Nutritional Considerations in Colorectal Cancer Prevention

Abstract

Introduction

Colorectal cancer is the second most common cause of cancer-related death among people in the United States, second only to lung cancer as the cause of cancer mortality. The American Cancer Society (ACS) estimated that close to 150,000 people would be newly diagnosed with colorectal cancer, and that 53,200 people would die of colorectal cancer, in 2020. Most colon cancers start as adenomatous polyps, with colonoscopy being the gold standard for polyp detection and removal. As screening methods, imaging, and treatment have improved, colon cancer survival rates have also improved. In the 1970s, five-year survival was around 50%, while in 2009–2015 this figure increased to 64%. Overall gains in the areas of incidence and survival have been largely driven by changes in older people with colorectal cancer: there was a 3.3% annual decrease in incidence among people ≥65 years between 2011 and 2016, but incidence has increased by 1% annually among those ages 50–64 during the same time period. Especially concerning are increasing case numbers in people under age 50, with incidence rising by 2% annually in this population during the time period referenced earlier. As of 2019, there were over 1.5 million people in the United States living with a history of colorectal cancer.¹

Colon cancer diagnosis, treatment, and survivorship may be associated with significant physical, social, psychological, and even economic hardship. Considering the significant burden a colon cancer diagnosis entails, prevention has an especially important role to play. The ACS estimates that more than 50% of colon cancer cases are related to lifestyle factors, such as unhealthy diet, cigarette smoking, lack of physical activity, excess body weight, or excessive alcohol consumption.¹ These cases could, therefore, potentially be prevented. In this article, we will review several nutritional factors and their roles in colon cancer prevention. In a forthcoming article, the potential role of botanical medicines in the prevention of colon cancer will be discussed.

Dietary and Nutritional Factors

Both overall diet quality as well as specific nutritional factors play fundamental roles in the health of the gastrointestinal tract and colon, and diet is considered one of the most important risk factors for colorectal cancer.² Diet modifies the gut microbiome and provides substrates for bacterial fermentation end products such as protective short chain fatty acids (SCFA). Observational studies have found that people with colorectal cancer have lower fecal SCFA levels than do healthy controls, and that they also harbor lower levels of butyrate-producing gut bacteria.³ Alterations to the microbiome may also mediate the impact of environmental or lifestyle factors on colon cancer risk.

Diet is also a well-known gene expression modifier.⁴ Dietary nutrients and dietary patterns may reduce inflammation or modify cytokines or the immune response. Bioactive compounds from plant foods (such as polyphenols and isothiocyanates), or additional dietary nutrients (including folate, choline, B vitamins, and methionine) may modulate or provide substrates required for methylation. DNA methylation is an important factor in the regulation of gene transcription, and methylation changes may contribute to oncogene activation, DNA breakage, and instability of the genome. Abnormal methylation is a strong factor in both the development and progression of colon cancer.⁵ Additional mechanisms by which dietary factors may modify gene expression related to colorectal cancer risk include histone modification and acetylation, chromatin remodeling, and inhibition of DNA methyltransferase.⁶ Upregulation of histone deacetylase (which is influenced by a variety of dietary phytochemicals, such as polyphenols, organosulfur or organoselenium compounds, indoles, and sesquiterpene lactones) may be of particular importance as one of the earliest events in the carcinogenesis of colon cancers.^7,8 The effects of diet may also be modulated or compounded by other lifestyle factors, such as excess calorie or alcohol intake, lack of exercise, overweight or obesity, and smoking.⁹

As part of the Multiethnic Cohort Study, a large prospective cohort (N = 190,949) of people ages 45–75 was followed for an average of 16 years, with dietary pattern analyzed by four dietary quality indexes (DQI), the Healthy Eating Index 2010, the Alternative Healthy Eating Index 2010, the alternate Mediterranean diet score, and Dietary Approaches to Stop Hypertension (DASH). Dietary assessment was performed by self-administered quantitative food frequency questionnaire (FFQ). DQI scores by all four indexes were inversely associated with the risk of colorectal cancer in both men and women (P ≤ 0.003). The positive association between diet quality and risk was stronger for left-sided colon tumors and rectal cancer, and was suggested for all racial/ethnic groups in the cohort.¹⁰

