Dietary Fibre and Colorectal Adenoma

Dietary Fibre and Colorectal Adenoma: Comparison

Please note this is a comparison between Version 2 by Vivi Li and Version 1 by Vincenza Gianfredi.

diet
fibre
colorectal
adenoma
systematic review

1. Introduction

Colorectal cancer is the third most common cancer among men (after lung and prostate cancer) and the second among women (after breast cancer) worldwide, with approximately 2 new million cases (among both men and women) in 2020 ^[1]. Colorectal cancer is one of the few cancers for which a population screening program is in place practically all over the world ^[2]. There are several important reasons why colorectal cancer is suitable for population screening, including cancer progression from a preneoplastic (and subclinical) lesion (adenoma), the long lag time before invasive and malignant transformation, an easily detectable and treatable preneoplastic lesion, and the direct association between the stage of the disease and mortality ^[3]. It should be noted that colorectal adenoma is a proliferative dysplastic epithelial lesion that is harmful in most cases. It can have a malignant evolution based on the size, number, histology (grade of dysplasia) and duration in time ^[4]. Moreover, some other unmodifiable and modifiable factors might play an important role, such as age, ethnicity and genetics. Smoking, body mass index and diet seem to be the most important modifiable risk factors ^[5]. A high-fibre diet provide several plausible biological mechanisms that potentially provide a beneficial effect. Fibre might play a protective role through several mechanisms, including physical mechanisms, anti-inflammatory properties and prebiotic effects. Results from two extensive and recent meta-analyses confirm the protective role of fibre on colon ^[6] and rectal cancer risk ^[7]. However, despite the fact that adenoma as a preneoplastic lesion is recognized as a precursor of colorectal cancer, previous studies failed to univocally assess the role of dietary fibre intake and the risk of colorectal adenoma. These inconclusive results are probably due to a small population size, differences in the population’s characteristics, the adenoma site, the follow-up duration or the dose of fibre intake.

2. Association between Dietary Fibre Intake and Colorectal Adenoma

This is an extensive systematic review and meta-analysis of observational studies conducted by searching three different databases (PubMed/Medline, Scopus and EMBASE) and assessing the association between dietary fibre intake and the risk of colorectal adenoma. Our meta-analysis of 21 studies in total found an approximate 30% risk reduction of adenoma associated with a higher intake of dietary fibre. This result was confirmed in both the fixed and random effect models. Moreover, meta-regression analysis was performed since the original studies reported dietary fibre intake homogeneously. Meta-regression analysis predicts the changes of the outcome (colorectal adenoma) for a unit increase in dietary fibre intake. Our results showed a border-line significant negative linear correlation between the amount of dietary fibre intake and colorectal adenoma (the higher the intake of dietary fibre, the lower the risk of colorectal adenoma). This observation is in line with the cumulative analysis by dietary fibre dose, according to which the lowest risk of adenoma was associated with a dietary fibre intake equal to or higher than 26 g/d. However, it should be noted that the ES from the pooling of the 21 studies was associated with moderate heterogeneity and a potential publication bias. For these reasons, we performed several sensitivity analyses and the trim and fill method was applied. With regard to the potential publication bias, the trim and fill methods trimmed two possible studies on the right, however, the result did not change. Looking at the subgroup analysis by sex, a higher protective effect for men was found when compared to women, yet there was higher heterogeneity in men than in women. Furthermore, the highest strength of the association between dietary fibre intake and colorectal adenoma was found when focusing on cohort studies wherein higher heterogeneity was found when compared to case-control/cross-sectional studies. This is probably because a different duration of FU was considered among the original pooled cohort studies, and this hypothesis can be confirmed when considering a sensitivity analysis limited to 9 years (or more) of FU, where heterogeneity dramatically dropped. Moreover, the natural history of colorectal adenoma should be considered when interpreting these results. On the one hand, colorectal adenoma is characterized by a long latency period, which might not be better appraised in short cohort studies, nor in long cohort studies, where maintaining an FU might be difficult while increasing the risk of selection bias. On the other hand, case-control studies are more prone to potential recall bias. However, the high number of retrieved studies and consequently, the large sample size, might mitigate the risk. An important aspect that should be considered is that the vast majority of included studies were conducted in the USA, a population that largely did not meet healthy dietary guidelines, and where the eating pattern of approximately three-fourths of the population is low in vegetables, fruits, dairy, and oils and rich in refined grain, proteins, saturated fats, sodium and total calories [50]. This dietary pattern is frequently associated with several preventable, diet-related chronic diseases, including cancers. Based on this, we can speculate that the healthy beneficial effects of dietary fibre intake might be higher with respect to what we found in this meta-analysis if assessed in a population with a more Mediterranean—or, generally speaking, healthier—dietary pattern. It should be considered that the most relevant source of dietary fibre derives from vegetables, legumes and fruits which have been shown to prevent colorectal cancer [51] and which are heterogeneous in respect to their composition; therefore, it can be assumed that they have various anticarcinogenic properties. They are rich in bioactive compounds such as vitamins, anti-oxidants and polyphenols. Previous in vitro studies showed that some of these polyphenols, such as sulforaphane and epigallocatechin, are able to reprogram gene expression through epigenetic modification, thus reverting cancer progression [52,53]. Moreover, it should be considered that almost all the included studies used FFQs to assess dietary fibre intake, and even if they were frequently validated, it is difficult to precisely estimate the intake, often resulting in underestimation. Furthermore, our results suggest that there might be differences in the responses to fibre by sex.

