2009). Clinical manifestations for PUD are age related and often nonspecific (Pilotto et al., 2010). The most common symptom is epigastric pain. One-third of the patients also experience heartburn. Other symptoms include fullness, bloating, satiety, and nausea. Peptic ulcers could lead to bleeding and this occurs more in elderly patients (Malfertheiner et al., 2009). Two-thirds of elderly patients have atypical symptoms while only one-third experience epigastric pain. The diagnosis of PUD could be delayed in elderly patients if only atypical symptoms are manifested (Pilotto et al., 2010). The treatment of PUD is planned according to the causative factor. Treatment regimen for ulcers due to H. pylori and GERD are described in the earlier sections. Peptic ulcers due to NSAID therapy could be treated with PPIs such as omeprazole and histamine blockers such as ranitidine accompanied by discontinued use of the NSAID. Ulcers of idiopathic origin are also treated with PPI and histamine blockers (Malfertheiner et al., 2009).
4.2 Bioactive Foods Beneficial in PUD The bioactive compounds discussed under H. pylori infection and GERD are also beneficial for PUD treatment. Studies have shown that apple extract (D’argenio et al., 2008) and turmeric have beneficial effects toward treating gastric ulcers. Turmeric (Curcuma longa) is a rhizomatous herbaceous perennial plant of the ginger family and is a common Indian spice that is used in traditional folk medicine for treatment of various diseases. The turmeric extract has the ability to reduce gastric ulcer incidences in animal models by blocking histamine receptors (Kim et al., 2005). The important bioactive compound in turmeric is curcumin which is not, however, readily bioavailable when consumed as food.
4.3 Inflammatory Bowel Disease Inflammatory conditions of the GI-tract are collectively termed as inflammatory bowel disease (IBD). The two predominant forms of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). UC is confined to the large intestine with inflammation occurring primarily in the mucosal lining, while CD can affect any part of the alimentary tract with transmural inflammation. Although there are some unique symptoms distinguishing each disease, many of the symptoms in UC and CD are shared. IBD affects all age groups across
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the nations. A unimodel distribution with 15–30 years of age for IBD onset is the recent trend. But there could be a small second peak occurring at 40–70 age groups for UC (Sands and Grabert, 2009). The disease is more prevalent in North America and Western Europe. There are about 1.4 million patients in North America with 30 000 new cases reported annually. Prevalence of CD is higher in females, while UC occurs more in males. Also higher incidence of both CD and UC are noted among higher socioeconomic classes. Recent studies indicated that although the Caucasians are more affected, the gap between prevalence among Caucasians and African–Americans is diminishing (Sands and Grabert, 2009). The precise cause of IBD is unknown but hypotheses linking the etiology to environmental changes, dietary habits, immunologic factors, smoking, and genetic predisposition exist. Exposure to pollution, industrial waste, smoking, and sunlight is cited as major contributing factors for the development of IBD (Hanauer, 2006). Better sanitation and lesser exposure to infective agents are positively correlated to higher incidence rate. The intestinal microbiota may be altered in these cases rendering these individuals susceptible to IBD. Dietary habits such as higher fat and refined sugar consumption are also indicated as causative factors but remain inconclusive. Familial disposition to the disease ties IBD to genetic factors (Hanauer, 2006; Sands and Grabert, 2009). Symptoms of IBD that typically occur in alternate cycles of flare and remission include mild-to-severe diarrhea, blood in stool, pain associated with abdominal cramps, and severe urgency to have a bowel movement. Loss of appetite and weight loss are also common. IBD is a risk factor for anal fissures, fistulas, and cancer. Skin lesions, arthritis, and liver disorders could also occur as associated complications of IBD. Current treatments aim at reducing frequency, duration as well as intensity of flares and prolonging remission. Medications used in IBD therapy are anti-inflammatory agents, antibiotics, immunomodulators, and biologics. Majority of the patients will require surgery in advanced stages. Along with these conventional therapeutic agents, bioactive foods could yield additional support to alleviate the condition.
4.4 Bioactive Foods for Treatment of IBD Cruciferous vegetables: Phenethyl isothiocyanate (PEITC) is an organosulfur bioactive compound found in cruciferous plants. PEITC can suppress the expression of inflammatory markers in mammalian cells and has the potency comparable to aspirin in alleviating in vivo inflammation (Dey et al., 2006). The effectiveness of PEITC essential oil (PEO) in the treatment of acute and chronic UC as compared to a current prescription drug (5-amino salicylic acid) was investigated in mouse models (Dey et al., 2010). The response to treatment was expressed as disease activity index (Figure 30.2), reflecting five clinical signs: change in body weight, stool consistency, fecal occult blood, visible rearend bleeding and inflammation, and rectal protrusion. PEO reduced inflammation,
Gastroprotective Effects of Bioactive Foods
arrested intestinal bleeding, and helped in remission of the disease. Also expression of proinflammatory cytokines was downregulated by PEO in the mouse colon. The future direction of this study would be to follow up with effects of PEO in humans. Tea: Studies with chemically induced and genetically predisposed IBD mouse models have shown the efficacy of black and green tea extracts to reduce the severity of inflammation and weight loss (Ishihara et al., 2009; Varilek et al., 2001). But the dosage used in these experiments could be achieved only if an individual drinks 100–200 cups of tea every day. Hence, these results need validation in human beings and also the appropriate therapeutic dose needs to be established. Grape: Grape skin and seed contain 50–100 mg g1 of resveratrol, a phenolic compound. This compound is also present in grape wine, some berries, and nuts. Resveratrol has the ability to inhibit proinflammatory cytokine tumor necrosis factor-a, and inflammatory pathways involving cyclo-oxygenase 1 (Das and Das, 2007). In rats, resveratrol reduced the damage due to trinitrobenzene-induced colitis. A significant increase in the apoptosis of cells involved in colitis was also noted (Martin et al., 2006). But the low Acute model
(a) Induction
Chronic model
(b)
Treatment
Induction
Treatment
Disease activity index (DAI)
6 6 4 4
2
2
0
0 −5
0
5 Days
10
−30
15
Water DSS
−20
−10 Days
0
10
PEO 5-ASA
Figure 30.2 Effects of orally administered phytocompound PEO and a common prescription drug 5ASA on the disease activity index (DAI) in DSS-induced colitis in a mouse model study. Significance of treatments in PEO and 5-ASA groups in respect to diseased but untreated (DSS) group and are indicated by p < 0.05 and p < 0.01 and p < 0.001. Healthy control group from the study is also shown. Clinical signs included in the DAI score represent many of the human colitis symptoms: (a) acute colitis model. Data as mean SEM (n ¼ 6) are shown at 5-day intervals. (b) Chronic colitis model. Data as mean SEM (n 10) are shown at 3- and 2-day intervals during induction and treatment periods respectively. Amino salicylic acid, ASA; disease activity index, DAI; standard error mean, SEM. Reproduced from Dey, M., Kuhn, P., Ribnicky, D., et al., 2010. Dietary phenethylisothiocyanate attenuates bowel inflammation in mice. BMC Chemical Biology, 10, 4.
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bioavailability of resveratrol in body tissues and fast clearance rate from the body remains a challenge in using it for treatment of IBD in humans (Udenigwe et al., 2008). Fish oil and flax seed oil: These oils are rich in omega-3 fatty acids that have proven anti-inflammatory and immunomodulatory properties. However, animal efficacy studies using omega-3 fatty acids for treatment of IBD yielded inconclusive results (Calder, 2006). Whey culture: The milk whey culture using Propionibacterium freudenreichii ET-3 contains bioactive substance called 1,4-dihydroxy-2-naphthoic acid (DHNA). This compound can stimulate the growth of Bifidobacteria in humans and animals. DHNA reduced the severity of trinitrobenzene-sulfonic-acid-induced colitis (Uchida et al., 2007). Pomegranate: A recently concluded study in rats with dextran sodium-sulfateinduced colitis evaluated the use of pomegranate extract. It was found that both pomegranate extract and urolithin-A, a microbiota-derived metabolite from pomegranate, reduced the severity of colitis (Larrosa et al., 2010). Licorice: Ethanolic extract of licorice contains anti-inflammatory compound glabridin. Mice with dextran sodium-sulfate-induced colitis were treated for 7 days with the extract and this resulted in reduced weight loss, decreased mortality, and prevented shortening of colon (Kwon et al., 2008). Turmeric: Curcumin, the bioactive compound in turmeric, has been used in animal and human research for treating IBD. Studies with chemically induced colitis animal models suggested that curcumin could alleviate the symptoms of IBD. Curcumin also had beneficial effects at a concentration of 1000–1500 mg per day in a small human study. However, larger clinical trials are needed for conclusive efficacy and bioavailability of curcumin in IBD (Hanai and Sugimoto, 2009). Probiotics: Numerous independent studies have been conducted to evaluate the efficacy of probiotics in IBD treatment and remission but the results are inconsistent. A review on experiments conducted suggested that probiotics used in combination with standard therapy yielded positive results. But this beneficial effect is not obtained when probiotics are used alone (Cary and Boullata, 2010). Another study indicated that a combination of eight strains of probiotic bacteria was effective in the maintenance of remission of IBD, while any single strain of bacteria did not yield beneficial effects (Haller et al., 2010). Prebiotics: Dietary fibers that could be utilized by bacteria in the colon are termed as prebiotics. Bacteria ferment the fiber and produce metabolites. Short-chain fatty acids such as acetate, propionate, and butyrate are the major metabolites of bacterial fermentation in the colon. In vitro and in vivo studies indicate that butyrate has anti-inflammatory and antitumor properties. The hypothesis that dietary fiber is effective in the attenuation of IBD relies on these known properties of butyrate (Rose et al., 2007). Dietary fibers from sources such as oat bran (Hallert et al., 2003), psyllium seeds, inulin, and
Gastroprotective Effects of Bioactive Foods
oligofructosaccharides (Leenen and Dieleman, 2007) alleviated the symptoms of UC. Some experiments yielded conflicting results on the efficacy of dietary fiber for IBD treatment. This could be due to the presence of abnormal microbiota in IBD patients. Further evaluation of the efficacy of combination therapy using prebiotics and probiotics (together termed as synbiotics) is needed. Also the strains of bacteria and type of fiber that should be given as combinations for optimal effects remains to be determined. Both these agents have excellent safety profile and no known side effects.