Among people at high risk of colon cancer (with Lynch syndrome), a beneficial dietary pattern has also been shown to be associated with a reduced risk of the development of colorectal adenomas (adenomatous polyps). Lynch syndrome, an autosomal dominant genetic disorder and the most common cause of hereditary colon cancer, is associated with a roughly 52% lifetime incidence of colon cancer in women and 69% lifetime incidence in men. Colon adenomas among people with Lynch syndrome appear to progress more rapidly than those found in the general population.¹¹

In the GEOLynch cohort study, FFQ was used to gather data on the diets of 486 people with Lynch syndrome (confirmed by genetic testing). Over a median follow-up period of 20 months, 58 participants (12%) were found to have colorectal adenomas. After adjusting for age and sex, for people in the highest tertile of a “Prudent” dietary pattern (composed of higher amounts of fruits, vegetables, whole grains, low-fat or nonfat dairy, fish, poultry, and teas, and low in added sugars), there was a hazard ratio (HR) of 0.61 (95% confidence interval [CI]: 0.28–1.32) of developing colorectal adenoma, compared with people in the lowest tertile. A higher risk was seen for people following a less healthy dietary pattern, dubbed “Snack” pattern, composed of higher amounts of fast food snacks, chips, mayonnaise-based sauces, cooking fats, butter, ketchup, sweets, and diet soda pop. After adjusting for age and sex, people with Lynch syndrome in the highest tertile of the “Snack” pattern diet had a HR of 2.13 (95% CI: 0.99–4.60) for the development of colorectal adenoma, compared with those in the lowest tertile.¹²

As mentioned earlier, specific dietary components or patterns may modulate inflammation. The dietary inflammatory index (DII), a validated research tool used to assess the inflammatory potential of a person's diet, is also associated with colon cancer risk. The DII uses 45 specific dietary factors, including macronutrients, micronutrients, and a variety of polyphenols, to allow for calculation of a score that accounts for both pro- and anti-inflammatory elements of the diet.¹³

In Cho et al.'s¹³ case–control study of the association of DII with colon cancer risk, 2769 men and women in Korea (923 with colorectal cancer and 1846 controls) provided information about their average diets for the preceding year using a 106-item semiquantitative FFQ. Higher DII score (indicating a more inflammatory diet) was associated with an increased risk of colorectal cancer for the highest and lowest tertiles (P < 0.001). This effect was found to be modifiable by age and by lifestyle factors, including smoking and physical activity level. Stronger associations for DII and colorectal cancer risk were seen in people age ≥50 (odds ratio [OR]: 2.61, 95% CI: 1.98–3.43), in nonsmokers (OR: 2.58, 95% CI: 1.81–3.68), and in people who reported being engaged in regular physical activity (OR: 3.42, 95% CI: 2.37–4.95) for the highest, compared with lowest tertile.¹³ In other words, combining a diet that reduced inflammation with other healthy lifestyle factors, such as exercising and avoiding smoking, may be even more preventive.

A case–control study in Italians by Shivappa et al.¹⁴ also found that a proinflammatory diet was positively associated with the risk of colorectal cancer. This multicenter study included 1225 people with colon cancer, 728 with rectal cancer, and 4154 people who were hospitalized for acute noncancerous conditions who served as controls. DII was calculated based on a 78-item FFQ. People with a more proinflammatory diet, as indicated by higher DII score, had a higher risk of colorectal cancer (OR continuous variable: 1.13, 95% CI: 1.09–1.18 and OR categorical variable: 1.55, 95% CI: 1.29–1.85). These results were also seen when separate analyses were performed for cases of colon cancer versus rectal cancer.¹⁴

One dietary pattern that may help reduce inflammation is the Mediterranean Diet (MD). The MD, with most meals centered on vegetables, fruits, whole grains, olive oil, nuts, seeds, beans, and legumes, is a plant-based diet rich in sources of anti-inflammatory omega 3 fats and plant polyphenols. The MD also limits red meat and added sugars. A number of trials have found that the MD reduces markers of inflammation in a variety of clinical situations.

