N° 8 | March 2016

Polyphenols, inflammation and colorectal cancer

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The World Cancer Research Fund/American Institute for Cancer

Research (WCRF/AICR) report highlights clear associations between red and processed-meat intake, higher alcohol intake and higher colorectal cancer risk. Meanwhile, dietary fibre intake is associated with a lower risk. The evidence is less clear for milk and calcium, non-starch vegetables, fruit and fish. There has been, however, increased interest in the role of bioactive compounds found in plant foods, and the role they play in health.

Population studies have shown that habitual consumption of diets rich in plant foods (fruit, vegetables, and plant beverages such as tea or coffee) was linked to a lower risk of several chronic diseases including cancer. Plant foods contribute toward health via their amino acids, polyunsaturated fatty acids, vitamins, minerals, and dietary fibre, but also via a range of bioactive compounds, known as polyphenols. These polyphenols are ubiquitous in plant foods, and include flavonoids, flavonols, flavonones, phenolic acids, to name a few.

Colorectal cancer (CRC) is the 2nd most common cause of cancer-related death in the UK (2010), the third most common cancer throughout the world, and the fourth most common cause of death. There is still a limited understanding of how CRC occurs. However, both genetic and environmental factors are associated with an increased risk of CRC. With only 5-10% of CRC occurring in patients with familial history of the disease, most cases are “sporadic”, following spontaneous mutations. These cases of sporadic CRC are mostly associated with lifestyle factors, including the diet.

Inflammation

Inflammation is an important “hallmark” of cancer and has a role in the progression of CRC.

In a vicious cycle, inflammation promotes tumour development, which in turn generates further inflammation. Slowing down the inflammation “fire” is a key strategy in managing the disease. Anti-inflammatory molecules can achieve this, however, they can also be toxic in high doses.

Polyphenols are part of the diet, therefore their toxicity is low, in the doses usually ingested in foods. A key feature of polyphenols as “bioactives” is their anti-inflammatory properties. However, this has mostly been demonstrated in in vitro experiments, using human or animal cells. Therefore caution must be applied when interpreting the results of these studies. With focus mostly on “pure” compounds or “extracts”, tested in high dose, there is evidence that green tea extract enriched with catechin and epigallocatechin gallate (EGCG), genistein, quercetin, kaempferol, curcumin and resveratrol, may modulate some of the key inflammatory pathways (including, for example, COX-2, NFkB).

The bioavailability of polyphenols is poor, which means that they do not get easily absorbed and made available to the organs. They instead remain inside the gut, where they are metabolised by the microbiota. It is where they may be most potent. In animal models of inflammatory bowel disease, polyphenols administration successfully decreased inflammation. The evidence in humans is, however, not as convincing.

Cohort studies

The EPIC study (> 500,000 adults from ten European countries) showed a 40% reduced risk of CRC in those with the highest intake of fibre and fruit and vegetable. Population studies have been carried out around the globe, with focus on the association between polyphenol, flavonoid or phenolic-rich diets and the risk of CRC. The results are conflicting, with some studies finding negative associations between specific classes of polyphenols and CRC (in Italy, 36% reduction risk with increased intake of isoflavones, anthocyanidins, flavones, and flavonols but not flavan-3-ols, flavanones, or total flavonoids; in Spain, 41% CRC risk reduction with increased intake of total flavonoids, flavones, flavanols, procyanidins, and lignans but not anthocyanidines, flavanones, flavonols, flavan-3ols, or isoflavones). Other groups found no associations between CRC and polyphenol intakes, but evidence of reduction in colon cancer risk instead (including Scotland and US studies). The reasons for these conflicting results are many, and may include differences in patient dietary data collection (tools and methods), and confounding factors not consistently considered (age, activity level, smoking, alcohol consumption). Some studies may also have been too small to be able to show an association between polyphenols and CRC. Based on these studies, it is not possible to conclude that polyphenol intake is inversely related to CRC risk. The reduction of CRC could also be due to fibre, vitamins, and other bioactives present in fruit and vegetables.

Trials and interventions

There are very few trials or interventions in human subjects to test the hypothesis that polyphenols may be important in the management of CRC (possibly via anti-inflammatory action). Such trials are essential to establish a causal link between the dietary bioactives and disease protection. A trial in the US relied on dietary recommendations to increase polyphenols intake, with a view to study polyp recurrence, showed a 76% decrease in the risk of recurrence in those with a higher flavonols intake.

In another study, authors concluded that treatment with flavonoids could reduce the recurrence rate of neoplasia in those with resected colon cancer because the recurrence rate after resection was, after 4 years, 7% in the treated group compared to 47% in the control group. There are not enough trials available to draw a conclusion on the protective effect of polyphenols against CRC. Studies in other patient groups, where inflammation is a key disease contributor, are promising: a 6-month placebo-controlled trial of curcumin in patients with ulcerative colitis led to a decreased relapse rate in the treatment group (5%) versus placebo-control group (21%).

Recommendations

There is no reference for dietary intake of polyphenols. Recommendation of a diet rich in fruit and vegetables will provide a high amount of polyphenols. The evidence from population and intervention studies is not sufficient to draw a conclusion and prescribe polyphenols with a view to prevent or treat CRC. It is however safe to increase plant foods to increase polyphenols consumption, and this, combined with weight management, limiting alcohol and cigarettes and increasing physical activity, is the recommended approach to reduce CRC risk.

Further research may yield results supporting new recommendations, especially for those at increased risk, to complement the bowel screening programme. To achieve this, there is a need for well-designed studies, using the correct doses of bioactives, in the most appropriate dose and matrix (or “form”), in large numbers of patients whose diets will be closely monitored. Such study design is challenging, but nonetheless required to draw firm conclusions.

To know more
“Little, C. H., Combet, E., McMillan, D. C., Horgan, P. G., & Roxburgh, C. S. D. (2015). The Role of Dietary Polyphenols in the Moderation of the Inflammatory Response in Early Stage Colorectal Cancer. Critical reviews in food science and nutrition DOI:10.1080/10408398.2014.997866”

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