Description of retrospective case-control studies of grain legume consumption and colorectal neoplasia.
Abstract
Grain legume consumption has been linked in meta-analysis studies to decreased risk of metabolic syndrome, obesity, and cardiovascular diseases; however, the evidence for a chemo-protective effect of grain legume consumption against colorectal tumorigenesis has been considered inconclusive. We conducted a meta-analysis of human and animal studies to evaluate the effect of grain legume consumption on colorectal cancer (CRC) and its precursors. Twelve case-control studies (42,473 controls and 12,408 cases) and 11 prospective cohorts (1,533,527 participants including 12,274 cases) were included in the meta-analysis; the pooled risk ratio (95% confidence interval) for the highest versus the lowest legume intake group based on a random effects model was 0.72 (0.60–0.89) for incident adenoma, 0.91 (0.84–0.99) for prevalent adenoma, and 0.82 (0.74–0.91) for CRC. Fourteen animal studies (355 animals on grain legume diets and 253 animals on control diets) were included in the meta-analysis and showed in all but one study a chemo-preventive effect against colorectal tumorigenesis. Grain legumes contain various compounds (e.g., resistant starch, soluble fiber, insoluble fiber, phytosterols, saponins, phytates, flavonoids, proanthocyanidins, and phenolic acids) that have been shown to inhibit colorectal tumorigenesis in animal studies at concentrations that are relevant for human diets. Grain legume consumption alters several molecular pathways (e.g., p53, mTOR, NF-kB, Akt, and AMPK) that are critical for tumor induction, promotion, and progression. Based on our meta-analysis, daily grain legume consumption confers chemo-preventive effects against CRC.
Keywords
- grain legumes
- colorectal cancer
- meta-analyses
- bioactive compounds
- molecular mechanisms
1. Introduction
Grain legumes (i.e., pulses) are defined as plants belonging botanically to the family
Grain legume consumption dramatically decreased in westernizing countries [9] and is in the U.S., similar to other Western countries [10, 11], on average low (12.9 g/d) and infrequent (only 8 and 14% consumed grain legumes daily or every other day) [6, 12]. Given the health-promoting properties and nutrient profile of grain legumes and the growing interest in ethnic, gluten-free, and vegetarian cuisine in Western countries, increasing grain legume consumption represents an important public health opportunity for chronic disease prevention.
A research focus is the use of legumes for cancer prevention, specifically colorectal cancer (CRC) [4]. Globally, CRC is the third most common cancer in men and the second most common in women [13]. Two recent A meta-analysis study reported a protective effect of legume consumption for colorectal adenomas (CRAs) in case-control and cohort studies (combined odds ratio (OR) = 0.83; 95% confidence interval (CI): 0.75–0.93) and CRC in cohort studies (OR = 0.91; 95% CI: 0.84–0.98) [14, 15]. Both meta-analysis studies, however, included studies in which participants consumed legumes primarily as soy products (i.e., studies conducted in China, Japan, Malaysia, and South Korea), as opposed to grain legumes (i.e., studies conducted in Africa, North and South America, and Europe). Moreover, the meta-analysis of CRC showed a protective effect for soybeans (OR = 0.85; 95% CI: 0.73–0.99) but not for other beans (OR = 1.00; 95% CI: 0.89–1.13) [15]. A third meta-analysis study published in 2010 reported no statistically significant association between legume fiber consumption and CRC in four prospective U.S. and European studies combined (OR = 0.89; 95% CI: 0.78–1.02) [16].
The objective of this chapter is to evaluate the evidence of a chemo-preventive role of grain legume consumption in colorectal tumorigenesis in human (ecological, case-control, and cohort studies) and animal studies by conducting a literature review and meta-analyses. The goal is to suggest areas of future research and provide up-to-date scientific evidence for dietary recommendation of legume consumption.
2. Colorectal cancer: incidence, mortality, and risk factors
Worldwide, annually 1.361 million new CRC cases and 0.694 million deaths due to CRC accrue, according to GLOBOCAN in 2012 [13, 17]. In the U.S., the lifetime risk of being diagnosed with CRC is 5% and the treatment costs were estimated to be over $14 billion [18, 19], highlighting CRC prevention as a public health priority. CRC development is a multistep process over many years, often decades, involving usually random genetic mutations in colorectal epithelial cells causing the activation of tumor-promoting genes and the loss of tumor suppressor gene function [20, 21]. Starting often as aberrant crypt foci (ACF), most CRC arise from benign, adenomatous polyps (i.e., adenomas) that grow from glandular cells of the colorectal epithelial lining into advanced adenomas and then adenocarcinomas [22–24]. Over 50% of the Western population will develop colorectal adenomas (CRAs) by the age of 70 [23]. Less than 10% of adenomas, however, progress to become invasive and spread to adjacent blood or lymph vessels [25]. Success of CRC treatment depends on early detection. If CRC has not spread beyond the colorectal wall (i.e., localized stage), 5-year survival rates are 90.3%; however, survival rates decline when CRC has spread to lymph nodes and/or nearby tissue (i.e., regional disease; a 5-year survival of 70.4%) and are low when CRC has spread to other organs (i.e., distant disease; a 5-year survival of 12.5%) [26]. Currently, only 40% of CRC patients are diagnosed with localized stage, highlighting that importance of early detection and treatment of CRC and its precursors [27].
Genetics is an important CRC risk factor. About 20% of CRC patients have a family history of CRC (10–15% lifetime risk for patients with one first-degree relative; 20% lifetime risk for patients with at least two first-degree relatives or one first-degree relative diagnosed with CRC before age 45) and 2–4% have a well-defined genetic syndrome (i.e., Lynch syndrome and familial polyposis; 80–90% lifetime risk) [19]. Chronic inflammation, specifically inflammatory bowel disease (IBD), is another important CRC risk factor with a 10–20% lifetime risk, which is increased among patients with a longer IBD history [19, 28]. Other important medical CRC risk factors are obesity, insulin resistance, and diabetes mellitus; CRC risk increases linearly with duration and severity of those morbidities [19, 29–33]. Modifiable CRC risk factors include smoking, heavy alcohol consumption, and sedentary behavior, each with a 6% lifetime risk [19], whereas medications such as aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) and hormone-replacement therapy in postmenopausal women can decrease CRC risk [19].
Food and nutrition play an important part in the etiology and prevention of CRC and may account for 70–90% of all cases [34–36]. A panel of experts, primarily epidemiologists organized by the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR), evaluated the scientific evidence on food, nutrition, and physical activity on cancer risk [34]. Human studies were ordered according to the quality of the study design as follows: (1) ecological studies (lowest quality; most susceptible to confounders; i.e., factors that are associated with both disease status and the evaluated food); (2) case-control studies (very susceptible to recall bias; i.e., selective reporting of the diet after disease diagnosis); (3) Prospective cohort studies; and (4) clinical trials (gold standard and least susceptible to bias). In the case of substantial amount of evidence available, the panel focused on studies using high-quality designs. Evidence from animal and cell culture studies was taken into account to demonstrate plausible mechanism for diet and cancer association. Based on the evidence, an individual food, food group, or individual nutrient was classified for each cancer site as “convincing”, “probable”, “limited-suggestive”, or “limited-no conclusion” decreases the risk or increases the risk [34].