A 2020 meta-analysis of 13 prospective cohorts studied (9 of which reported colorectal cancer incidence, and 5 of which reported on colorectal cancer mortality) confirmed an inverse relationship between adherence to the MD and the incidence of colorectal cancer. For the highest, compared with lowest MD adherence, relative risk (RR) was 0.90 (95% CI: 0.84–0.96). For site-specific disease, the RR for rectal cancer was 0.82, for proximal colon cancer was 0.94, and for distal colon cancer was 0.91 for the highest, compared with lowest MD adherence (95% CI: 0.71–0.95, 95% CI: 0.87–1.02, and 95% CI: 0.79–1.04, respectively).¹⁵

It is postulated that some of the effects of the MD on colon cancer risk may be modulated by effects on methylation. In a subset of subjects from the PREDIMED trial (a Spanish trial conducted to assess the effects of the MD on primary cardiovascular disease prevention), adherence to the MD was associated with positive methylation changes. Thirty-six participants were assessed with DNA methylation arrays at baseline and after five years of MD. Adherence to MD was positively associated with methylation of genes regulating inflammation and immunocompetence, and methylation of eukaryotic elongation factor 2 was also correlated with changes to markers of systemic inflammation, including C-reactive protein and tumor necrosis factor-α.¹⁶ Additional analysis by the same group found that beneficial fatty acids (from nuts and extra virgin olive oil) consumed with the MD led to methylation changes in peripheral white blood cell genes related to regulation of signal transduction.¹⁷

Aside from the overall dietary pattern, a number of specific nutritional factors have been studied for their potential to impact colon cancer prevention. These include dietary fiber, fruit and vegetable intake, micronutrients (including folic acid and calcium), and probiotics.

Fiber Intake

Findings on dietary fiber in relation to colon cancer risk have evolved and changed over time, creating confusion around this subject among both health care providers and the general public. Earlier large-scale studies from the 1990s, including the NHS, or Nurses' Health Study (in women) and the HPFS, or Health Professionals Follow-up Study (in men), failed to find any clear association between fiber intake and risk of colorectal cancers.^18,19

As evidence has accumulated over time, the tide has turned on this subject, with more recent studies finding a preventive effect with fiber intake. In the European Prospective Investigation into Cancer and Nutrition (EPIC) trial, 519,978 people from 10 European countries were followed over an average of 6.2 years, with a total of 1721 cases of colorectal cancer detected. Comparing people in the highest intake quintile with the lowest intake quintile for fiber, there was a 21% reduced risk. In addition, for each uncalibrated quintile increase in fiber intake, there was a 9% reduction in colorectal cancer risk.²⁰ As the EPIC cohort has been followed over time, this association has been confirmed. Using data from 2012, with an 11-year mean follow-up period, total fiber intake was inversely associated with colorectal cancer incidence, with a HR of 0.81 per 10 g per day increase in fiber intake (95% CI: 0.79–0.96). This association did not differ by other dietary variables or by age, gender, or other lifestyle factors. Associations were similar for both colon and rectal cancers.²¹ Later meta-analysis of 25 data sets from 2018 also confirmed the protective association with fiber intake, comparing individuals with highest versus lowest levels of consumption (P = 0.000 and effect size of 0.74).²² A 2019 Asian meta-analysis also supported the association. Ten studies with 49,964 people were included, with results confirming a protective association of fiber intake (P = 0.008, OR: 0.66 [95% CI: 0.56–0.77]).²³

Why the discrepant findings between older and newer studies? One possibility is that people in these different studies ate different types of dietary fiber, or that fiber came from varying sources, which may have provided variable benefits. Another is that the range of fiber intake affected findings, or that these studies defined high fiber intake differently. What actually constitutes a high fiber diet? In the NHS, for example, average fiber consumption ranged from around 10 g in the lowest intake group, to 25 g in the highest intake group. In EPIC, average fiber consumption ranged from around 13 g in the lowest intake group, to 33 g in the highest. The amount of fiber consumed by those in the “highest consumption” group in NHS may have been insufficient to show an impact on colon cancer risk. People in traditional societies have been found to consume 100 g of fiber or more daily, an amount that clearly far exceeds the numbers used to define high intake in these trials.^24,25

In addition, these studies do not further examine fiber consumption by subtype (soluble vs. insoluble), or assess for intake of prebiotic fibers specifically. Fermentation of prebiotic fibers by gut flora results in high concentrations of SCFA. This includes the SCFA butyrate, which has been shown to inhibit the genotoxic potential of carcinogenic compounds, such as nitrosamide, in human colon cells.²⁶ Butyrate also improves gut barrier integrity and inhibits procarcinogenic histone deacetylase.²⁷