5. GI CANCER 5.1 Oral, Pharyngeal, and Esophageal Cancer Approximately 30 000 new cases of oral and pharyngeal cancer and 13 000 new cases of esophageal cancer are reported annually in the United States (Greenlee et al., 2001). About 90% of oral and pharyngeal cancer is squamous cell carcinoma. Both squamous cell carcinoma and adenocarcinoma occur in esophagus. The common etiology of these tumors is smoking, alcohol consumption, tobacco and betel nut chewing, as well as dietary, genetic, and environmental. Vitamins, fruits, vegetables, tea, and coffee have been shown to have protective effect against oral cancer (Chainani-Wu, 2002). Diversified diets are highly recommended to achieve protection against these multifactorial diseases.
5.2 Gastric Cancer Worldwide incidence of gastric cancer has declined over last few decades (Everhart, 2008). This could be due to availability of efficient diagnostic tools such as endoscopy for precancerous signs and surgical removal options of these precancerous cells and tissues. The two main sites for gastric adenocarcinoma are proximal and distal stomach. The major risk factors are H. pylori infection, dietary factors, tobacco, obesity, familial predisposition, and radiation exposure (Crew and Neugut, 2006). Intake of antioxidants such as vitamin C and E provides protection against gastric cancer. Annual endoscopic screening in high risk groups may help to detect the tumors in early stage and mortality could be reduced (Crew and Neugut, 2006).
5.3 Colorectal Cancer Although incidences of colorectal cancer are declining in the recent years, still it ranks second in causing death among all cancers in the United States (Everhart, 2008). The average lifetime risk of developing colorectal cancer for a person is 5.12%. Genetic, environmental, and dietary factors contribute to the development of the disease. The normal colon mucosa is lined by columnar cells and forms invaginations or crypts. When exposed to carcinogenic factors, proliferative cells in the crypts lose the ability to control cell division and leads to the formation of aberrant crypt foci (ACF) or polyps. These
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polyps are the early markers of cancer risk and have the potential to develop into adenoma and adenocarcinoma if left untreated. Periodic screening for ACF is an effective tool for early diagnosis. If detected early, surgical intervention is possible.
5.4 Bioactive Food Components in Prevention of GI Cancer Black Raspberry: Addition of black raspberry in diet for 2 weeks reduced dimethylsulfoxide-induced oral tumor incidence in hamsters (Casto et al., 2002). Black raspberry contains various anticarcinogenic agents such as ellagic acid, vitamin E and C, ferulic acid, and folic acid. Tomato: Lycopene is the major bioactive compound in tomatoes. Human case control studies conducted in 12 countries including in the United States reported an inverse relationship between tomato or lycopene intake and gastric cancer occurrence (Giovannucci, 1999). A study in Japan that examined the plasma level of lycopene in blood indicated that regions where people have high plasma lycopene concentration had lesser incidences of gastric cancer and vice versa. Tomato consumption exhibits the most consistent negative association to gastric cancer among all vegetable and fruit consumption data (Giovannucci, 1999). Tea and coffee extracts: Bioactive compounds in tea leaf extracts include gallic acid kaempferol, quercetin, catechin, epicatechin, oleic acid, palmitic acid, linoleic acid, and linolenic acid. When the oral squamous carcinoma cells were treated with tea leaf extract, it induced apoptosis or cell death (Chia et al., 2010). The proapoptotic genes were upregulated and anti-apoptotic genes were downregulated, likely due to the presence of polyphenols. Prebiotics: Dietary fibers include inulin, resistant starch, cellulose, hemicelluloses, and pectins. Rich sources of dietary fiber include bran, fruits, vegetables, nuts, legumes, seeds, and berries. Dietary fibers are fermented by colon bacteria to produce short-chain fatty acids such as butyrate with known anticarcinogenic property. The suggested mechanism of the action of butyrate is given in Figure 30.3 (Andoh et al., 2003). Fiber also increases the fecal bulk and decrease transit time. This will reduce the exposure time of intestinal mucosa to mutagens that lead to the development of cancer. Probiotics and synbiotics: Bifidobacterium lactis, Lactobacillus bulgaricus, Streptococcus thermophilus, L. casie, L. acidophilus, L. gassrei, B. breve, Streptococcus cremoris, and S. lactis are shown to reduce colon cancer risk. Combination of L. rhamnosus and B. lactis with inulin given for 33 weeks reduced the number of azoxymethane-induced colon carcinomas in rats (Wollowski et al., 2001). Cruciferous vegetables: This includes cabbage, broccoli, cauliflower, kale, Brussels sprouts, and watercress. These vegetables contain bioactive compounds such as folate, vitamin C, tocopherols, carotenoids, glucosinolates, isothiocyanates, and polyphenols. Glucosinolates metabolize to produce isothiocyanates and indoles, which possess potent
Gastroprotective Effects of Bioactive Foods
Butyrate (short chain fatty acid)
Anti-inflammatory actions
Provides energy to colonocytes
Anti-carcinogenic mechanisms
Inhibits histone deacetylation and alters gene expression
•Stimulate cell proliferation – could be helpful in ulcerative colitis
• p21, NFκB
Inhibits NFκB •Suppresses inflammation •Favors apoptosis
Inhibits decayaccelerating factor expression •Increases cell death through complement pathway
Figure 30.3 Scheme showing proposed anti-inflammatory mechanisms of butyrate, a by-product of dietary fibers and prebiotics. Modified from Figures 3 and 5 in Andoh, A., Tsujikawa, T., Fujiyama, Y., 2003. Role of dietary fiber and short-chain fatty acids in the colon. Current Pharmaceutical Design, 9, 347–58, published by Bentham Science Publishers Ltd.
anticarcinogenic property. Isothiocyanates such as sulforaphane are cytotoxic and indoles are cytostatic (Pappa et al., 2007).
6. CONCLUSION Consumption of fruits, nuts, and vegetables offer protective benefits against GI diseases (Jedrychowski et al., 2010). But intake of whole food that contains bioactive compounds does not always guarantee GI health protection. Concentration of these health-benefiting compounds in food might vary and can be lower than that required to elicit a therapeutic effect. Additionally, bioavailability parameters may vary depending on the form consumed, such as cooked versus raw, and other factors. Scientifically established standardized processing of these bioactive agents into supplements may help to overcome some of these hurdles. Genetic makeup of an individual may determine how much benefit can potentially be derived from the intake of fruits and vegetables or even processed supplements. This concept has given birth to the newer research field of nutritional genomics, which provides the tools and framework to study diet–gene interactions (Debusk, 2010). Advancement in this direction could ultimately provide guidelines for individualized diet
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plans to deliver healthy dosage of bioactive compounds and the quantity of whole food containing bioactive compounds. It is generally accepted that bioactive compounds could provide a safer alternative to prevailing chemotherapeutic agents that are known to have side effects. While this is partially true given the existing history of human use and folklore in many cases, toxic concentration and pharmacological dose must be established before the purified bioactive substances are marketed. An extensive body of research has demonstrated the ability of bioactive agents to modulate pathophysiological processes producing GI health benefits. However, many of these investigations relied on in vitro or preclinical observations. Controlled human trials must be conducted in future to validate these observations and scientifically establish the potential health-promoting benefits.