In 2007, the panel classified red and processed meat consumption as convincingly increases CRC risk, whereas calcium and foods containing fiber were classified as probably decreases CRC risk, and selenium and foods containing folate were classified as limited-suggestive evidence for decreasing CRC risk [34]. No conclusion was made for legumes and CRC risk because of the limited data available in 2007 [34]. As in the last 8 years more data have been collected, we reevaluate in this chapter the evidence on the relation between grain legume consumption and CRC risk. We hypothesized a protective effect of grain legume consumption on CRC risk because grain legumes are an excellent dietary source of fiber (5.7–9.0 g/100 g of cooked legumes) and folate (83–174 μg/100 g of cooked legumes) [7], both of which were classified as decreasing CRC risk in 2007 [34].
3. Grain legumes and colorectal neoplasia in human studies
Ecological studies examine the association between diet and disease on the population level; five studies evaluated the relation between legume intake and risk of CRC incidence or mortality on the population level and observed inconsistent relations [9, 37–40]. Correa reported that countries with higher bean consumption in 1964–1966 had lower colon cancer mortality rates 7–9 years later (
In case-control studies, participants with (cases) or without (controls) a disease recall their diet. Besides recalling a diet from past years, participants try to make sense of their disease outcome based on their lifestyle choices. Thus, foods and food groups that have been known to be associated with disease outcomes by the public are often erroneously associated with the disease outcome (i.e., selective reporting bias). Nineteen peer-reviewed publications (46,769 controls and 14,567 cases; two studies had each two publications [43, 44] and [45, 46]) evaluated in 17 case-control studies the relation between legume consumption and colorectal neoplasia; six studies reported prevalent adenomas as endpoint [47–52] and 11 studies reported carcinomas as endpoint [42–46, 53–60] (Table 1). Most case-control studies were from the U.S. (
Reference, region (country) |
Study period | Study design, no. controls/cases | Sex, age | Diet assessment | Grain legume, quantity for comparison, risk estimates (95% CI) | Matching/adjusting for confounders |
---|---|---|---|---|---|---|
North Carolina (U.S.) |
1988–1990 | Colonoscopy Cases: 236 Controls: 409 |
Both, ≥30 years, no CRC, IBD history |
Phone interview: FFQ with >100 food items for previous yr | Grain legume fiber Men: ≥3.14 vs. <0.97 g/d OR = 0.99 (0.43–2.29) Women: ≥2.17 vs. <0.61 g/d OR = 1.26 (0.63–2.51) |
No matching specified Adjusted for age, alcohol intake, BMI, and total energy intake |
California (U.S.) |
1991–1993 | Sigmoidoscopy Cases: 488 Controls: 488 |
Both 50–74 years; no CRA, IBD history |
Personal interview: FFQ with 126 food items for previous yr | Legumes (beans, lentils, peas, lima beans, tofu, soybeans, peanut butter) Mean 8.5 vs. 0.5 servings/wk OR: 0.85 (0.56–1.28) |
Matched by age, sex, day of sigmoidoscopy, Kaiser center Adjusted by race, BMI, physical activity, smoking, and intake of total energy and saturated fat |
Minnesota Cancer Prevention Research Unit Study (U.S.) |
1991–1994 | Colonoscopy and population Cases: 564 Controls: 682 colonoscopy, 535 population |
Both, 30–74 years, no CRA, IBD history | Self-administered FFQ precolonoscopy with >153 food items for previous yr | Legumes (alfalfa sprouts, beans, peas) Men: Mean 5.0 vs. 1.0 servings/wk Colonoscopy: OR = 0.96 (0.62–1.49) Population: OR = 1.15 (0.77–1.72) Women: Mean 5.5 vs. 1.1 servings/wk Colonoscopy: OR = 1.08 (0.68–1.74) Population: OR = 0.96 (0.58–1.59) |
Matched by age, sex, and residence Adjusted for age, total energy and fat intake, BMI, smoking, alcohol, NSAID use, multivitamin use, and hormone replacement therapy |
African-American (U.S.) |
2001–2003 | Colonoscopy Cases: 53 Controls: 133 |
Both, 29–81 years |
FFQ with 39 food items (Rate Your Diet Quiz) | Grain legumes (dry beans, split peas, lentils) ≥3× vs. ≤1×/wk OR = 0.19tab1_1 (0.04–0.91) |
No matching specified Adjusted for age, smoking, alcohol, sex, weight, aspirin use, alcohol, family CRC history, and exercise |
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) |
1993–2001 | Sigmoidoscopy Cases: 3057 Controls: 29,413 |
Both, 55– 74 years; no CRA, IBD history |
Self-administered FFQ pre-, on, or post-sigmoidoscopy with 137 food items for previous yr | Legumes (beans, peas, tofu, and soybeans) Median 0.4 vs. 0.05 energy-adjusted servings/wk OR = 0.92 (0.81–1.03) Sex and age adjusted: OR = 0.85tab1_1 (0.75–0.96) |
Matching not specified Adjusted for age, sex, race, education, family CRC history, smoking, alcohol use, aspirin use, replacement hormone use, physical activity, BMI |
[52] Tennessee Colorectal Polyp Study (U.S.) |
2003–2005 | Colonoscopy Cases: 764 Controls: 1517 |
Both, 40– 75 years, no CRA, IBD history |
FFQ with >108 food items for previous yr | Grain legumes (green beans and peas, dry and canned beans) Tertile T3 vs. T2 Quantity N/A OR = 0.95 (0.74–1.24) |
No matching specified Adjusted for age, sex, race, study location, BMI, smoking, alcohol consumption, NSAID use, physical activity, education level, family income, family CRC history, and intake or total energy and red meat |
La Plata (Argentina) |
1985–1987 | Population Cases: 110 Controls: 220 |
Both, 35– 80 years |
Personal interview FFQ with 140 food items for previous 5 yrs |
Grain legumes (beans, lentils, peas, and chick peas) Quartile 4 vs. 1 OR = 0.52 (0.24–1.12) Quartile 3 vs. 1 OR = 0.32tab1_1 (0.14–0.73) Quantity N/A |
Matched by age and gender Adjustment not specified |
Adelaide (Australia) |
1979–1980 | Population Cases: 220 Controls: 438 |
Both, 30–74 years |
Self-administered FFQ with 141 food items a yr ago | Legumes (green, dry and broad beans, lentils, dry and chick peas, and soybeans) Men: >1 vs. 0 servings/wk OR = 0.74 (0.38–1.45); Women: >0.6 vs. 0 servings/wk OR = 0.43tab1_1 (0.20–0.93) |
Matched by age and gender Adjusted for protein intake, occupation, Quetelet’s index, alcohol consumption, and age at first live birth (only women) |
(Netherlands) |
1989–1993 | Population Cases: 232 Controls: 259 |
Both, ≤75 years, no history of CR tumors |
Personal interview: FFQ with 289 food items for previous yr |
Legumes Quartile 4 vs. 1 (infrequent legume consumption) OR = 1.08 (0.67–1.76) |
Matched by age, gender, and degree of urbanization Adjustment not specified |
Hawaiian born in Japan (U.S.) |
1966–1970 | Hospital Cases: 179 Controls: 357 |
Both Age N/A |
Personal interview: four legumes, soybeans excluded |