This is an extensive systematic review and meta-analysis of observational studies conducted by searching three different databases (PubMed/Medline, Scopus and EMBASE) and assessing the association between dietary fibre intake and the risk of colorectal adenoma. Our meta-analysis of 21 studies in total found an approximate 30% risk reduction of adenoma associated with a higher intake of dietary fibre. This result was confirmed in both the fixed and random effect models. Moreover, meta-regression analysis was performed since the original studies reported dietary fibre intake homogeneously. Meta-regression analysis predicts the changes of the outcome (colorectal adenoma) for a unit increase in dietary fibre intake. Our results showed a border-line significant negative linear correlation between the amount of dietary fibre intake and colorectal adenoma (the higher the intake of dietary fibre, the lower the risk of colorectal adenoma). This observation is in line with the cumulative analysis by dietary fibre dose, according to which the lowest risk of adenoma was associated with a dietary fibre intake equal to or higher than 26 g/d. However, it should be noted that the ES from the pooling of the 21 studies was associated with moderate heterogeneity and a potential publication bias. For these reasons, we performed several sensitivity analyses and the trim and fill method was applied. With regard to the potential publication bias, the trim and fill methods trimmed two possible studies on the right, however, the result did not change. Looking at the subgroup analysis by sex, a higher protective effect for men was found when compared to women, yet there was higher heterogeneity in men than in women. Furthermore, the highest strength of the association between dietary fibre intake and colorectal adenoma was found when focusing on cohort studies wherein higher heterogeneity was found when compared to case-control/cross-sectional studies. This is probably because a different duration of FU was considered among the original pooled cohort studies, and this hypothesis can be confirmed when considering a sensitivity analysis limited to 9 years (or more) of FU, where heterogeneity dramatically dropped. Moreover, the natural history of colorectal adenoma should be considered when interpreting these results. On the one hand, colorectal adenoma is characterized by a long latency period, which might not be better appraised in short cohort studies, nor in long cohort studies, where maintaining an FU might be difficult while increasing the risk of selection bias. On the other hand, case-control studies are more prone to potential recall bias. However, the high number of retrieved studies and consequently, the large sample size, might mitigate the risk. An important aspect that should be considered is that the vast majority of included studies were conducted in the USA, a population that largely did not meet healthy dietary guidelines, and where the eating pattern of approximately three-fourths of the population is low in vegetables, fruits, dairy, and oils and rich in refined grain, proteins, saturated fats, sodium and total calories ^[8]. This dietary pattern is frequently associated with several preventable, diet-related chronic diseases, including cancers. Based on this, we can speculate that the healthy beneficial effects of dietary fibre intake might be higher with respect to what we found in this meta-analysis if assessed in a population with a more Mediterranean—or, generally speaking, healthier—dietary pattern. It should be considered that the most relevant source of dietary fibre derives from vegetables, legumes and fruits which have been shown to prevent colorectal cancer ^[9] and which are heterogeneous in respect to their composition; therefore, it can be assumed that they have various anticarcinogenic properties. They are rich in bioactive compounds such as vitamins, anti-oxidants and polyphenols. Previous in vitro studies showed that some of these polyphenols, such as sulforaphane and epigallocatechin, are able to reprogram gene expression through epigenetic modification, thus reverting cancer progression ^[10][11]. Moreover, it should be considered that almost all the included studies used FFQs to assess dietary fibre intake, and even if they were frequently validated, it is difficult to precisely estimate the intake, often resulting in underestimation. Furthermore, our results suggest that there might be differences in the responses to fibre by sex.