ACKNOWLEDGMENTS This work was made possible by funds from National Institutes of Health [grant # R00 AT004245], United States Department of Agriculture [#328100], and South Dakota Agriculture Experiment Station [# 318000]. The authors are also thankful to numerous authors who have contributed to the research in the field of gastric diseases and effects of bioactive compounds in gastrointestinal disorders. Owing to word limitation, the authors were unable to cite many excellent research contributions. Therefore, they urge the readers to cross reference from within the cited articles.
REFERENCES Andoh, A., Tsujikawa, T., Fujiyama, Y., 2003. Role of dietary fiber and short-chain fatty acids in the colon. Current Pharmaceutical Design 9, 347–358. Bandyopadhyay, U., Biswas, K., Sengupta, A., et al., 2004. Clinical studies on the effect of neem (Azadirachta indica) bark extract on gastric secretion and gastroduodenal ulcer. Life Sciences 75, 2867–2878. Bekar, O., Yilmaz, Y., Gulten, M., 2011. Kefir improves the efficacy and tolerability of triple therapy in eradicating Helicobacter pylori. Journal of Medicinal Food 14 (4), 344–347. Bhatnagar, M., Sisodia, S.S., 2006. Antisecretory and antiulcer activity of Asparagus racemosus Willd. against indomethacin plus phyloric ligation-induced gastric ulcer in rats. Journal of Herbal Pharmacotherapy 6, 13–20. Bodet, C., Grenier, D., Chandad, F., et al., 2008. Potential oral health benefits of cranberry. Critical Reviews in Food Science and Nutrition 48, 672–680. Brown, J.C., Huang, G., Haley-Zitlin, V., Jiang, X., 2009. Antibacterial effects of grape extracts on Helicobacter pylori. Applied and Environmental Microbiology 75, 848–852. Burger, O., Ofek, I., Tabak, M., et al., 2000. A high molecular mass constituent of cranberry juice inhibits Helicobacter pylori adhesion to human gastric mucus. FEMS Immunology and Medical Microbiology 29, 295–301. Calder, P.C., 2006. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. American Journal of Clinical Nutrition 83, 1505S–1519S. Cary, V.A., Boullata, J., 2010. What is the evidence for the use of probiotics in the treatment of inflammatory bowel disease? Journal of Clinical Nursing 19, 904–916. Casto, B.C., Kresty, L.A., Kraly, C.L., et al., 2002. Chemoprevention of oral cancer by black raspberries. Anticancer Research 22, 4005–4015. Chainani-Wu, N., 2002. Diet and oral, pharyngeal, and esophageal cancer. Nutrition and Cancer 44, 104–126.
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Chia, Y.C., Rajbanshi, R., Calhoun, C., Chiu, R.H., 2010. Anti-neoplastic effects of gallic acid, a major component of Toona sinensis leaf extract, on oral squamous carcinoma cells. Molecules 15, 8377–8389. Cowan, M.M., 1999. Plant products as antimicrobial agents. Clinical Microbiology Reviews 12, 564–582. Crew, K.D., Neugut, A.I., 2006. Epidemiology of gastric cancer. World Journal of Gastroenterology 12, 354–362. D’argenio, G., Mazzone, G., Tuccillo, C., et al., 2008. Apple polyphenol extracts prevent aspirin-induced damage to the rat gastric mucosa. British Journal of Nutrition 100, 1228–1236. Das, S., Das, D.K., 2007. Anti-inflammatory responses of resveratrol. Inflammation & Allergy Drug Targets 6, 168–173. Debusk, R., 2010. The role of nutritional genomics in developing an optimal diet for humans. Nutrition in Clinical Practice 25, 627–633. Dent, J., El-Serag, H.B., Wallander, M.A., Johansson, S., 2005. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 54, 710–717. Dey, M., Kuhn, P., Ribnicky, D., et al., 2010. Dietary phenethylisothiocyanate attenuates bowel inflammation in mice. BMC Chemical Biology 10, 4. Dey, M., Ribnicky, D., Kurmukov, A.G., Raskin, I., 2006. In vitro and in vivo anti-inflammatory activity of a seed preparation containing phenethylisothiocyanate. Journal of Pharmacology and Experimental Therapeutics 317, 326–333. Everhart, J.E., 2008. The burden of digestive diseases in the United States. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. US Government Printing Office, Washington, DC NIH Publication No. 09-6443. Ghosh, S., Playford, R.J., 2003. Bioactive natural compounds for the treatment of gastrointestinal disorders. Clinical Science (London, England) 104, 547–556. Giovannucci, E., 1999. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. Journal of the National Cancer Institute 91, 317–331. Gotteland, M., Brunser, O., Cruchet, S., 2006. Systematic review: are probiotics useful in controlling gastric colonization by Helicobacter pylori? Alimentary Pharmacology and Therapeutics 23, 1077–1086. Greenlee, R.T., Hill-Harmon, M.B., Murray, T., Thun, M., 2001. Cancer statistics 2001. CA: A Cancer Journal for Clinicians 51, 15–36. Guggenheim, B., Schmid, R., Aeschlimann, J.M., Berrocal, R., Neeser, J.R., 1999. Powdered milk micellar casein prevents oral colonization by Streptococcus sobrinus and dental caries in rats: a basis for the cariesprotective effect of dairy products. Caries Research 33, 446–454. Haller, D., Antoine, J.M., Bengmark, S., et al., 2010. Guidance for substantiating the evidence for beneficial effects of probiotics: probiotics in chronic inflammatory bowel disease and the functional disorder irritable bowel syndrome. Journal of Nutrition 140, 690S–697S. Hallert, C., Bjorck, I., Nyman, M., et al., 2003. Increasing fecal butyrate in ulcerative colitis patients by diet: controlled pilot study. Inflammatory Bowel Diseases 9, 116–121. Hanai, H., Sugimoto, K., 2009. Curcumin has bright prospects for the treatment of inflammatory bowel disease. Current Pharmaceutical Design 15, 2087–2094. Hanauer, S.B., 2006. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflammatory Bowel Diseases 12 (supplement 1), S3–S9. Herbella, F.A., Patti, M.G., 2010. Gastroesophageal reflux disease: from pathophysiology to treatment. World Journal of Gastroenterology 16, 3745–3749. Ishihara, S., Aziz, M.M., Yuki, T., Kazumori, H., Kinoshita, Y., 2009. Inflammatory bowel disease: review from the aspect of genetics. Journal of Gastroenterology 44, 1097–1108. Jedrychowski, W., Maugeri, U., Popiela, T., et al., 2010. Case-control study on beneficial effect of regular consumption of apples on colorectal cancer risk in a population with relatively low intake of fruits and vegetables. European Journal of Cancer Prevention 19, 42–47. Jung, H.K., 2011. Epidemiology of gastroesophageal reflux disease in Asia: A systematic review. Journal of Neurogastroenterology and Motility 17, 14–27. Kim, D.C., Kim, S.H., Choi, B.H., et al., 2005. Curcuma longa extract protects against gastric ulcers by blocking H2 histamine receptors. Biological and Pharmaceutical Bulletin 28, 2220–2224.