Grain legumes (green and red beans, peas, and Chinese peas) >21× vs. <8×/mo legumes RR = 3.5tab1_1 95% CI N/A |
Matched by sex and birth place Adjustment not specified |
Milan (Northern Italy) |
1985–1987 | Hospital Cases: 339 colon, 236 rectal Controls: 778 |
Both, <75 years |
Personal interview: 29 food items prior to disease diagnosis |
Grain legumes Tertile 3 vs. 1 Quantity N/A Colon: RR = 1.04; Rectum: RR = 0.94 95% CI N/A |
Matching not specified Adjusted for social class, age, sex, and area of residence |
Majorca (Spain) |
1984–1988 | Population and Hospital Cases: 286 Controls: 203 hospital 286 population |
Both, <80 years |
Personal interview: FFQ with 99 food items for previous yr |
Grain legume fiber Quartile 4 vs. 1 Quantity N/A RR = 0.40tab1_1 95% CI N/A |
Matched by age and gender Adjusted for age, sex, body weight, and total energy intake |
Pordenone (North Eastern Italy) |
1986–1990 | Hospital Cases: 123 colon, 125 rectal Controls: 699 |
Both Age not specified |
Personal interview: FFQ (number of food items N/A before disease) onset |
Grain legumes Tertile 3 vs. 1 Quantity N/A Colon: RR = 1.2 Rectum: RR = 0.8 95% CI N/A |
Matched by hospital Adjusted for age, gender, and social status |
Hawaii Multiethnic (U.S.) |
1987–1991 | Population Cases: 1192 Controls: 1192 |
Both <85 years, no history of colorectal tumors |
Personal interview: FFQ with 282 food items 3 yrs before disease onset |
Legumes (including soy products) Men: >46 vs. <11 g/d OR = 0.8 (0.5–1.2) Women: >44 vs. <9 g/d OR = 0.5tab1_1 (0.3–0.9) |
Matched by age, sex, and race Adjusted for age, family CRC history, alcohol consumption, smoking, physical activity, Quetelet index, and intake of total calories, eggs, and calcium |
(Italy) |
1991–1996 | Hospital Cases: 1225 colon 728 rectal Controls: 5155 |
Both Age not specified |
Personal interview: FFQ with 98 food items 2 yrs before disease diagnosis |
Grain legumes (beans and peas) >3 vs. <0.5 servings/wk Colon: OR = 0.5tab1_1 (0.4–0.7) Rectum: OR = 0.7tab1_1 (0.5–0.9) |
Matching not specified Adjusted for age, sex, center, year of interview, education, physical activity, alcohol consumption, and total energy intake |
Montevideo (Uruguay) |
1996–2002 | Hospital Cases: 484 Controls: 1452 |
Both 30–89 years |
Personal interview: FFQ with 64 food items a yr before disease diagnosis |
Grain legumes (kidney beans and lentils) Quartile 4 vs. 1 Quantity N/A Overall: OR = 0.7tab1_1 (0.5–0.9) Men: OR = 0.8 (0.5–1.2) Women: OR = 0.5tab1_1 (0.3–0.9) Colon: OR = 0.9 (0.9–1.1) Rectum: OR = 0.8tab1_1 (0.7–0.9) |
Matched on age, sex, residence, and urban/rural status Adjusted for age, sex, rural/urban status, education, first-degree family CRC history, BMI, and intake of total energy and red meat |
Montevideo (Uruguay) |
1996–2004 | Hospital Cases: 3539 Controls: 2032 |
Both 26–89 years |
Personal interview: FFQ with 64 food items a yr before disease diagnosis |
Grain legumes (kidney beans and lentils) Legume: Median 14.38 vs. 1.35 g/d OR = 0.43tab1_1 (0.32–0.59) Beans: Median 9.44 vs. 0 g/d OR = 0.44tab1_1 (0.31–0.61) Lentils: Median 11.68 vs. 0 g/d OR = 0.53tab1_1 (0.38–0.75) |
Matching not specified Adjusted for age, sex, residence, BMI, education, income, interviewer, smoking status and history, alcohol consumption, mate drinking status, and intake of total energy, dairy products, fatty foods (eggs, cake, custard, butter), fruits and vegetables, and total meat |
(Jordan) |
2010–2012 | Hospital Cases: 167 Controls: 240 |
Both >18 years |
Self-administered FFQ with 109 food and beverage items (DHQ 1) a yr before disease diagnosis |
Lentils >1× vs. <1×/wk OR = 1.49 (0.80–2.79) |
Matched by age, sex, occupation, and marital status Adjusted for age, sex, family CRC history, physical activity, smoking, education level, marital status, work, income, and total energy intake |
(Jordan) |
2010–2012 | Hospital Cases: 220 Controls: 281 |
Both >18 years |
Self-administered FFQ with 109 food and beverage items (DHQ 1) a yr before disease diagnosis | Lentils 1×/wk vs. <1×/mo OR = 1.3 (0.72–2.4) White beans 1×/wk vs. <1×/mo OR = 0.86 (0.37–2.1) Green beans 1×/wk vs. <1×/mo OR = 1.0 (0.57–2.2) Peas 1×/wk vs. <1×/mo OR = 1.0 (0.44–2.0) |
Matched by age, sex, occupation, and marital status Adjusted for age, sex, family CRC history, physical activity, smoking, education level, marital status, work, income, and total energy intake |
Meta-analysis using a random effects model of natural log odds ratios (OR) in STATA was possible for 12 case-control studies [46–52, 55–57, 59, 60] that included 12,408 cases and 42,473 controls. We had to exclude the four oldest case-control studies [42, 53, 54, 58] because the 95% CIs were not reported and two case-control studies [43, 44] provided only estimates of individual grain legumes. We checked for heterogeneity of estimates, influential risk estimates, and publication bias using funnel plots and Egger’s method. When comparing the highest versus the lowest legume intake group, we observed a protective effect of legume consumption on CRA (relative risk (RR) = 0.93; 95% CI: 0.84–1.03;
In prospective cohort studies, dietary information of cohorts or groups of healthy individuals at the time of study recruitment is linked to subsequent disease outcomes. We evaluated the relation between legume consumption and colorectal neoplasia in 15 peer-reviewed publications from 11 prospective cohorts (1,621,519 participants with 13,546 cases), 11 reported cancer as endpoint [61–71] and the remaining four studies reported incident and/or prevalent adenomas as endpoint [72–75] (Table 2). All, except for two European cohorts, were U.S. cohorts. Risk estimates were reported for men in six and for women in eight prospective cohorts. Risk estimates specific to colon and rectum were reported in two and one cohorts, respectively. Risk estimates specific to the intake of legumes, legume fiber, grain legumes, and grain legume fiber were reported in three, three, three, and two cohorts, respectively. Two cohorts (Adventist Health Study and Polyp Prevention Trial) showed significant protective effects of grain legume consumption [69, 72, 75]. Four cohorts (Breast Cancer Detection Demonstration Project, Women’s Health Study, Multiethnic Cohort Study, and NIH-AARP Study) showed a protective effect on CRC risk, the effect was statistically significant in some statistical models in the latter three cohorts [63, 64, 66–68]. Two cohorts (Nurses’ Health Study and Health Professionals’ Follow-up Study) showed a protective effect of legume consumption for CRA only [65, 73, 74]. Only three of the 11 cohorts (Iowa Women’s Health Study and two European cohorts) showed no effects of legume consumption on CRC risk [61, 62, 70, 71].