Regardless, the message is clear in the more recent studies of colorectal cancer risk and fiber intake. And for the average American, there is ample room for improvement when it comes to dietary fiber. While the Institute of Medicine recommends 19–38 g of fiber daily as part of the diet (with no specification as to soluble vs. insoluble fiber intake), just 5% of the population is estimated to be achieving this level of consumption.²⁸ By taking careful diet histories and providing education on both benefits and practical measures for improving fiber intake, clinicians have a tremendous opportunity to support their patients in this area.

Fruits and Vegetables

Fruits and vegetables provide several obvious benefits, not only providing essential vitamins, minerals, fiber, and folate, but also contributing bioactive phytochemicals and antioxidants to the diet. Despite this (as with dietary fiber), consumption of fruits and vegetables in relation to the risk of colon cancer has been a source of conflicting research findings. The NHS and HPFS, including a follow-up of 1,743,645 person-years and 937 colon cancer cases, found no association between fruit and vegetable intake (as assessed by FFQs) and risk of colorectal cancer.²⁹

More recent analyses, however, paint different pictures. Results from the Shanghai Men's Health Study, including 61,274 male subjects, 390,688 person-years of follow-up, 236 cases of colon cancer, and 162 cases of rectal cancer, found an inverse association between fruit intake and colorectal cancer for the highest, compared with lowest quintile (HR: 0.67, 95% CI: 0.48–0.95, P trend = 0.03), while finding no association with vegetable intake.³⁰

In the EPIC trial, including 452,755 people with an average follow-up of 8.8 years and 2819 cases of colorectal cancer, fruit and vegetable intake was inversely associated with risk when comparing the highest and lowest quintiles of consumption (HR: 0.86, 95% CI: 0.75–1.00, P for trend = 0.04). This association was even stronger for colon cancer risk (HR: 0.76, 95% CI: 0.63–0.91, P for trend <0.01). This effect seemed to be modifiable by smoking status, with smoking negating the beneficial effects of vegetables on risk.³¹

In a Swedish study including 61,463 women with an average of 9.6 years follow-up and 460 cases of colorectal cancer, total fruit and vegetable intake was inversely associated with colorectal cancer risk (P = 0.03), with this association largely driven by fruit consumption (P = 0.009). Among women who were consuming the lowest amount of fruits and vegetables, the association and dose–response effect were even stronger. For women consuming less than 1.5 servings of fruits and vegetables daily, compared with those consuming more than 2.5 servings daily, RR for developing colorectal cancer was 1.65 (95% CI: 1.23–2.20, P trend = 0.001).³²

In an analysis of data from the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study, 488,043 people were included, with a five-year follow-up during which 2972 cases of colorectal cancer were observed. The RR for colorectal cancer was 0.82 for men (95% CI: 0.71–0.94) and 1.12 for women (95% CI: 0.90–1.38) when the lowest intake of vegetables was compared with the highest intake quintile. In men, an increased risk of colorectal cancer was associated with very low intake of fruits and vegetables (RR for <1 vs. ≥2.0 servings per 1000 kcal/day = 1.26, 95% CI: 1.03–1.54), and intake of green leafy vegetables was associated with a lower risk (RR for the highest, compared with lowest quintile = 0.86, 95% CI: 0.74–0.99). There was no association with fruit intake and colorectal cancer risk in either men or women in this study.³³

Again, why the discrepancy in these various findings? Several explanations have been posited. FFQ may be inaccurate for estimating actual intake, and can be subject to significant recall bias. In addition, the amount of fruit and vegetable intake defined as high or low varies by study. Some studies did not include many people with very low levels of vegetable intake, so may not have captured the impact of very low intakes on colorectal cancer risk.³⁰ Studies showing that very low intakes of fruits and vegetables are associated with an increased risk (while moderate to high intakes do not lower risk) point to a possible threshold effect.³³ In some studies, it is possible that the lowest level of fruit and vegetable intake observed was already above the range at which a beneficial effect occurs. In NHS and HPFS, the presumably health-conscious cohorts comprising health care providers were consuming higher amounts of fruits and vegetables than average Americans, so perhaps most or all of the participants were getting adequate amounts of these foods, skewing the results.³²