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Krasse, P., Carlsson, B., Dahl, C., et al., 2006. Decreased gum bleeding and reduced gingivitis by the probiotic Lactobacillus reuteri. Swedish Dental Journal 30, 55–60. Kwon, H.S., Oh, S.M., Kim, J.K., 2008. Glabridin, a functional compound of liquorice, attenuates colonic inflammation in mice with dextran sulphate sodium-induced colitis. Clinical and Experimental Immunology 151, 165–173. Larrosa, M., Gonzalez-Sarrias, A., Yanez-Gascon, M.J., et al., 2010. Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism. The Journal of Nutritional Biochemistry 21, 717–725. Leenen, C.H., Dieleman, L.A., 2007. Inulin and oligofructose in chronic inflammatory bowel disease. Journal of Nutrition 137, 2572S–2575S. Lesbros-Pantoflickova, D., Corthesy-Theulaz, I., Blum, A.L., 2007. Helicobacter pylori and probiotics. Journal of Nutrition 137, 812S–818S. Mahattanadul, S., Ridtitid, W., Nima, S., et al., 2010. Effects of Morinda citrifolia aqueous fruit extract and its biomarker scopoletin on reflux esophagitis and gastric ulcer in rats. Journal of Ethnopharmacology 134 (2), 243–250. Maity, P., Biswas, K., Chattopadhyay, I., Banerjee, R.K., Bandyopadhyay, U., 2009. The use of neem for controlling gastric hyperacidity and ulcer. Phytotherapy Research 23, 747–755. Malfertheiner, P., Chan, F.K., Mccoll, K.E., 2009. Peptic ulcer disease. The Lancet 374, 1449–1461. Marsh, P.D., 2005. Dental plaque: biological significance of a biofilm and community life-style. Journal of Clinical Periodontology 32 (supplement 6), 7–15. Martin, A.R., Villegas, I., Sanchez-Hidalgo, M., De La Lastra, C.A., 2006. The effects of resveratrol, a phytoalexin derived from red wines, on chronic inflammation induced in an experimentally induced colitis model. British Journal of Pharmacology 147, 873–885. Martini, F.H., 2006. Fundamentals of Anatomy and Physiology, 7th ed. Benjamin/Cummings Publishing Company, San Francisco, CA. Matsushima, M., Suzuki, T., Masui, A., et al., 2008. Growth inhibitory action of cranberry on Helicobacter pylori. Journal of Gastroenterology and Hepatology 23 (supplement 2), S175–S180. Molan, P.C., 2001. The potential of honey to promote oral wellness. General Dentistry 49, 584–589. Oh, D.S., Demeester, S.R., 2010. Pathophysiology and treatment of Barrett’s esophagus. World Journal of Gastroenterology 16, 3762–3772. Opara, E.C., Rockway, S.W., 2006. Antioxidants and micronutrients. Disease-a-Month 52, 151–163. Pappa, G., Strathmann, J., Lowinger, M., Bartsch, H., Gerhauser, C., 2007. Quantitative combination effects between sulforaphane and 3,30 -diindolylmethane on proliferation of human colon cancer cells in vitro. Carcinogenesis 28, 1471–1477. Petersen, P.E., Day, S.E., Ndiaye, C., 2003. The world oral health report 2003: continuous improvement of oral health in 21st century – the approach of the WHO global oral health Programme. Community Dentistry and Oral Epidemiology 31 (supplement 1), 3–24. Petti, S., Scully, C., 2009. Polyphenols, oral health and disease: a review. Journal of Dentistry 37, 413–423. Pilotto, A., Franceschi, M., Maggi, S., Addante, F., Sancarlo, D., 2010. Optimal management of peptic ulcer disease in the elderly. Drugs & Aging 27, 545–558. Reynolds, E.C., 1997. Remineralization of enamel subsurface lesions by casein phosphopeptide-stabilized calcium phosphate solutions. Journal of Dental Research 76, 1587–1595. Rose, D.J., Demeo, M.T., Keshavarzian, A., Hamaker, B.R., 2007. Influence of dietary fiber on inflammatory bowel disease and colon cancer: importance of fermentation pattern. Nutrition Reviews 65, 51–62. Sands, B.E., Grabert, S., 2009. Epidemiology of inflammatory bowel disease and overview of pathogenesis. Medicine and Health, Rhode Island 92, 73–77. Song, M.J., Park, D.I., Park, J.H., et al., 2010. The effect of probiotics and mucoprotective agents on PPI-based triple therapy for eradication of Helicobacter pylori. Helicobacter 15, 206–213. Sung, J.J., Kuipers, E.J., El-Serag, H.B., 2009. Systematic review: the global incidence and prevalence of peptic ulcer disease. Alimentary Pharmacology and Therapeutics 29, 938–946. Uchida, M., Mogami, O., Matsueda, K., 2007. Characteristic of milk whey culture with Propionibacterium freudenreichii ET-3 and its application to the inflammatory bowel disease therapy. Inflammopharmacology 15, 105–108.
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Udenigwe, C.C., Ramprasath, V.R., Aluko, R.E., Jones, P.J., 2008. Potential of resveratrol in anticancer and anti-inflammatory therapy. Nutrition Reviews 66, 445–454. Uemura, N., Okamoto, S., Yamamoto, S., et al., 2001. Helicobacter pylori infection and the development of gastric cancer. The New England Journal of Medicine 345, 784–789. Varilek, G.W., Yang, F., Lee, E.Y., et al., 2001. Green tea polyphenol extract attenuates inflammation in interleukin-2-deficient mice, a model of autoimmunity. Journal of Nutrition 131, 2034–2039. Wollowski, I., Rechkemmer, G., Pool-Zobel, B.L., 2001. Protective role of probiotics and prebiotics in colon cancer. American Journal of Clinical Nutrition 73, 451S–455S. Wroblewski, L.E., Peek Jr., R.M., Wilson, K.T., 2010. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clinical Microbiology Reviews 23, 713–739. Wu, C.D., 2009. Grape products and oral health. Journal of Nutrition 139, 1818S–1823S. Zou, J., Dong, J., Yu, X., 2009. Meta-analysis: Lactobacillus containing quadruple therapy versus standard triple first-line therapy for Helicobacter pylori eradication. Helicobacter 14, 449–459.
RELEVANT WEBSITES http://www.ccfa.org/ – Crohn’s & Colitis Foundation of America Disease Information. (accessed 07.01.2011). http://www.ccfa.org – Crohn’s & Colitis Foundation of America. Epidemiology. (accessed 07.01.2011). http://seer.cancer.gov/statfacts/ – Lifetime risk for colorectal cancer information. (accessed 07.01.2011).
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Gastroprotective Effects of Bioactive Foods M. Dey, M. Thomas South Dakota State University, Brookings, SD, USA
ABBREVIATIONS ACF Aberrant crypt foci AIDS Acquired immunodeficiency syndrome CD Crohn’s disease DHNA 1,4-Dihydroxy-2-naphthoic acid GI Gastrointestinal GERD Gastric esophageal reflux disease GMP Glycomacropeptide HIV Human immunodeficiency virus IBD Inflammatory bowel disease NDM Nondialyzable material PUD Peptic ulcer disease PEITC Phenethyl isothiocyanate PEO PEITC essential oil PPI Proton-pump inhibitors UC Ulcerative colitis WHO World Health Organization
1. INTRODUCTION Gastrointestinal (GI) diseases and digestive disorders, hereafter referred to as GI diseases, affect the alimentary tract, liver, biliary system, and pancreas. Increasingly, GI-related ambulatory care visits and hospitalization were reported in 35% of the US population in 2004 (Everhart, 2008). Annual GI disorder-related healthcare expenditure was estimated at 141 billion dollars in the US for 2004 (Everhart, 2008). Digestive diseases accounted for 10% of all deaths in the United States (Everhart, 2008). GI diseases result in loss of work days, reduced quality of life, decreased life span, and also pose an economic burden to the individual as well as to the society. Chronic GI diseases have multifactorial etiology and only symptomatic treatments are available. Infectious GI diseases that are treated using antibiotics are increasingly developing resistance toward these drugs. Nutritional management offers a pragmatic alternative for prevention and treatment of GI Bioactive Food as Dietary Interventions for Liver and Gastrointestinal Disease http://dx.doi.org/10.1016/B978-0-12-397154-8.00006-3
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2013 Elsevier Inc. All rights reserved.
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diseases. But the quantity and composition of the food and frequency of intake could influence the progression or prevention of pathological conditions. A better understanding of nutrients and non-nutritional compounds in the food and knowledge about their mechanisms for biological activities in the context of health and diseases are necessary for adopting nutrition as a tool to manage health. The American Dietetic Association defines ‘biologically active’ (bioactive) food components as “physiologically active constituents in foods or dietary supplements derived from both animal and plant sources, including those needed to meet basic human nutrition needs, that have been demonstrated to have a role in health and to be safe for human consumption in intended food and dietary supplement uses.” Bioactive compounds must contribute to better health in addition to any nutritional role these components might possess. Biologically active compounds from plants are often products of a plant’s secondary metabolism. Many of these compounds have evolved over centuries as the plant’s defense mechanism against pests, pathogens, and predators (Cowan, 1999). Examples of bioactive compounds obtained from plants are polyphenols, phytosterols, carotenoids, sesquiterpene lactones, tocopherols, tocotrienols, organosulfur compounds including isothiocyanates, soluble and insoluble fibers, inulin, and oligofructosaccharides. Polyphenols are the most abundant among plant bioactive compounds. There are more than 8000 polyphenols (Opara and Rockway, 2006) of which flavonoids, isoflavones, theaflavins, and catechins are widely used for treatment of diseases. Fruits, cereals, legumes, nuts, grains, and vegetables are good sources of polyphenols (Opara and Rockway, 2006). Milk and whey protein are excellent sources of bioactive compounds that are of animal origin. Fermented dairy products contain bacteria that are beneficial to human health (Ghosh and Playford, 2003). These bacteria are designated as probiotic and are considered as bioactive food components (Ghosh and Playford, 2003). Although many of these food components have been part of human diet for ages, their use for prevention and treatment of various diseases is a relatively new concept in ‘nutrition and health’ research. Experiments on model animals and human clinical trials have demonstrated the beneficial role of bioactive compounds in managing GI health. In this chapter, scientific information evidencing GI health protection from the use of bioactive compounds is discussed. All major diseases of the GI-tract for which interventions with bioactive food components are known have been covered here. However, diseases of the associated organs such as the gallbladder and liver have not been discussed here, in an attempt to stay within the word limit.