Reference, cohort, country | Follow-up period | Study size, case no. | Sex, age | Diet assessment | Grain legume, quantity for comparison, risk estimates (95% CI) | Adjustment for confounders |
---|---|---|---|---|---|---|
Incident colorectal adenoma | ||||||
U.S., Polyp Prevention Trial (PPT) |
1991–1994; 4-yr trial; incident CRA <3 yrs old | 1905, 629 No CRC, IBD history |
Both, >35 years |
Four annual self-administered FFQ with 27 food items and one grain legume question for previous yr | Grain legumes (dry beans and lentils) Mean: 45.1 vs. 3.1 g/d Any: OR = 0.78 (0.58–1.04) Men: OR = 0.69tab2_1 (0.48–0.99) Advanced: OR = 0.30tab2_1 (0.15–0.60) |
Adjusted for age, NSAIDs, sex, intervention group, and sex by intervention group |
U.S., Nurses’ Health Study (NHS) |
Diet: 1980–1994, incident CRA >2 yrs old | 9735, 633 No CRA, IBD history |
Women 30–55 years in 1976 |
Self-administered FFQ with 61 food items for previous yr | Legumes (beans, lentils, peas, lima beans, tofu, soybeans) ≥5 vs. ≤ 1 serving/wk New Incidence only: OR = 0.67tab2_1 (0.51–0.90) Trend: OR = 0.92tab2_1 (0.87–0.98) |
Adjusted for age, family CRC history, height, BMI, regular vigorous exercise, regular aspirin use, pack-years of smoking, current multivitamin supplement use, alcohol consumption, menopausal status, postmenopausal hormone use, and intake of total energy, red meat, and calcium |
U.S., Adventist Health Study (AHS) |
Diet: 1976–1977, Endpoint: 2002–2004 incident CRA <20 yrs old |
2818, 441 No CRC, IBD history |
Both, All underwent colonoscopy, no age exclusion | Self-administered FFQ with 55 food and beverage items | Grain legumes (beans, lentils, split peas) ≥3×/wk vs. <1×/mo OR = 0.67 (0.44–1.01) Trend: |
Adjusted for age, sex, education, BMI, and red meat intake |
U.S., Health and Professionals’ Follow-up Study (HPFS) |
1986–1994 | 16,448, 690 No CRA, IBD history |
Men 40–75 years All underwent colonoscopy |
Self-administered FFQ with 127 food items for previous yr | Legume fiber (beans, lentils, peas, lima beans, tofu, soybeans) Median 2.6 vs. 0.5 g/d RR = 0.82 (0.60–1.11) Trend: |
Adjusted for age, family CRC history, prior endoscopy, BMI, smoking, multivitamin use, physical activity, regular aspirin use, and intake of energy, alcohol, red meat, folate, and methionine |
U.S., Nurses’ Health Study (NHS) |
Diet: 1980–1994 Endpoint: 1980–1998 |
34,467, 1720 No CRC and IBD history |
Women 30–55 years in 1976 |
Self-administered FFQ with 61 food items for previous yr | Legumes (beans, lentils, peas, lima beans, tofu, soybeans) ≥5 vs. ≤1 serving/wk OR = 0.89 (0.75–1.05) Trend: OR = 0.96tab2_1 (0.93–1.00) |
Adjusted for age, family CRC history, height, BMI, regular vigorous exercise, regular aspirin use, pack-years of smoking, current multivitamin supplement use, alcohol consumption, menopausal status, postmenopausal hormone use, and intake of total energy, red meat, and calcium |
U.S., Iowa Women’s Health Study (IWHS) |
1986–1990 | 41,837, 212 |
Women, 55–69 years at baseline, no CRC history | Self-administered FFQ with 127 food items for previous yr | Legumes (beans, lentils, peas, lima beans, tofu, soybeans) ≥1.0 vs. 0 servings/wk RR = 0.95 (0.66–1.36) |
Adjust for age and total energy intake |
1976–1982 | 32,051 157 Non-hispanic white |
Both >25 years |
Self-administered FFQ with 55 food items | Grain legumes (beans, lentils, split peas) >2× vs. <1×/wk RR = 0.53tab2_1 (0.33–0.86) |
Adjusted for age, sex, BMI, physical activity, parental CRC history, smoking, alcohol consumption, and aspirin use | |
U.S., Nurses’ Health Study (NHS) |
1980–1996 | 88,764, 724 |
Women 30–55 years |
Self-administered FFQ with 127 food items for previous yr | Legumes (beans, lentils, peas, lima beans, tofu, soybeans) ≥4 vs. <1 serving/wk RR = 1.26 95% CI N/A RR = 1.49tab2_1 (1.04–2.12) per additional serving/wk |
Adjusted for age, family CRC history, sigmoidoscopy, height, BMI, pack-years of smoking, alcohol consumption, physical activity, intake of total energy and red meat, and use of menopausal hormones, aspirin, and vitamin supplements |
U.S., Health and Professionals’ Follow-up Study (HPFS) |
1986–1996 | 47,325, 457 | Men 40–75 years |
Self-administered FFQ with 127 food items for previous yr | Legumes (beans, lentils, peas, lima beans, tofu, soybeans) ≥4 vs. <1 serving/wk RR = 0.97 95% CI N/A RR = 0.90 (0.57–1.42) per additional serving/wk |
Adjusted for age, family CRC history, sigmoidoscopy, height, BMI, pack-years of smoking, alcohol consumption, physical activity, intake of total energy and red meat, and use of menopausal hormones, aspirin, and vitamin supplements |
Netherlands Cohort Study on Diet and Cancer (NCSDC) |
1986–1992 | Male: 58,279, 514 Women: 62,573, 396 |
Both, 55–69 years |
Self-administered FFQ with 155 food items for previous yr | Grain legumes (green and lima beans) Male: Median 62 vs. 11 g/d Colon RR = 1.13 (0.77, 1.64) Rectum: RR = 0.92 (0.58–1.47) Female: Median 58 vs. 11 g/d Colon RR = 0.79 (0.52, 1.20) Rectum: RR = 1.01 (0.53–1.94) |
Adjusted for age, alcohol consumption, and family CRC history |
1987–1998 | 45,491, 487 |
Women Age range N/A |
Self-administered FFQ with 62 food items for previous yr | Grain legume fiber >1.38 vs. <0.20 g/1000 kcal/d RR = 0.84 (0.63–1.10) |
Unadjusted | |
10 EU countries, EPIC |
1992–2002 | 519,978, 1065 |
Both, 35–70 years | Country-specific FFQ with 300–350 food items | Legume fiber Mean: 1.73 vs. 0.45 g/d HR = 1.04 (0.84–1.30) |
Adjusted for age, weight, height, sex, intake of nonfat and fat energy, and stratified by center |
10 EU countries, EPIC |
1992–2004 | 519,978, 1721 |
Both, 35–70 years | Country-specific FFQ with 300–350 food items | Legume fiber Mean: 1.9/1.0 vs. 0 g/d HR = 0.94 (0.79–1.14) |
Adjusted for age, weight, height, sex, intake of nonfat and fat energy, and stratified by center |
U.S., Women’s Health Study (WHS) |
1993–2003 | 39,876, 223 |
Women ≥45 years |
Self-administered FFQ with 131 food items for previous yr | Legumes (dry beans, lentils, peas, lima and green beans, tofu, soybeans) Median 0.9 vs. 0.1 serving/d RR = 0.83 (0.54–1.28) Legume fiber Median 1.8 vs. 0.4 g/d RR = 0.60tab2_1 (0.40–0.91) |
Adjusted for age, randomized treatment assignment, BMI, first-degree CRC family history, colon polyp history, physical activity, smoking status, baseline use of aspirin, hormone replacements, menopausal status, alcohol consumption, and intake of total energy and red meat |
U.S., Multiethnic Cohort Study (MEC) |
1993–2001 | 191,011, 2110 |