In addition, the variety of fruits and vegetables people consume contain a wide range of phytochemicals and nutrients. Combining all fruits and vegetables into a single category could dilute the potential benefits seen with intake of certain genera, such as Brassica vegetables, a high intake of which is associated with a reduced risk of various cancers, including colorectal cancer.³⁴ In addition, the form in which these foods were consumed (i.e., fresh, frozen, canned, or processed) is also potentially meaningful. These considerations are not addressed by the trials mentioned earlier, and indeed may be difficult to capture in epidemiologic nutritional research, but nonetheless are potentially important factors to keep in mind when interpreting these results.

Folic Acid

The water-soluble B vitamin folate is found naturally in many foods. These include green vegetables, such as leafy greens, asparagus, broccoli, and Brussels sprouts, as well as in beef liver, avocado, and black-eyed peas, to name a few. As a cofactor for the processes of cell growth and division, folate is an important regulator of cellular proliferation. Folate may also help maintain the stability and integrity of DNA through its effects on methylation.³⁵ In fact, folic acid supplementation at a dose of 400 mcg daily has been shown to increase DNA methylation in the colonic mucosa by 25% in people with colorectal adenomas.³⁶

Some studies have examined the role of folate supplementation in people at higher risk of colon cancer (with history of adenomatous polyps). In Jaszewski et al.'s³⁷ double-blind placebo-controlled trial, 137 people with adenomatous polyps were randomized to receive either folic acid 5 mg daily, or a matched placebo, for three years. Ninety-four people completed the trial. During follow-up colonoscopy at the three-year time point, the mean number of recurrent polyps for people who received folic acid was significantly improved, 0.36 with folic acid, compared with 0.82 for people in the placebo group (P = 0.02514). This was equivalent to a threefold increase in polyps for placebo group participants. People who seemed to benefit most from folic acid in this trial were those less than age 70, those with left-sided colon adenomas, or those with advanced adenomas.³⁷

In a small trial by Khosraviani et al.³⁸ specifically assessing colon mucosal cell proliferation, 11 people with recurrent colon polyps were randomized to receive either folic acid 2 mg daily, or a placebo, for three months. After three months of supplementation, colon mucosal cell proliferation was reduced in the folate group (from 9.1 to 7.4) while it was not significantly altered in the placebo group (from 9.3 to 9.6) (P = 0.05). This trial also found that most of the reduction in cellular proliferation occurred at the luminal aspect of colonic crypts, an important finding since changes in the upper portions of the crypt may be good indicators of higher risk proliferation.³⁸

In an additional small trial of folic acid supplementation, Kim et al.³⁹ randomized 20 people with adenomatous polyps to receive either folic acid 5 mg daily, or a placebo, for one year. Folic acid seemed to accelerate the improvement of colon cancer biomarkers. After one year, both placebo group and folic acid group subjects had experienced a decrease in p53 strand breaks and an increase in genomic DNA methylation. However, the folic acid group got to this point sooner, with significant improvements in these measures after 6 months, compared with the full 12 months in the placebo group. The authors speculated that undetermined confounders may modulate these biomarkers, leading to the results seen in this trial.³⁹

Epidemiologic evidence also points to a preventive benefit for dietary (rather than supplemental) folic acid in colorectal cancer. In a Danish cohort of 56,332 individuals ages 50–64 years, 465 colon and 283 rectal cancer cases were detected during a median follow-up of 10.6 years. A significant protective effect was seen for dietary folate intake with a colorectal cancer incidence rate ratio of 0.85 per 100 mg intake daily (95% CI: 0.65–0.97). This protective effect was not seen for folate supplements, but rather only for dietary intake.⁴⁰

Keep in mind that, as with the trials discussed earlier for other dietary factors, not all studies on folic acid indicate a preventive benefit.^41
–43 As Kim³⁵ points out in his 2006 review, the effects of folate may vary depending on both amount (dose) as well as tissue type (where cells are on the continuum of the normal histology-to-adenoma-to-carcinoma sequence). In healthy normal colorectal epithelial cells, folate deficiency as well as very high amounts of supplemental folate may promote neoplastic transformation. In contrast, supplemental folate in modest doses of 4–10 times the standard recommended dietary allowance suppresses this transformation.³⁵ This concept is in agreement with analysis by Lee et al., whose findings from NHS/HPFS suggested that a higher folate intake may be more critical (or preventive) early on in the development of a colon cancer, during the preadenoma stage.⁴⁴