2. ORAL DISEASES The mouth or oral cavity is the anterior opening of the digestive tract (Martini, 2006). It is bound by the lips anteriorly, hard and soft palate dorsally, and tongue ventrally. The oral cavity contains two layers, each of teeth and alveolar ridge or gum. The inside of the mouth is lined by mucus membrane. Salivary glands open into the oral cavity and
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secrete saliva. The normal functioning of these body parts is important in initiating the digestion of food. Oral diseases are prevalent among all populations and affect general health and quality of life. The most common conditions are dental caries and periodontal diseases. Globally, 5–15% of the population has severe periodontal diseases and signs of gingivitis. According to World Health Organization, 60–90% of school children and a majority of adults have dental caries (Petersen et al., 2003). Common symptoms include halitosis, orofacial pain, reduced salivary flow, loose teeth, and altered sense of taste and smell. It has been demonstrated that oral lesions are associated with cardiovascular diseases, diabetes mellitus, cancer, chronic obstructive pulmonary disease, and human immunodeficiency virus/ acquired immunodeficiency syndrome (Petersen et al., 2003). Biofilm formation in the mouth is critical in developing dental caries and periodontal diseases. Biofilm is a complex arrangement of multiple communal bacteria and can lead to plaque formation that remains adherent to the teeth. Toxic products and virulent factors from plaques can elicit inflammatory responses in the host and damage soft tissues and bones leading to gingivitis and periodontal diseases. Bacteria in the biofilm ferment the sugars in the food producing organic acids, which will reduce the pH, and leads to dental caries (Marsh, 2005). Thus reducing biofilm formation is critical to prevent dental caries and periodontal diseases. The inhibitory effect of food-based bioactive compounds on biofilm formation is well documented.
2.1 Oral Health Benefits of Bioactive Compounds Dried fruits and cranberry: Dried fruits, especially raisins, contain phytochemicals known for their antibacterial actions. Raisins contain oleanolic acid, oleanolic aldehyde, linoleic acid, linolenic acid, betulin, betulinic acid, 5-(hydroxymethyl)-2-furfural, rutin, and their derivatives. These agents can inhibit S. mutans (cariogenic) and Porphyromonas gingivalis (periodontopathic; Wu, 2009). The nondialyzable material (NDM) in cranberries has a potent anti-adhesion property that prevents biofilm formation. The NDM contains 65% proanthocyanidin-like compounds, which accounts for anti-adhesive property. The biofilm formation was inhibited by cranberry polyphenol fraction. Also mouthwash supplemented with NDM decreased total bacterial count and S. mutans count. The NDM also inhibited the adhesion of S. sobrinus to saliva-coated hydroxyapatite. These experiments indicate that the polyphenol fraction or NDM in cranberry can prevent or reduce the biofilm formation mostly by counteracting the bacterial adhesion to dental enamel (Petti and Scully, 2009). Cranberry NDM can also inhibit periodontal diseases because of its anti-inflammatory properties. The experiments conducted by Bodet and coworkers suggested that NDM fraction inhibits the production of proinflammatory cytokines by macrophages stimulated with lipopolysaccharides (Bodet et al., 2008). Cranberry polyphenols are suggested to play a role in reducing the release of bacterial toxic products.
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Figure 30.1 illustrates the mechanisms by which cranberry prevents periodontitis (Bodet et al., 2008). Milk and milk products: Bioactive peptides are embedded in milk protein, especially in the casein fraction, which are capable of inhibiting bacterial growth (Guggenheim et al., 1999). The diets containing casein could inhibit the growth of S. sobrinus and alter overall bacterial composition of plaque in rats (Guggenheim et al., 1999). Glycomacropeptide (GMP), a major component of cheese whey protein, can prevent the adhesion of carcinogenic bacteria and also alter the microbiota of plaque favorably. Other milk proteins such as lactoferrin, lactoperoxidase, and lysozyme also have antibacterial properties. Also, casein phosphopeptide can reduce enamel demineralization and promote remineralization by stabilizing the calcium phosphates in the plaque (Reynolds, 1997). Tea: Black tea contains theaflavin that is produced by the oxidation of catechins during the manufacturing process. In vitro and in vivo experiments have shown that catechins have an inhibitory effect on bacterial enzymes such as amylase and glucosyl transferase and thus prevent bacterial propagation and adhesion. Although human studies have remained inconclusive, some of those studies have exhibited a correlation between tea drinking and reduced plaque scores (Petti and Scully, 2009). Honey (Molan, 2001): Honey has been used for the treatment of skin wounds, ulcers, and burns throughout the ages. Hydrogen peroxide in honey is responsible for the
Streptococci adhesion to enamel ·Inhibits bacterial enzymes and
Bacterial multiplication and tissue distruction ·Inhibits bacterial proteolytic
glucan binding protein activity
enzymes – gingipain, dipeptidyl peptidase IV, trypsin, and chymotrypsin like enzymes
·Reduces the hydrophobicity of oral streptococci ·Partially inhibits acid production
Prevents dental caries
Coaggregation of streptococci ·Inhibits bacterial pairs in which one or both are Gram-negative anaerobic bacteria
Cranberry polyphenols
Prevents periodontal diseases
Modify host responses ·Reduces pro-inflammatory cytokines, nitric oxide, and reactive oxygen species production ·Inhibits production and activity of matrix metalloproteinases
Figure 30.1 Scheme showing proposed mechanisms by which bioactive compounds in cranberry inhibit localization of pathogens involved in the initiation and development of periodontitis. Modified from Figure 2 in Bodet, C., Grenier, D., Chandad, F., et al., 2008. Potential oral health benefits of cranberry. Critical Reviews in Food Science and Nutrition 48, 672–860, Taylor and Francis Group, LLC.
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antibacterial activity. Honey also has antioxidants that could reduce the damage due to free oxygen radicals during periodontitis. Probiotics: These are the bacteria that potentially benefit human health on ingestion. Several species under genus Lactobacillus as well as other genera have been studied in context of oral health. Some examples are L. paracasei, L. rhamnosus, L. lactis, L. reuteri, L. brevis, L. helveticus, Weissella cibaria, and Streptococcus thermophilus. Probiotic organisms inhibit the growth of pathogenic organisms, by competing and displacing them from biofilms and thus prevent their adhesion. L. reuteri can prevent gingivitis and gum bleeding (Krasse et al., 2006). Probiotic strains could also prevent periodontal, halitosis, or oral malodor and inhibit the production of toxins by pathogenic strains of bacteria.
3. ESOPHAGEAL AND GASTRIC DISEASES The esophagus (Martini, 2006) is a flattened muscular tube that connects the pharynx to the stomach. It is lined by mucosal membrane that secretes mucus to lubricate and move the food bolus. The peristaltic movement of the esophagus propels the food to the stomach. The lower and upper sphincters in the esophagus prevent retrograde movement of food. The stomach (Martini, 2006) is the muscular sac lying between the esophagus and small intestine. Glands in the stomach wall secrete mucus, enzymes, and hydrochloric acid, which help in the digestion of food. The muscular wall of the stomach aids in churning and evacuating its contents into the small intestine.
3.1 Gastric Esophageal Reflux Disease and Barret's Esophagus Reflux of gastric contents into the esophagus (esophagitis) develops from either dysfunctional esophageal motility or improper functioning of lower esophageal sphincter or both (Herbella and Patti, 2010). Common symptom of gastric esophageal reflux disease (GERD) is heartburn. The incidence of GERD is 10–20% among Western population (Dent et al., 2005). In Asian population, the rate was less than 5% in 2005, but has reached 8.5% by 2010 (Jung, 2011). This increase could be a reflection of changes in lifestyle and eating habits in recent years due to changing socio-economic structure or due to improvement in reporting and record keeping or both. Occurrence of GERD is highly correlated to obesity and diabetes mellitus, which are on rise globally (Dent et al., 2005). Complications of GERD include stomach and esophageal ulcers and Barrett’s esophagus. Gastric and esophageal ulcers are discussed later under the Section 4.1. Barrett’s esophagus is an abnormal benign change in the epithelial cell morphology (metaplasia) of the lower esophagus typically in response to chronic acid exposure in GERD. Metaplastic cells can potentially progress to develop dysplasia, and then malignant neoplasia (cancer). About 10–15% of GERD patients develop Barrett’s disease and are, therefore, at an increased risk for developing esophageal adenocarcinoma, a particularly lethal cancer
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(Oh and Demeester, 2010). Current treatment options for Barrett’s and GERD include antacids, H2 blockers, and proton-pump inhibitors (PPIs). The disease could be better managed by life style and dietary changes such as reducing body weight, carbonated drinks, citrus fruits, and smoking. Surgery could be beneficial if other treatments fail (Oh and Demeester, 2010).