Both, 45–75 years |
Self-administered FFQ with 180 food items | Legume fiber Men: Median 7.6 vs. 0.3 g/1000 kcal/d CRC: RR = 0.81 (0.65–1.01) Women: Median 5.8 vs. 0.2 g/1000 kcal/d CRC: RR = 1.02 (0.82–1.27) |
Adjusted by age, ethnicity, time since cohort entry, and age at cohort |
U.S., NIH–AARP Diet and Health Study |
1995–2000 | 488,043, 2972 |
Both, 50–71 years at baseline |
Self-administered FFQ with 124 food items for previous yr | Grain legumes (dried beans, green beans, and peas) Men: Median 0.69 vs. 0.08 servings/d RR = 0.95 (0.83–1.09) Significant for age adjusted RR = 0.85 (0.74–0.97) Women: Median 0.81 vs. 0.09 servings/d RR = 1.13 (0.91–1.40) |
Adjusted for education, physical activity, smoking, alcohol consumption, and intake of total energy, red meat, and calcium |
U.S., NIH–AARP Diet and Health Study |
1995–2000 | 489,611, 2974 |
Both, 50–71 years at baseline |
Self-administered FFQ with 124 food items for previous yr | Grain legume fiber Median 2.3 vs. 0.2 g/1000 kcal/d RR = 0.93 (0.83–1.04) Significant for age-and sex- adjusted RR = 0.89 (0.79–0.99) |
Adjusted for sex, physical activity, smoking, menopausal hormone therapy, and intake of total energy, red meat, calcium, and folate |
For the meta-analysis, we had to exclude the CRC risk estimates of two cohorts because the risk estimates did not include 95% CI [65], leaving us with 1,533,527 participants including 12,408 cases. When comparing the highest versus the lowest legume intake group, we observed, as shown in Figure 2, a protective effect of grain legume consumption on colorectal neoplasia (RR = 0.89; 95% CI: 0.59–0.88;
Our risk estimates (Table 3) are similar to those obtained previously from meta-analyses between legume consumption (including soybeans) and CRA (RR = 0.73; 95% CI: 0.61–0.88) and CRC (RR = 0.91; 95% CI: 0.84–0.98) [14, 15], as well as legume fiber consumption and CRC (RR = 0.89; 95% CI: 0.78–1.02) [16]. Thus, we conclude that there is limited evidence suggesting that daily grain legume consumption decreases CRC risk in humans, all of which are based on observational studies. This is consistent with what has been previously concluded for the evidence on the relation between stomach or prostate cancer risk and legume consumption [34].
Factor | Studies | Pooled risk ratio | Heterogeneity | Eggers | References | ||
---|---|---|---|---|---|---|---|
(estimates) | RR (95% CI) | ||||||
23 (36) | 0.84 (0.78–0.90) | 0.005 | 41.9 | <0.001 | 0.02 | [46–52, 55–57, 59, 60, 62–64, 66, 67, 69–75] | |
Incident adenoma | 3 (3) | 0.72 (0.60–0.87) | <0.001 | 0 | 0.76 | 0.90 | [72, 73, 75] |
Prevalent adenoma |
8 (10) | 0.91 (0.84–0.99) | 0.03 | 0 | 0.73 | 0.60 | [47–52, 73, 74] |
Cancer | 14 (23) | 0.82 (0.74–0.91) | <0.001 | 54.4 | 0.001 | 0.02 | [46, 55–57, 59, 60, 62–64, 66, 67, 69–71] |
Retrospective | 12 (18) | 0.77 (0.66–0.89) | <0.001 | 53.3 | 0.004 | 0.11 | [46–52, 55–57, 59, 60] |
Prospective | 11 (18) | 0.89 (0.83–0.96) | 0.001 | 18.3 | 0.24 | 0.13 | [62–64, 66, 67, 69–75] |
Men | 10 (11) | 0.89 (0.81–0.97) | 0.009 | 0 | 0.80 | 0.40 | [46, 47, 49, 59, 60, 66, 67, 71, 72, 74] |
Women | 11 (13) | 0.86 (0.75–0.98) | 0.03 | 50.7 | 0.02 | 0.14 | [46, 47, 49, 59, 60, 64, 66, 67, 70, 71] |
Legume | 13 (17) | 0.88 (0.82–0.94) | <0.001 | 4.5 | 0.40 | 0.10 | [48, 49, 51, 57, 59, 60, 62, 63, 66, 70, 73, 74] |
Grain legume | 11 (19) | 0.80 (0.71–0.92) | 0.001 | 58.1 | 0.001 | 0.09 | [46, 47, 50, 52, 55, 56, 64, 67, 69, 71, 72, 75] |
Grain | 18 (29) | 0.82 (0.74–0.89) | <0.001 | 49.6 | 0.001 | 0.01 | [46, 48–52, 55–57, 59, 60, 63, 67, 69–73, 75] |
Fiber | 6 (8) | 0.92 (0.85–0.99) | 0.02 | 0 | 0.78 | 0.92 | [47, 62, 64, 66, 68, 74] |
Colon | 8 (10) | 0.69 (0.54–0.88) | 0.003 | 63.6 | 0.003 | 0.94 | [45, 55–57, 60, 69–71] |
Rectum | 3 (4) | 0.70 (0.49–1.00) | 0.05 | 63.9 | 0.04 | 0.69 | [45, 55, 71] |
Europe | 4 (8) | 0.83 (0.67–1.03) | 0.09 | 64.9 | 0.006 | 0.77 | [55, 57, 62, 71] |
USA | 16 (23) | 0.88 (0.82–0.94) | <0.001 | 24.5 | 0.14 | 0.04 | [47–52, 59, 63, 64, 66, 67, 69, 70, 72–75] |
The next step needs to be a long-term intervention study of daily grain legume consumption in a high CRC risk cohort. Dietary compliance will be a major challenge in Western countries because <10% of the population consumes grain legumes on a daily basis [6, 10, 11]. Moreover, it is much easier to take a daily supplement or a medication than consuming a chemo-preventive diet. At the same time, it is unrealistic to expect a chemo-preventive effect of a food, supplement, or medication when it is sporadically consumed. We previously identified markers of dietary compliance for grain legume consumption in human and animal studies [77], which allows for compliance monitoring. Intention-to-treat analysis, the gold standard for statistical evaluation of intervention studies, assumes high compliance. Statistical methods that account for dietary exposure markers and low compliance are needed when evaluating the evidence from dietary intervention studies.
4. Grain legumes and colorectal neoplasia in animal studies
As shown in Table 4, 14 animal studies evaluated the effect of grain legume consumption on colorectal tumorigenesis using 253 animals (248 males and five females) on control diets and 355 animals (350 males and five females) on 19 different grain-legume-containing diets [78–89]. Eight diets contained whole dry beans, seven contained dry bean fractions (three fiber factions, three ethanol extract, and one ethanol extract residue); two diets each contained lentils or chickpeas, and one diet each contained black-eyed peas or dry peas. In three studies, the animals were intragastrically tubed with dry beans and/or dry bean fiber [85, 87], whereas in the remaining 11 studies grain legumes or their fractions were included in the diet. Ten studies were conducted with rats and four with mice. All but one study [79] used azoxymethane (AOM), which is commonly used in animal models of human CRC to induce DNA mutations by alkylating DNA primarily at the O6-guanidine residues [90, 91]. After AOM induction, we promoted tumor formation in two unpublished studies with the colon irritant dextran sodium sulfate (DSS); this is an established inflammation-associated animal model of human CRC [92]. Bean treatment started before tumor induction in nine studies, after tumor induction in three, and after tumor induction and promotion in two studies. Study endpoints were ACF in seven studies, adenomas and adenocarcinomas in five, and tumors in two studies.