In established tumors, in contrast, folate deficiency inhibits progression, while folic acid supplementation may promote progression. Therefore, modest supplemental folate may be beneficial when given in people with no neoplastic foci (although the challenge with this lies in identifying exactly who these people are). In addition, it is theoretically possible that, according to one hypothesis, folate may be preventive for people with some preneoplastic lesions, but may promote progression of such lesions in others.³⁵

It should be pointed out that this is a largely theoretical concern, based on specific in vitro and animal models. The clinical relevance of this concept remains undetermined. In the Aspirin/Folate Polyp Prevention Study (AFPPS), a randomized clinical trial published in 2007, folic acid supplementation at 1 mg daily for six years in people at higher risk (with a recent history of adenomas) significantly increased the risk of recurrence of advanced adenomas with features indicating high malignant potential by 67% (RR: 1.67, 95% CI: 1.00–2.80), and the risk of having multiple adenomas 2.3-fold (RR: 2.32, 95% CI: 1.23–4.35).⁴⁵ In contrast to these findings, additional small- and large-scale trials with doses ranging from 0.5 to 1 mg daily (and up to 5 mg in the case of Jaszewski et al.'s trial³⁷) for periods of 2–6.5 years in people with a history of adenomas demonstrate either a neutral or positive effect with folic acid supplementation, in opposition to the results seen in AFPPS.^37,46
–48

Based on evidence from a large-scale nutrition cohort (the Cancer Prevention Study II Nutrition Cohort), Stevens et al. assert that “intake of high levels of total folate reduces risk of colorectal cancer; there is no evidence that dietary fortification or supplementation… increases colorectal cancer risk.”⁴⁹ In addition, the public health benefits in other areas (i.e., food fortification to prevent neural tube defects) are an important consideration, and a recent article based on a 2020 NIH workshop concluded that “observations indicating adverse effects from excess folic acid intake… remain inconclusive; the data do not provide the evidence needed to affect public health recommendations” and that “strong biological and mechanistic premises connecting elevated folic acid intake… or high folate status to adverse health outcomes are lacking.”⁵⁰

Calcium

Experimental studies support a preventive role for calcium in colorectal cancer, with a number of mechanisms thought to underlie calcium's benefits. Calcium may reduce colonic inflammation, and bind fatty acids as well as bile acids, reducing irritation to the colon.⁵¹ Clinical study demonstrates the ability of calcium supplementation to reduce proliferation and normalize differentiation of colonic epithelial cells, as well as to reduce the risk of recurrent adenomas.⁵²

In an analysis of pooled data from 10 cohort studies in 5 countries, over 530,000 people were followed for between 6 and 16 years. During follow-up, 4992 cases of colorectal cancer were identified. Calcium intake was inversely associated with the risk of colorectal cancer, with the RR for the highest versus lowest intake quintile being 0.86 for dietary calcium (95% CI: 0.78–0.95, P trend = 0.02), and 0.78 for dietary plus supplemental calcium (95% CI: 0.69–0.88, P trend <0.001). Regarding the daily dose of calcium, for participants with an intake of <500 mg daily used as the referent, RRs were 0.90 for those with calcium intake of 500–599 mg daily, 0.83 for those with calcium intake of 600–699 mg daily, 0.79 for those with calcium intake of 700–799 mg daily, 0.89 for those with calcium intake of 800–899 mg daily, 0.79 for those with calcium intake of 900–1099 mg daily, 0.76 for those with calcium intake of 1100–1299 mg daily, and 0.74 for those with a calcium intake at or exceeding 1300 mg daily.⁵²

Data from the NIH-AARP Diet and Health Study confirmed a protective association of calcium for colorectal cancer. Over an average seven-year follow-up period, 1635 cases of colorectal cancer were identified in women, and 3463 cases in men. Intakes of dietary calcium, supplemental calcium, and total calcium were inversely associated with the risk of colorectal cancer in both men (P = 0.03, P = 0.01, and P = 0.001, respectively) and women (P = 0.001, P = 0.02, and P = 0.001, respectively) comparing the highest with lowest quintiles of intake.