3.2 Bioactive Foods for Esophageal and Gastric Diseases Neem (Azadiracta indica): Neem bark extract has shown potent antisecretory and antiulcer properties in animals and human (Bandyopadhyay et al., 2004; Maity et al., 2009; Malfertheiner et al., 2009). Lyophilized bark extract at 30-mg daily oral dose for 10 days significantly reduced gastric acid secretion in patients with chronic acid reflux and gastric ulcers. Further experiments are required to identify the bioactive compounds in neem bark extract. Morinda citrifolia aqueous fruit extract: Morinda fruit (Noni fruit) extract containing the bioactive compound scopoletin showed antisecretory and antiulcer properties in rats (Mahattanadul et al., 2010). Asparagus racemosus: Crude extract derived from Asparagus racemosus administered orally at 100 mg kg1 reduced ulcers in rats that compared with the effects of Ranitidine, a current prescription drug. The extract also decreased gastric acid secretion (Bhatnagar and Sisodia, 2006).
3.3 Helicobacter pylori Infection H. pylori colonize gastric mucosa. These organisms enzymatically metabolize urea into ammonia, thereby neutralizing the acidic environment in the stomach (Wroblewski et al., 2010). The infection is prevalent in 50% of the world population but often do not produce apparent symptoms. Among long-term carriers, 10% develop peptic ulcers and 1–3% may develop gastric adenocarcinoma (Uemura et al., 2001). Although the symptoms are not specific to H. pylori infection, the disease could be suspected if there is severe abdominal pain, nausea, vomiting, weight loss, and bloating. Treatment for H. pylori infection is indicated for gastric and duodenal ulcer, dyspepsia, patients on long-term nonsteroidal anti-inflammatory drug (NSAID) therapy, atropic gastritis, gastric cancer, unexplained iron-deficiency anemia, and gastric mucosa-associated lymphoid tissue lymphoma. Antimicrobial agents in combination with PPIs are used successfully to treat H. pylori infection. However, resistance to these drugs is increasing and alternate antimicrobial and gastroprotective agents are being developed.
3.4 Bioactive Foods Against H. pylori Infection Bioactive components do not eradicate the bacteria, but are useful when used in combination with antibiotics. Bioactive foods provide an alternate solution for the growing
Gastroprotective Effects of Bioactive Foods
antibiotic resistance. The major bioactive foods against H. pylori infection as substantiated by research are as follows: Cranberry and grape extracts: The NDM fraction of cranberry extract rich in plant polyphenols inhibits H. pylori adhesion to gastric mucosa in vitro (Burger et al., 2000) in an NDM-concentration-dependent and bacterial strain specific manner. It was observed that the bacteria went into a coccoid form after NDM treatment and were unable to proliferate likely due to this morphological change (Matsushima et al., 2008). The polyphenolic extracts from grapes containing resveratrol also showed inhibitory effect on H. pylori growth (Brown et al., 2009). Probiotics: Probiotics inhibit the growth of H. pylori by multiple mechanisms (Lesbros-Pantoflickova et al., 2007). Some of the probiotic organisms synthesize antibacterial compounds such as bacteriocin, which is capable of inhibiting H. pylori growth. Also the end products of bacterial fermentation, especially lactic acid, inhibits H. pylori urease enzyme, lowers pH, and creates unfavorable environment for H. pylori growth. Another proposed mechanism is that probiotics such as L. johnsonii La1, L. salivarius, L. acidophilus, and W. confuse compete with H. pylori for adhesion to gastric epithelium (Lesbros-Pantoflickova et al., 2007). Probiotic bacteria also increase the mucin production in stomach. This thickens the gastric mucosal layer, which acts as a physical barrier against H. pylori colonization (Lesbros-Pantoflickova et al., 2007). The summary of clinical trials that used probiotics in combination with antibiotics is given in Table 30.1. (Gotteland et al., 2006). In a separate study where probiotics were supplemented to a standard triple therapy (two antibiotics and a PPI), supplementation improved H. pylori eradication rate, and lowered side effects such as nausea, diarrhea, and taste disturbance that are generally associated with the triple therapy (Song et al., 2010). Dairy products: Human trials have demonstrated that bovine lactoferrin has beneficial effect on H. pylori eradication. Whey protein isolates such as GMP, a-lactalbumin, and lactoperoxidase could also inhibit H pylori growth, but further research is warranted to obtain conclusive results. Kefir, a fermented milk product, is proposed to have antimicrobial, antimutagenic, and anticarcinogenic properties (Bekar et al., 2011) but further research is needed to establish the dose range and mechanism of such biological activities.
4. INTESTINAL DISEASES The small intestine is divided into three parts: duodenum, jejunum, and ileum (Martini, 2006). Mucosal layer of small intestine is modified into villi, finger-like projections, which increases the surface area for absorption of nutrients. The mucus from the goblet cells in the mucosa protects the intestine from acid in the chime (digesta from the stomach). Digestion of food is completed in the small intestine and the digested wastes are moved into the large intestine. Large intestine has three parts: cecum, colon, and rectum. Illeocecal valve at the juncture of the two intestines prevents the retrograde flow of chime from cecum to ileum.
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Table 30.1 Summary of Clinical Trials that used Probiotics in Association with Antibiotics for the Treatment of H. pylori Colonization Study design Subjects Eradication therapy Probiotic Results
RCT
Dyspeptic adults
Rabeprazole, clarithromycin, amoxicillin
Lactobacillus acidophilus LB for 10 days
RCT
Asymptomatic adults
Pantoprazole, clarithromycin, tinidazole
L. rhamnosus GG for 10 days
RCT
Dyspeptic adults
DBPC
Asymptomatic adults
Lansoprazole, clarithromycin, amoxicillin Rabeprazole, clarithromycin, tinidazole
DBPC
Asymptomatic adults
Clarithromycin
RCT
Dyspeptic patients with resistant H. pylori infection H. pylori positive
Esomeprazole or pantoprazole, ranitidine bismuth citrate, amoxicillin and tinidazole Esomeprazole Clarithromycin Amoxycillin Pantoprazole, clarithromycin, Amoxycillin Amoxycillin, Clarithromycin, Omeprazole
L. acidophilus LA5 þ B. lactis for 4 weeks L. rhamnosus, Saccharomyces boulardii Lactobacillus þ B. lactis for 2 weeks L. johnsonii LA1 acidified milk for 3 weeks L. casei DG for 10 days
DBPC
RCT
Symptomatic children
RCT
H. pylori symptomatic
L. casei for 4 weeks
L. acidophilus, L. rhamnosus BID for 20 days S. boulardii for 4 weeks
E.R.: increased A. E.: no effect E.R.: no effect A:E.: decreased E.R.: increased E.R.: no effect A:E.: decreased E.R.: no effect E.R.: no effect A:E.: decreased E. R: no effect E.R: increased E.R.: increased A.E.: decreased
Abbreviations: E.R., eradication rate; A.E., adverse effects; RCT, randomized clinical trial; DBPC, double-blind placebo controlled. Information for the table is obtained from Gotteland et al. (2006), Song et al. (2010), and Zou et al. (2009).
Most of the water in the digesta is absorbed in the large intestine, although a small amount of water is absorbed in the small intestine. Large intestine harbors bacteria that can ferment carbohydrates and fiber that are not digested in the small intestine.
4.1 Peptic Ulcer Disease Peptic ulcer disease (PUD) includes esophageal, gastric, and duodenal ulcers. Among these, esophageal ulcers are least common and are mostly associated with GERD.
Gastroprotective Effects of Bioactive Foods
Common cause for gastric ulcers and proximal duodenal ulcers is H. pylori infection (Malfertheiner et al., 2009). General causes of all types of ulcers include side effects of drugs (NSAIDs, some antibiotics, and metronidazole), chronic vomiting, infections, and idiopathic origin. In the elderly, 70% of PUD patients are H. pylori positive and 40% of peptic ulcers are caused by NSAID or other drugs. About 20–25% of PUD incidences are idiopathic of origin (Pilotto et al., 2010).The annual incidence of physician-diagnosed cases of PUD range from 0.1 to 0.19% of the global population (Sung et al., 2009). Clinical manifestations for PUD are age related and often nonspecific (Pilotto et al., 2010). The most common symptom is epigastric pain. One-third of the patients also experience heartburn. Other symptoms include fullness, bloating, satiety, and nausea. Peptic ulcers could lead to bleeding and this occurs more in elderly patients (Malfertheiner et al., 2009). Two-thirds of elderly patients have atypical symptoms while only one-third experience epigastric pain. The diagnosis of PUD could be delayed in elderly patients if only atypical symptoms are manifested (Pilotto et al., 2010). The treatment of PUD is planned according to the causative factor. Treatment regimen for ulcers due to H. pylori and GERD are described in the earlier sections. Peptic ulcers due to NSAID therapy could be treated with PPIs such as omeprazole and histamine blockers such as ranitidine accompanied by discontinued use of the NSAID. Ulcers of idiopathic origin are also treated with PPI and histamine blockers (Malfertheiner et al., 2009).