Reference | Animal | Diet, animals/diet | Experimental design | Tumor endpoints |
---|---|---|---|---|
Colorectal tumors: | ||||
F344 male rats | Control: casein diet, Treatment: Pinto beans (59% of diet) |
2× AOM (15 mg/kg BW) a wk apart First AOM: 6 wk of age Diet Start: 1 wk after last AOM Study End: 34 wk after last AOM |
Colon adenomas, adenocarcinomas (incidence and multiplicity) | |
Sprague-Dawley male rats | Control: modified AIN-1976, Treatment: Chickpeas (45% of diet) |
3× DMH (15 mg/kg BW) a wk apart First DMH: 9 wk of age Diet start: 4 wk before first DMH Study End: 22 wk after last DMH |
Colon adenomas + adenocarcinomas (incidence and multiplicity) | |
[80] |
F344 male rats | Control: modified AIN-93G, Treatments: Black beans (75% of diet) Navy beans (75% of diet) |
2× AOM (15 mg/kg BW) a wk apart First AOM: 7 wk of age Diet Start: 4 wk before first AOM Study End: 31 wk after last AOM |
Colon adenomas, adenocarcinomas (incidence and multiplicity) |
Ob/Ob male mice | Control: modified AIN-93G, Treatments: Navy beans (74% of diet) Navy bean ethanol residue (74% of diet) Navy bean ethanol extract (9% of diet) n=39 |
2× AOM (7 mg/kg BW) a wk apart First AOM: 7 wk of age Diet Start: 1 wk after last AOM Study End: 27 wk after last AOM |
Colon adenomas, adenocarcinomas, tumors (incidence and multiplicity) | |
[82] |
F344 male rats | Control: modified AIN-93G, Treatment: Black beans (74% of diet) |
2× AOM (15 mg/kg BW) a wk apart First AOM: 4 wk of age Diet Start: 1 wk after last AOM Study End: 31 wk after last AOM |
Colon adenomas + adenocarcinomas incidence |
FVB/N male mice | Control: AIN-93G, Treatment: Navy bean ethanol extract (10% of diet) |
AOM (10 mg/kg BW) 6 wk of age DSS (2% drinking water) 1 week starting 1 wk after DSS Diet Start: 10 days after AOM Study End: 102 days after AOM |
Colorectal tumor multiplicity | |
FVB/N male mice | Control: AIN-93G, Treatment: Navy bean ethanol extract (10% of diet) |
AOM (10 mg/kg BW) 6 wk of age DSS (2% drinking water) 1 week starting 1 wk after DSS Diet Start: 10 days after AOM Study End: 53 days after AOM |
Colorectal tumor multiplicity | |
Sprague-Dawley male rats | Control: AIN-93M, Treatment: Dry peas (5.9% of diet) |
2× AOM (15 mg/kg BW) 3 d apart First AOM: 10 wk of age Diet Start: 2 wk before first AOM Study End: 11 wk after last AOM |
Colon aberrant crypt foci (total, multiplicity) | |
CF-1 female mice | Control: Harland Teklad 4% Diet 7001, Treatment: Chickpea flour (10% of diet) |
2× AOM (10 mg/kg BW) a wk apart First AOM: 5 wk of age Diet Start: 2 wk before first AOM Study End: 7 wk after last AOM |
Control: 1.13 ACF/cm2 colon 0 >4 foci ACF Chickpea: 0.41 ACF/cm2 colon 2.2 ± 0.37 >4 foci ACF |
|
F344 male rats | Control: AIN-93G, Treatments: Pinto beans (20% of diet) Black-eyed peas (20% of diet) |
2× AOM (15 mg/kg BW) a wk apart First AOM: 7 wk of age Diet Start: 3 wk before first AOM Study End: 9 wk after last AOM |
Control: 183 ± 23 ACF Pinto: 64 ± 8 ACF Peas: 40 ± 4 ACF |
|
Sprague-Dawley male rats | Control:2018S Harland Teklad Treatments: Daily intragastric tubing Dry bean Negro 8025 (3.2 g/kg BW) Dry bean Negro 8025 fiber fraction (1.84 g/kg BW) |
2× AOM (15 mg/kg BW) a wk apart First AOM: 5 wk of age Diet Start: 1 wk before first AOM Study End: 5 wk after last AOM |
Distal colon zone: Control: 4.2 ± 0.6 ACF Dry bean: 2.2 ± 0.6 ACF Fiber fraction: 2.0 ± 0.8 ACF Using DAPI stain |
|
F344 male rats | Control: AIN-93G, Treatments: Whole lentils (5% of diet) Split lentils (5% of diet) |
2× AOM (15 mg/kg BW) a wk apart First AOM: 10 wk of age Diet Start: 5 wk before first AOM Study End: 17 wk after last AOM |
Control: 178 ± 24 ACF 12.0 ± 1.04 >3 foci ACF Dry bean: 70 ± 8 ACF 2.66 ± 0.09 >3 foci ACF Fiber fraction: 94 ± 17 ACF 5.56 ± 1.05 >3 foci ACF |
|
Sprague-Dawley rats male | Control:2018S Harland Teklad Treatments: Daily intragastric tubing Dry bean Bayo Madero (5.7 g/kg BW) Dry bean Bayo Madero fiber fraction (2.5 g/kg BW) |
2× AOM (15 mg/kg BW) a wk apart First AOM: 6 wk of age Diet Start: 1 wk before first AOM Study End: 7 wk after last AOM |
Distal colon zone: Control: 6.6 ± 0.40 ACF Dry bean: 0.8 ± 0.20ACF Fiber fraction: 1.5 ± 0.72 ACF |
|
Sprague-Dawley male rats | Control:2018S Harland Teklad Treatments: Daily intragastric tubing Dry bean Negro 8025 fiber fraction (1.84 g/kg BW) |
2× AOM (15 mg/kg BW) a wk apart First AOM: 5 wk of age Diet Start: 1 wk before first AOM Study End: 5 wk after last AOM |
Distal colon zone: Control: 21.0 ± 3.25 ACF Fiber fraction: 7.20 ± 2.95 ACF |
Table 5 shows individual and pooled risk estimates of the seven studies with tumor endpoints. For calculating risk estimates of tumor and ACF multiplicity, we calculated standardized mean differences and variation from reported means and standard errors. Grain legume consumption inhibited colorectal tumorigenesis. The protective effect of dry bean consumption attenuated with progressive tumor stage from tumor incidence (OR = 0.21; 95% CI: 0.11–0.43) over combined adenoma and adenocarcinoma incidence (OR = 0.32; 95% CI: 0.17–0.60) to adenocarcinoma incidence (OR = 0.38; 95% CI: 0.20–0.74). Similarly, the protective effect of grain legume consumption attenuated from ACF multiplicity (OR = 0.07; 95% CI: 0.03–0.14 with stronger effect on larger ACFs; Table 4) over tumor multiplicity (OR = 0.24; 95% CI: 0.16–0.36) to combined adenoma and adenocarcinoma multiplicity (OR = 0.52; 95% CI: 0.31–0.89) and adenocarcinoma multiplicity (OR = 0.52; 95% CI: 0.27–0.98;
Reference, | Legume | Adenocarcinoma | Adenoma + adenocarcinoma | Tumor | |||
---|---|---|---|---|---|---|---|
Year | Incidence | Multiplicity | Incidence | Multiplicity | Incidence | Multiplicity | |
Hughes1997 | PintoBW | 0.38 (0.10–1.45) |
0.19 (0.06–0.60) |
0.31 (0.08–1.19) |
0.20 (0.06–0.66) |
||
Hangen2002 | BlackBW | 0.19 (0.05–0.77) |
0.25 (0.09–0.75) |
||||
Bennink2012 | BlackBW | 0.15 (0.04–0.52) |
|||||
Hangen2002 | NavyBW | 0.30 (0.08–1.11) |
0.22 (0.07–0.68) |
||||
Bobe2008 | NavyBW | 1.55 (0.38–6.31) |
1.11 (0.48–2.55) |
0.59 (0.18–1.98) |
0.90 (0.39–2.07) |
0.32 (0.11–0.95) |
0.29 (0.12–0.68) |
Bobe2008 | NavyBER | 0.24 (0.03–2.28) |
0.56 (0.25–1.26) |
0.23 (0.07–0.71) |
0.61 (0.27–1.36) |
0.23 (0.07–0.71) |
0.22 (0.09–0.51) |
Bobe2008 | NavyBEE | 0.23 (0.02–2.16) |
0.45 (0.20–1.01) |
0.09 (0.01–0.74) |
0.46 (0.21–1.04) |
0.08 (0.02–0.38) |
0.17 (0.07–0.39) |
BobeUnpubl | NavyBEE | 0.20 (0.05–0.74) |
|||||
BobeUnpubl | NavyBEE | 0.34 (0.14–0.85) |
|||||
McIntosh1998 | ChickpeaW | 2.50 (0.65–9.65) |
|||||