Probiotics

Certainly, the gut microbiome plays an integral role in helping maintain the function and health of the colon. Beneficial flora act on dietary substrates to produce protective bacterial fermentation end products, including SCFA, and as mentioned earlier, studies indicate that individuals with colorectal cancer have lower fecal SCFA levels, compared with healthy controls. In addition, people with colorectal cancer may have lower levels of beneficial butyrate-producing gut bacteria.³ As Uccello et al.⁵³ point out, probiotics may serve to inactivate carcinogenic compounds in the gut, improve the host immune response, inhibit tyrosine kinase signaling, and compete with pathogenic microbes implicated in the pathogenesis of colorectal cancer. In addition, lactic acid bacteria may help regulate apoptosis and cellular differentiation, effects demonstrated in cell line and animal studies.⁵³ Might probiotics or probiotic foods as part of the diet therefore provide some protective effects?

Rafter et al.⁵⁴ examined the effects of a synbiotic supplement in a 12-week randomized double-blind placebo-controlled trial among colon cancer survivors as well as people with a history of adenomatous polyps. Thirty-seven people who had undergone resection for colon cancer within the preceding five years were included, as were 43 people with a history of polyps. Participants received a probiotic plus prebiotic combination (probiotic as Bifidobacterium lactis Bb12 and Lactobacillus delbrueckii subspecies rhamnosus strain GG at a dose of 10 billion colony forming units each, and prebiotic containing a mixture of long-chain inulin and short-chain oligofructose at a dose of 12 g) once daily for 12 weeks.

The synbiotic combination was found to have a number of benefits in these subjects at higher risk of colon cancer. Among people with a history of polyps, there were significant increases in fecal Bifidobacterium and Lactobacillus, and significant decreases in fecal Clostridium perfringens with use of the synbiotic (P = 0.021, P = 0.008, and P = 0.022, respectively). Synbiotic supplementation also led to significantly reduced DNA damage in the colonic mucosa (P = 0.04781), and improved epithelial barrier function (P = 0.02502).⁵⁴

As part of HPFS and NHS, the intake of fermented food, specifically as yogurt, was also assessed for protective effects. Participants (32,606 men from HPFS and 55,743 women from NHS) who had undergone lower endoscopy were prospectively assessed. Among men from HPFS, men who consumed yogurt (≥2 servings per week) had a lower risk of adenomas, compared with men who did not consume yogurt in the diet (P trend = 0.01). The protective effect was strongest for high-risk adenomas, compared with low-risk adenomas (P trend = 0.01, compared with P trend = 0.25). In addition, the association was stronger for colon adenomas than for rectal adenomas (P trend = 0.01, compared with P trend = 0.95). These effects were not observed in the women from NHS.⁵⁵

Nutritional Factors in Secondary Prevention

For people who have already been diagnosed with colon cancer, there are several nutritional factors that appear to have protective benefits for either recurrence or secondary prevention (preventing occurrence of second primary colorectal tumors). These include following a low glycemic-load (GL) dietary pattern, regular inclusion of nuts in the diet, and consumption of coffee.

Insulin-resistant states, hyperinsulinemia, and metabolic syndrome confer an elevated risk of colorectal cancer.^56,57 It is thought that increased insulin may drive higher levels of insulin-like growth factor-1 or other hormones, in addition to having direct effects on colonic epithelial cell proliferation.⁵⁸ The glycemic index provides a measure of the postprandial glycemic effect of a food, assigning a relative ranking (on a scale of 0–100) for how quickly a given food may raise blood glucose levels. Simple sugars and carbohydrates have high glycemic index scores, while foods with higher fat or protein content have lower scores. While the glycemic index provides a useful first glance for consumers in helping them understand glycemic impacts of given foods, there are limitations to the glycemic index. Glycemic index scores are based on the effect of a test food when eaten alone, not in combination with other foods. The glycemic index scores are also calculated based on a reference portion of 50 g of carbohydrate for the food in question. This portion may not be especially practical or relevant in daily life (e.g., 50 g of carbohydrate from popcorn equals roughly 9 cups popped, and 50 g carbohydrate from peanuts would be roughly equal to 2 cups of nuts). This renders glycemic index scores less useful for comparisons of different foods and for typical portion sizes. The GL attempts to compensate for these limitations by multiplying the glycemic index by the carbohydrate content found in a standard serving of a given food.