4.2 Bioactive Foods Beneficial in PUD The bioactive compounds discussed under H. pylori infection and GERD are also beneficial for PUD treatment. Studies have shown that apple extract (D’argenio et al., 2008) and turmeric have beneficial effects toward treating gastric ulcers. Turmeric (Curcuma longa) is a rhizomatous herbaceous perennial plant of the ginger family and is a common Indian spice that is used in traditional folk medicine for treatment of various diseases. The turmeric extract has the ability to reduce gastric ulcer incidences in animal models by blocking histamine receptors (Kim et al., 2005). The important bioactive compound in turmeric is curcumin which is not, however, readily bioavailable when consumed as food.
4.3 Inflammatory Bowel Disease Inflammatory conditions of the GI-tract are collectively termed as inflammatory bowel disease (IBD). The two predominant forms of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). UC is confined to the large intestine with inflammation occurring primarily in the mucosal lining, while CD can affect any part of the alimentary tract with transmural inflammation. Although there are some unique symptoms distinguishing each disease, many of the symptoms in UC and CD are shared. IBD affects all age groups across
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the nations. A unimodel distribution with 15–30 years of age for IBD onset is the recent trend. But there could be a small second peak occurring at 40–70 age groups for UC (Sands and Grabert, 2009). The disease is more prevalent in North America and Western Europe. There are about 1.4 million patients in North America with 30 000 new cases reported annually. Prevalence of CD is higher in females, while UC occurs more in males. Also higher incidence of both CD and UC are noted among higher socioeconomic classes. Recent studies indicated that although the Caucasians are more affected, the gap between prevalence among Caucasians and African–Americans is diminishing (Sands and Grabert, 2009). The precise cause of IBD is unknown but hypotheses linking the etiology to environmental changes, dietary habits, immunologic factors, smoking, and genetic predisposition exist. Exposure to pollution, industrial waste, smoking, and sunlight is cited as major contributing factors for the development of IBD (Hanauer, 2006). Better sanitation and lesser exposure to infective agents are positively correlated to higher incidence rate. The intestinal microbiota may be altered in these cases rendering these individuals susceptible to IBD. Dietary habits such as higher fat and refined sugar consumption are also indicated as causative factors but remain inconclusive. Familial disposition to the disease ties IBD to genetic factors (Hanauer, 2006; Sands and Grabert, 2009). Symptoms of IBD that typically occur in alternate cycles of flare and remission include mild-to-severe diarrhea, blood in stool, pain associated with abdominal cramps, and severe urgency to have a bowel movement. Loss of appetite and weight loss are also common. IBD is a risk factor for anal fissures, fistulas, and cancer. Skin lesions, arthritis, and liver disorders could also occur as associated complications of IBD. Current treatments aim at reducing frequency, duration as well as intensity of flares and prolonging remission. Medications used in IBD therapy are anti-inflammatory agents, antibiotics, immunomodulators, and biologics. Majority of the patients will require surgery in advanced stages. Along with these conventional therapeutic agents, bioactive foods could yield additional support to alleviate the condition.
4.4 Bioactive Foods for Treatment of IBD Cruciferous vegetables: Phenethyl isothiocyanate (PEITC) is an organosulfur bioactive compound found in cruciferous plants. PEITC can suppress the expression of inflammatory markers in mammalian cells and has the potency comparable to aspirin in alleviating in vivo inflammation (Dey et al., 2006). The effectiveness of PEITC essential oil (PEO) in the treatment of acute and chronic UC as compared to a current prescription drug (5-amino salicylic acid) was investigated in mouse models (Dey et al., 2010). The response to treatment was expressed as disease activity index (Figure 30.2), reflecting five clinical signs: change in body weight, stool consistency, fecal occult blood, visible rearend bleeding and inflammation, and rectal protrusion. PEO reduced inflammation,
Gastroprotective Effects of Bioactive Foods
arrested intestinal bleeding, and helped in remission of the disease. Also expression of proinflammatory cytokines was downregulated by PEO in the mouse colon. The future direction of this study would be to follow up with effects of PEO in humans. Tea: Studies with chemically induced and genetically predisposed IBD mouse models have shown the efficacy of black and green tea extracts to reduce the severity of inflammation and weight loss (Ishihara et al., 2009; Varilek et al., 2001). But the dosage used in these experiments could be achieved only if an individual drinks 100–200 cups of tea every day. Hence, these results need validation in human beings and also the appropriate therapeutic dose needs to be established. Grape: Grape skin and seed contain 50–100 mg g1 of resveratrol, a phenolic compound. This compound is also present in grape wine, some berries, and nuts. Resveratrol has the ability to inhibit proinflammatory cytokine tumor necrosis factor-a, and inflammatory pathways involving cyclo-oxygenase 1 (Das and Das, 2007). In rats, resveratrol reduced the damage due to trinitrobenzene-induced colitis. A significant increase in the apoptosis of cells involved in colitis was also noted (Martin et al., 2006). But the low Acute model
(a) Induction
Chronic model
(b)
Treatment
Induction
Treatment
Disease activity index (DAI)
6 6 4 4
2
2
0
0 −5
0
5 Days
10
−30
15
Water DSS
−20
−10 Days
0
10
PEO 5-ASA
Figure 30.2 Effects of orally administered phytocompound PEO and a common prescription drug 5ASA on the disease activity index (DAI) in DSS-induced colitis in a mouse model study. Significance of treatments in PEO and 5-ASA groups in respect to diseased but untreated (DSS) group and are indicated by p < 0.05 and p < 0.01 and p < 0.001. Healthy control group from the study is also shown. Clinical signs included in the DAI score represent many of the human colitis symptoms: (a) acute colitis model. Data as mean SEM (n ¼ 6) are shown at 5-day intervals. (b) Chronic colitis model. Data as mean SEM (n 10) are shown at 3- and 2-day intervals during induction and treatment periods respectively. Amino salicylic acid, ASA; disease activity index, DAI; standard error mean, SEM. Reproduced from Dey, M., Kuhn, P., Ribnicky, D., et al., 2010. Dietary phenethylisothiocyanate attenuates bowel inflammation in mice. BMC Chemical Biology, 10, 4.
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bioavailability of resveratrol in body tissues and fast clearance rate from the body remains a challenge in using it for treatment of IBD in humans (Udenigwe et al., 2008). Fish oil and flax seed oil: These oils are rich in omega-3 fatty acids that have proven anti-inflammatory and immunomodulatory properties. However, animal efficacy studies using omega-3 fatty acids for treatment of IBD yielded inconclusive results (Calder, 2006). Whey culture: The milk whey culture using Propionibacterium freudenreichii ET-3 contains bioactive substance called 1,4-dihydroxy-2-naphthoic acid (DHNA). This compound can stimulate the growth of Bifidobacteria in humans and animals. DHNA reduced the severity of trinitrobenzene-sulfonic-acid-induced colitis (Uchida et al., 2007). Pomegranate: A recently concluded study in rats with dextran sodium-sulfateinduced colitis evaluated the use of pomegranate extract. It was found that both pomegranate extract and urolithin-A, a microbiota-derived metabolite from pomegranate, reduced the severity of colitis (Larrosa et al., 2010). Licorice: Ethanolic extract of licorice contains anti-inflammatory compound glabridin. Mice with dextran sodium-sulfate-induced colitis were treated for 7 days with the extract and this resulted in reduced weight loss, decreased mortality, and prevented shortening of colon (Kwon et al., 2008). Turmeric: Curcumin, the bioactive compound in turmeric, has been used in animal and human research for treating IBD. Studies with chemically induced colitis animal models suggested that curcumin could alleviate the symptoms of IBD. Curcumin also had beneficial effects at a concentration of 1000–1500 mg per day in a small human study. However, larger clinical trials are needed for conclusive efficacy and bioavailability of curcumin in IBD (Hanai and Sugimoto, 2009). Probiotics: Numerous independent studies have been conducted to evaluate the efficacy of probiotics in IBD treatment and remission but the results are inconsistent. A review on experiments conducted suggested that probiotics used in combination with standard therapy yielded positive results. But this beneficial effect is not obtained when probiotics are used alone (Cary and Boullata, 2010). Another study indicated that a combination of eight strains of probiotic bacteria was effective in the maintenance of remission of IBD, while any single strain of bacteria did not yield beneficial effects (Haller et al., 2010). Prebiotics: Dietary fibers that could be utilized by bacteria in the colon are termed as prebiotics. Bacteria ferment the fiber and produce metabolites. Short-chain fatty acids such as acetate, propionate, and butyrate are the major metabolites of bacterial fermentation in the colon. In vitro and in vivo studies indicate that butyrate has anti-inflammatory and antitumor properties. The hypothesis that dietary fiber is effective in the attenuation of IBD relies on these known properties of butyrate (Rose et al., 2007). Dietary fibers from sources such as oat bran (Hallert et al., 2003), psyllium seeds, inulin, and
Gastroprotective Effects of Bioactive Foods
oligofructosaccharides (Leenen and Dieleman, 2007) alleviated the symptoms of UC. Some experiments yielded conflicting results on the efficacy of dietary fiber for IBD treatment. This could be due to the presence of abnormal microbiota in IBD patients. Further evaluation of the efficacy of combination therapy using prebiotics and probiotics (together termed as synbiotics) is needed. Also the strains of bacteria and type of fiber that should be given as combinations for optimal effects remains to be determined. Both these agents have excellent safety profile and no known side effects.