The animal studies have limitations: first, in four of the seven tumor endpoint studies, grain legumes made up the majority of the diet (45–75%; Table 4) [78–80, 82], concentrations that are not relevant for human consumption. However, three studies showed a protective effect of the ethanol extract of navy beans fed at 10% of the diet (Table 4); the 2015 U.S. dietary guidelines for legume consumption are equivalent to ~2–5% of the diet [76], concentrations that should be evaluated in future animal studies. Second, none of the reported studies included more than one grain legume dosage (Table 4), demonstrating a need for dose-response studies in animal CRC models. Third, only one study examined the chemo-preventive effect of grain legumes other than dry beans at the tumor stage (Table 4), indicating a need to evaluate the chemo-preventive effect of other grain legumes at the tumor stage. Fourth, further research is needed to demonstrate a chemo-preventive response in female animals, as all but one study [84] examined the response in male animals. Despite these limitations, there is sufficient evidence to conclude that at least dry bean consumption probably decreases colorectal tumorigenesis in male animal models of human CRC.
5. Chemo-preventive compounds in grain legumes
To elucidate which fractions of grain legumes have chemo-preventive properties against colorectal tumorigenesis, we previously fractionated cooked navy beans using 60% ethanol [81]. Both the ethanol extract and the residue inhibited colorectal tumorigenesis in AOM-induced mice, indicating that both fractions contain chemo-preventive compounds. Several studies conducted by Loarca-Piňa’s research group demonstrated that the non-digestible fraction of dry beans inhibits colon ACF formation in AOM-induced rats [85, 87].
Grain legumes contain three major carbohydrate classes that inhibited colorectal ACF and tumor formation in animal CRC models: resistant starches (cooked grain legumes contain 0.6–4.2%), soluble fiber including the flatulence-inducing α-galacto-oligosaccharides stachyose, verbascose, and raffinose (cooked grain legumes contain 0–3%), and insoluble fiber (cooked grain legumes contain 15–23%); concentrations of those carbohydrate classes vary considerably based on processing methods [1, 2, 7, 93–97]. Resistant starches can be effective at 5–10% of the diet [7, 98–102]. Soluble fiber can inhibit ACF and tumor formation at 2.5–15% of the diet [103, 104], and insoluble fiber can be effective at 5–15% of the diet [104–107].
Grain legumes contain lipid classes that inhibited colorectal ACF and tumor formation in animal models of CRC. Plant sterols (e.g., β-sitosterol, campesterol, and stigmasterol; 0.13–0.24% of grain legume dry weight) attenuate colorectal tumorigenesis in animal studies (gastric intubation of 10–20 mg β-sitosterol/kg body weight or 0.2% of diet) [108–111]. Saponins (0.1–0.5% of grain legume dry weight) are glycolipids, which inhibit ACF formation at concentrations of 0.01–3% of the diets [112–116]; the lower concentrations are relevant for human diets [117]. Processing can decrease saponin concentrations in grain legumes up to 40% [118]. Besides containing phytosterols and saponins, grain legumes are low in lipids and have a favorable fatty acid composition for chemo-prevention (i.e., low in saturated fatty acids and a low Ω3: Ω6 fatty acid ratio) [3, 119, 120].
Grain legumes contain protein classes that inhibited colorectal ACF and tumor formation in animal models of CRC. Trypsin and chymotrypsin protease inhibitors of the Bowman-Birk family inhibit at dietary concentrations of 0.1–0.5% of the diet or 20 mg/kg of body weight for colorectal ACF and tumor formation [121–125]. Lectins (i.e., agglutinins; 0.1–3.5% of grain legume dry weight), which are glycoproteins that bind to epithelial cells, have been shown to inhibit cancer growth in animal tumor transplant studies and colon cancer cells [126–128]. Grain legumes have significant α-amylase inhibitor activity, which may indirectly decrease CRC risk by increasing microbial butyrate production and decreasing blood glucose and insulin after starch consumption [129]. The importance of Bowman-Birk inhibitors, α-amylase inhibitors, and lectins is debatable because 80–90% is lost and denatured during soaking and cooking, respectively [7, 96, 117].
The mineral and vitamin content of grain legumes may confer chemo-preventive effects against colorectal tumorigenesis. Grain legumes contain high concentrations of folate (83–174 μg/100 g of cooked legumes) and potassium (0.29–0.51% of cooked legumes) and low concentrations of sodium (<0.01% of cooked legumes) [7]. A high ratio of potassium to sodium has been reported to decrease CRC risk, and folate intake is established as a protective nutrient against CRC [130, 131]. Chemo-preventive compounds associated with minerals are phytates (0.1–1.9% of grain legume dry weight), the primary plant storage forms of phosphorus [117]. Processing decreases phytate content up to 50% [97, 132]. Phytates inhibit ACF formation at dietary concentrations of 0.02–2% [133–136]; the lower concentrations are relevant for human diets [137].
Grain legumes are a good dietary source of phenolic compounds (1–10 mg gallic acid equivalents/g legume, which is ~0.1–1.0% of grain legume dry weight) [117, 118, 132, 138, 139], many of which inhibited colorectal ACF and tumor formation in animal models of CRC. The three major phenolic groups with chemo-preventive properties are flavonoids (0–5 mg catechin equivalents/g legume), proanthocyanidins (i.e., condensed tannins; 0.2–12 mg catechin equivalents/g legume), and phenolic acids (0.02–0.1% of cooked legume dry weight) [118, 132, 138, 139]. Flavonols (i.e., kaempferol and quercetin), anthocyanidins, and flavan-3-ols are major flavonoid classes in grain legumes that have been demonstrated by us and others to inhibit colorectal tumor multiplicity at concentrations of 0.05–0.3% of the diet [140–144]. Proanthocyanidins can inhibit ACF formation at concentrations of 0.002–1% of the diet or by gavage [145–147]. Phenolic acids include ferulic acid (~0.003% of grain legume dry weight) that inhibited ACF formation at concentrations of 0.25–1% [148–150] and sinapic acid that inhibited ACF formation at concentrations of 20–80 mg/kg of body weight by gavage [151]. The concentrations of the phyto-estrogen group’s isoflavonoids (0.005–0.095 mg/kg grain legume) and lignans (0.018–0.266 mg/kg grain legume) are relatively low in grain legumes [152] and, thus, probably contribute little to the chemo-preventive effect of grain legumes. Processing and cooking of grain legumes result in various losses of phenolic compounds, which decreased not only their antioxidant activities but also their antiproliferative properties against colon cancer cells [118, 132, 139]. Thus, food processing plays an important role for the chemo-preventive role of grain legumes [117, 127].