In a 2012 observational prospective study, Meyerhardt et al.⁵⁹ examined the impact of dietary GL on outcomes in 1011 survivors of stage III colon cancer. Over a median follow-up of 7.3 years, 343 of 1011 people in this study experienced a recurrence of colon cancer (defined in this trial as either a recurrence of the original cancer or the occurrence of a new primary colon cancer). For participants in the highest quintile for dietary GL, the HR for disease-free survival was 1.79 (95% CI: 1.29–2.48), compared with people in the lowest quintile (P trend <0.001). Recurrence-free survival and overall survival were also decreased in people with increased GL (P trend <0.001 for both). This association was significantly modified by BMI. In people with a BMI <25, GL was not associated with disease-free survival. However, in people with a BMI ≥25, higher GL was significantly associated with worse disease-free survival (HR: 2.26, 95% CI: 1.53–3.32, P trend <0.001).⁵⁹

Coffee consumption has also been found to be associated with a reduction in colon cancer recurrence. Utilizing data from NHS and HPFS, 1599 people with stages I to III colorectal cancer were followed prospectively for a median 7.8 years. Around 800 deaths occurred, 188 related to colorectal cancer. Compared with people who did not drink coffee, individuals who consumed ≥4 cups daily had a 52% lower risk of death from colorectal cancer (HR: 0.48, 95% CI: 0.28–0.83; P for trend = 0.003). Both caffeinated and decaffeinated coffee when imbibed at ≥2 cups daily were associated with a benefit for both colorectal cancer and all-cause mortality. The authors speculate that coffee may exert a protective effect through several mechanisms, including polyphenol content, an insulin-sensitizing effect, anti-inflammation, or by supporting proper hepatic function.⁶⁰

Guercio et al.⁶¹ also found a protective association for coffee consumption in survivors or stage III colon cancer. In this prospective observational study, 953 people reported on their intake of caffeinated coffee, decaffeinated coffee, and nonherbal tea during and for six months after adjuvant chemotherapy. Subjects consuming four cups of coffee per day (caffeinated plus decaffeinated) had a 41% reduction in their risk of recurrence, compared with nondrinkers. Increasing total intake of coffee was also associated with a significant improvement in overall survival (P = 0.008). In addition, caffeinated coffee was found to confer a stronger risk reduction in this study. People consuming four cups of caffeinated coffee per day had a 51% reduction in risk of recurrence or mortality (HR: 0.49, P = 0.003), compared with nondrinkers.⁶¹

Finally, inclusion of nuts in the diet has been shown to have a protective effect for secondary prevention. In a prospective observational study of 826 subjects with stage III colon cancer who received adjuvant chemotherapy, the association of cancer recurrence and mortality with dietary nut consumption was assessed. During a median follow-up period of 6.5 years, 199 people experienced a cancer recurrence or a new primary tumor. One hundred seventy-seven people died, 39 of whom died with no documented recurrence of cancer. Compared with people who did not eat nuts, participants who consumed ≥2 servings a week had significant improvements in disease-free survival as well as overall survival (HR: 0.58, 95% CI: 0.37–0.92, P trend = 0.03, and HR: 0.43, 95% CI: 0.25–0.74, P trend = 0.01, respectively). These associations were independent of other diet and lifestyle factors.⁶²

Conclusions

Numerous dietary components may be associated with the primary and secondary prevention of colorectal cancers. Intake of sufficient fruits and vegetables, fiber, dietary folate, and calcium have all been found to be associated with a reduced risk or preventive effect. Some trials that have examined the association of these specific dietary components with colorectal cancer risk have had discrepant findings. These discrepancies highlight some of the challenges inherent in performing epidemiologic nutrition research.

Overall diet quality, including the inflammatory potential of the diet, is also an important factor in preventing colorectal cancer. Diets that are more anti-inflammatory, such as the Mediterranean Diet, are associated with a reduced risk of colon cancer occurrence. In addition, modulation of the composition and/or function of the gut microbiome by either specific dietary elements, or overall dietary pattern, may impact colon cancer risk.▪

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