5. GI CANCER 5.1 Oral, Pharyngeal, and Esophageal Cancer Approximately 30 000 new cases of oral and pharyngeal cancer and 13 000 new cases of esophageal cancer are reported annually in the United States (Greenlee et al., 2001). About 90% of oral and pharyngeal cancer is squamous cell carcinoma. Both squamous cell carcinoma and adenocarcinoma occur in esophagus. The common etiology of these tumors is smoking, alcohol consumption, tobacco and betel nut chewing, as well as dietary, genetic, and environmental. Vitamins, fruits, vegetables, tea, and coffee have been shown to have protective effect against oral cancer (Chainani-Wu, 2002). Diversified diets are highly recommended to achieve protection against these multifactorial diseases.
5.2 Gastric Cancer Worldwide incidence of gastric cancer has declined over last few decades (Everhart, 2008). This could be due to availability of efficient diagnostic tools such as endoscopy for precancerous signs and surgical removal options of these precancerous cells and tissues. The two main sites for gastric adenocarcinoma are proximal and distal stomach. The major risk factors are H. pylori infection, dietary factors, tobacco, obesity, familial predisposition, and radiation exposure (Crew and Neugut, 2006). Intake of antioxidants such as vitamin C and E provides protection against gastric cancer. Annual endoscopic screening in high risk groups may help to detect the tumors in early stage and mortality could be reduced (Crew and Neugut, 2006).
5.3 Colorectal Cancer Although incidences of colorectal cancer are declining in the recent years, still it ranks second in causing death among all cancers in the United States (Everhart, 2008). The average lifetime risk of developing colorectal cancer for a person is 5.12%. Genetic, environmental, and dietary factors contribute to the development of the disease. The normal colon mucosa is lined by columnar cells and forms invaginations or crypts. When exposed to carcinogenic factors, proliferative cells in the crypts lose the ability to control cell division and leads to the formation of aberrant crypt foci (ACF) or polyps. These
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polyps are the early markers of cancer risk and have the potential to develop into adenoma and adenocarcinoma if left untreated. Periodic screening for ACF is an effective tool for early diagnosis. If detected early, surgical intervention is possible.
5.4 Bioactive Food Components in Prevention of GI Cancer Black Raspberry: Addition of black raspberry in diet for 2 weeks reduced dimethylsulfoxide-induced oral tumor incidence in hamsters (Casto et al., 2002). Black raspberry contains various anticarcinogenic agents such as ellagic acid, vitamin E and C, ferulic acid, and folic acid. Tomato: Lycopene is the major bioactive compound in tomatoes. Human case control studies conducted in 12 countries including in the United States reported an inverse relationship between tomato or lycopene intake and gastric cancer occurrence (Giovannucci, 1999). A study in Japan that examined the plasma level of lycopene in blood indicated that regions where people have high plasma lycopene concentration had lesser incidences of gastric cancer and vice versa. Tomato consumption exhibits the most consistent negative association to gastric cancer among all vegetable and fruit consumption data (Giovannucci, 1999). Tea and coffee extracts: Bioactive compounds in tea leaf extracts include gallic acid kaempferol, quercetin, catechin, epicatechin, oleic acid, palmitic acid, linoleic acid, and linolenic acid. When the oral squamous carcinoma cells were treated with tea leaf extract, it induced apoptosis or cell death (Chia et al., 2010). The proapoptotic genes were upregulated and anti-apoptotic genes were downregulated, likely due to the presence of polyphenols. Prebiotics: Dietary fibers include inulin, resistant starch, cellulose, hemicelluloses, and pectins. Rich sources of dietary fiber include bran, fruits, vegetables, nuts, legumes, seeds, and berries. Dietary fibers are fermented by colon bacteria to produce short-chain fatty acids such as butyrate with known anticarcinogenic property. The suggested mechanism of the action of butyrate is given in Figure 30.3 (Andoh et al., 2003). Fiber also increases the fecal bulk and decrease transit time. This will reduce the exposure time of intestinal mucosa to mutagens that lead to the development of cancer. Probiotics and synbiotics: Bifidobacterium lactis, Lactobacillus bulgaricus, Streptococcus thermophilus, L. casie, L. acidophilus, L. gassrei, B. breve, Streptococcus cremoris, and S. lactis are shown to reduce colon cancer risk. Combination of L. rhamnosus and B. lactis with inulin given for 33 weeks reduced the number of azoxymethane-induced colon carcinomas in rats (Wollowski et al., 2001). Cruciferous vegetables: This includes cabbage, broccoli, cauliflower, kale, Brussels sprouts, and watercress. These vegetables contain bioactive compounds such as folate, vitamin C, tocopherols, carotenoids, glucosinolates, isothiocyanates, and polyphenols. Glucosinolates metabolize to produce isothiocyanates and indoles, which possess potent
Gastroprotective Effects of Bioactive Foods
Butyrate (short chain fatty acid)
Anti-inflammatory actions
Provides energy to colonocytes
Anti-carcinogenic mechanisms
Inhibits histone deacetylation and alters gene expression
•Stimulate cell proliferation – could be helpful in ulcerative colitis
• p21, NFκB
Inhibits NFκB •Suppresses inflammation •Favors apoptosis
Inhibits decayaccelerating factor expression •Increases cell death through complement pathway
Figure 30.3 Scheme showing proposed anti-inflammatory mechanisms of butyrate, a by-product of dietary fibers and prebiotics. Modified from Figures 3 and 5 in Andoh, A., Tsujikawa, T., Fujiyama, Y., 2003. Role of dietary fiber and short-chain fatty acids in the colon. Current Pharmaceutical Design, 9, 347–58, published by Bentham Science Publishers Ltd.
anticarcinogenic property. Isothiocyanates such as sulforaphane are cytotoxic and indoles are cytostatic (Pappa et al., 2007).
6. CONCLUSION Consumption of fruits, nuts, and vegetables offer protective benefits against GI diseases (Jedrychowski et al., 2010). But intake of whole food that contains bioactive compounds does not always guarantee GI health protection. Concentration of these health-benefiting compounds in food might vary and can be lower than that required to elicit a therapeutic effect. Additionally, bioavailability parameters may vary depending on the form consumed, such as cooked versus raw, and other factors. Scientifically established standardized processing of these bioactive agents into supplements may help to overcome some of these hurdles. Genetic makeup of an individual may determine how much benefit can potentially be derived from the intake of fruits and vegetables or even processed supplements. This concept has given birth to the newer research field of nutritional genomics, which provides the tools and framework to study diet–gene interactions (Debusk, 2010). Advancement in this direction could ultimately provide guidelines for individualized diet
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plans to deliver healthy dosage of bioactive compounds and the quantity of whole food containing bioactive compounds. It is generally accepted that bioactive compounds could provide a safer alternative to prevailing chemotherapeutic agents that are known to have side effects. While this is partially true given the existing history of human use and folklore in many cases, toxic concentration and pharmacological dose must be established before the purified bioactive substances are marketed. An extensive body of research has demonstrated the ability of bioactive agents to modulate pathophysiological processes producing GI health benefits. However, many of these investigations relied on in vitro or preclinical observations. Controlled human trials must be conducted in future to validate these observations and scientifically establish the potential health-promoting benefits.
ACKNOWLEDGMENTS This work was made possible by funds from National Institutes of Health [grant # R00 AT004245], United States Department of Agriculture [#328100], and South Dakota Agriculture Experiment Station [# 318000]. The authors are also thankful to numerous authors who have contributed to the research in the field of gastric diseases and effects of bioactive compounds in gastrointestinal disorders. Owing to word limitation, the authors were unable to cite many excellent research contributions. Therefore, they urge the readers to cross reference from within the cited articles.
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RELEVANT WEBSITES http://www.ccfa.org/ – Crohn’s & Colitis Foundation of America Disease Information. (accessed 07.01.2011). http://www.ccfa.org – Crohn’s & Colitis Foundation of America. Epidemiology. (accessed 07.01.2011). http://seer.cancer.gov/statfacts/ – Lifetime risk for colorectal cancer information. (accessed 07.01.2011).
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