There is sufficient evidence that grain legumes contain various compounds that can exert chemo-preventive effects against colorectal tumorigenesis in animal models of CRC at concentrations that are relevant for human diets. One has to consider that several of the aforementioned compounds are developed by plants as defense mechanisms against herbivores and are at sufficiently high concentrations to be toxic. It has to be noted that most of the aforementioned compounds do not show a consistent chemo-preventive effect in animal models of CRC; further investigation is necessary to elucidate factors, including food processing, that affect the response. Further studies are also warranted to examine whether the effect of the chemo-preventive compounds differs when they are consumed alone or in combination.
6. Molecular mechanisms by which grain legumes inhibit colorectal tumorigenesis
Given the complex mixture of chemo-preventive compounds in grain legumes, it comes to no surprise that grain legumes inhibit hallmarks of cancer [153, 154] at multiple stages of the colorectal tumorigenesis process. (A) Grain legumes can inhibit tumor induction (i.e., the transition from normal to initiated colorectal epithelial cells). First, grain legumes can alter the metabolism of carcinogens (i.e., increased degradation) and pre-carcinogens (i.e., decreased activation). This is accomplished directly by activating the expression of cytochrome P450 and UDP-glucuronosyltransferase (UGT) protein-encoding genes in the liver and indirectly by altering microbiome metabolism of carcinogens (e.g., decreased β-glucuronidase activity) in the colon [87, 155]. Second, grain legumes can act as antioxidants and induce genes involved in the detection and repair of mutated genes [156, 157]. Third, grain legumes may prevent the exposure of colorectal epithelial cells to carcinogens in food and bile by (a) binding carcinogens with non-digestible grain legume compounds [87, 158] and by (b) increasing mucin production of colorectal epithelial cells [159]. Fourth, grain legumes can decrease the colon pH [80] and promote the growth of probiotic bacteria [160] and thereby inhibit the growth of genotoxic bacteria [161, 162].
(B) Grain legumes can inhibit tumor promotion and progression (i.e., the transformation from initiated to neoplastic colorectal epithelial cells). First, grain legumes can increase apoptosis through the mitochondrial-mediated and death receptor-mediated pathways in neoplastic colorectal epithelial cells [88, 156] and colon cancer cell lines [163–165]. Second, grain legumes can inhibit survival of neoplastic colorectal epithelial cells by attenuating the NF-kB pathway [163–165]. Third, grain legumes can decrease proliferation of neoplastic colorectal epithelial cells [156, 163] by inducing genes that promote cell cycle arrest in G1/S and G2/M phases through p53-mediated pathways [82, 156, 165]. Fourth, grain legumes can inhibit survival and proliferation of neoplastic cells by suppressing the Akt (protein kinase B)/mTOR (mammalian target of rapamycin) pathway and upregulating the AMPK pathway, as shown for mammary carcinomas [166, 167]. In addition, upregulation of the AMPK and p53 pathway and suppression of the Akt/mTOR pathway may limit the nutrient and energy supply for the rapidly growing cancer cells and thereby inhibit tumor growth and progression [168–170]. Fifth, grain legumes can inhibit survival and proliferation of neoplastic colorectal epithelial cells through increased butyrate production in the colon [80, 163, 171].
(C) Grain legumes can inhibit tumor promotion and progression indirectly by limiting and/or resolving inflammation. Inflammation creates a tumor microenvironment that encourages neoplastic transformations and promotes survival and proliferation of neoplastic colorectal epithelial cells. We previously showed in the Polyp Prevention Trial that the chemo-preventive effect of grain legumes against CRA recurrence is linked to a decrease in serum interleukin (IL)-6 [172]. Moreover, we demonstrated in AOM-induced ob/ob mice that navy beans and their ethanol extract decreased concomitantly colorectal neoplasia and IL-6 in serum and colon mucosa [173]. In support, others demonstrated that grain legumes can attenuate the DSS-induced increase in serum cytokine concentrations [139, 159]. Multiple mechanisms are involved in the anti-inflammatory effect of grain legumes: first, grain legume fractions can act as antioxidants and inhibit NF-kB pathways and gene expression of COX-2 and tumor necrosis factor (TNF)-α [165, 174]; second, grain legume consumption can increase mucin gene expression in the colon and thereby preserve epithelial integrity during inflammation [82, 159]; third, grain legumes can promote microbial butyrate production in the colon, which has anti-inflammatory and antitumor effects [175]; fourth, grain legumes can promote the growth of probiotic bacteria [160] and thereby inhibit the growth of inflammation-inducing bacteria [162, 176].
There is sufficient evidence in human studies, animal models, and colon cancer cell lines for multiple molecular pathways/mechanisms by which grain legume consumption inhibits early stages of colorectal tumorigenesis (i.e., tumor induction, promotion, and progression). The main molecular mechanisms involved are preventing genotoxic hits, DNA repair, inhibiting survival and proliferation of neoplastic colorectal epithelial cells, preventing, limiting, and/or resolving inflammation, and limiting nutrient supply for neoplastic colorectal epithelial cells. Identification of grain legume response biomarkers (i.e., indicators that are linked to both grain legume consumption and inhibition of colorectal tumorigenesis such as IL-6) will be important to evaluate the efficacy of grain legumes in future long-term intervention studies in humans. Grain legume consumption alters the composition and metabolism of colon microbiota, cell cycle kinetics, and metabolism of colorectal epithelial cells, as well as host immune response and barrier function of the colon. Future studies are warranted to examine how grain legumes and their components alter the interplay between microbiota and host. Furthermore, more research is needed to understand the effect of grain legumes on the later stages of colorectal carcinogenesis (i.e., metastasis and invasion).
7. Conclusions
The objective of this chapter was to evaluate the evidence of a chemo-preventive role of grain legume consumption in colorectal tumorigenesis. Based on a literature review and meta-analyses, we conclude that there is limited evidence from case-control and cohort studies suggesting that daily grain legume consumption decreases CRC risk in humans. There is considerable preclinical evidence in animal models of CRC that supports a chemo-preventive effect of dry beans in male animal CRC models. There is sufficient evidence that grain legumes contain various compounds that can exert chemo-preventive effects against colorectal tumorigenesis in animal models of CRC. This is accomplished at concentrations that are relevant for human diets through multiple molecular pathways, which are critical for induction and clonal expansion of neoplastic colorectal epithelial cells. In summary, on the basis of the current evidence, daily grain legume consumption confers chemo-preventive effects against CRC. The next step is to conduct a long-term grain legume CRC prevention intervention study in humans to further elucidate the effects of daily grain legume consumption using grain legume exposure biomarkers to validate compliance and grain legume response biomarkers to monitor efficacy.
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