2.1. Potential Biological Mechanisms

Since colorectal adenomas are considered to be potential precancerous lesions, they are likely to share a common etiopathogenesis with colorectal cancer.

According to the European Food Safety Authority (EFSA) dietary fibre is “non-digestible carbohydrates plus lignin, including non-starch polysaccharides, fructo-oligosaccharides, galactooligosaccharides, other resistant oligosaccharides and resistant” [54]. Major food sources for dietary fibre are cereals/grains, vegetables, fruits and legumes. Based on its components, previous studies suggested to differentiate dietary fibre into “soluble” and “insoluble”. Such distinction was used to differentiate between viscous, soluble types of fibre (e.g., pectins) and insoluble components such as cellulose. Even if the distinction was mainly proposed to identify different patterns of beneficial effects, it should be noticed that both soluble and insoluble components have different and synergic advantages. The insoluble fibre is mainly responsible for the increase in stool bulk, important for reducing transit time and diluting carcinogens in the lumen by means of both reducing exposure to carcinogens and lowering secondary bile acid production [5]. The soluble fibre, instead, seems to be implicated in the wellbeing of microbiota through fibre fermentation which, in turn, is able to promote the production of short-chain fatty acids (SCFA) and which, by lowering the colonic pH, might inhibit pathogenic microorganisms and increase the absorption of some nutrients [55]. In addition, experimental studies have shown that butyrate, SCFA, has anti-proliferative effects, promotes colon motility and induces apoptosis [56]. The consequent reduction in cholesterol, and insulin resistance, seem to inherently reduce the risk of colorectal cancer. Furthermore, dietary fibre intake seems to also promote the eubiosis of the gut microbiota ecosystem [57]. On the contrary, dysbiosis (increased number of harmful bacteria in the gut) seems to be associated with an increased release of enterotoxins that alter the immune system, inducing the production of pro-inflammatory cytokines responsible for the disease status [58], including colorectal cancer [59].

According to the European Food Safety Authority (EFSA) dietary fibre is “non-digestible carbohydrates plus lignin, including non-starch polysaccharides, fructo-oligosaccharides, galactooligosaccharides, other resistant oligosaccharides and resistant” ^[12]. Major food sources for dietary fibre are cereals/grains, vegetables, fruits and legumes. Based on its components, previous studies suggested to differentiate dietary fibre into “soluble” and “insoluble”. Such distinction was used to differentiate between viscous, soluble types of fibre (e.g., pectins) and insoluble components such as cellulose. Even if the distinction was mainly proposed to identify different patterns of beneficial effects, it should be noticed that both soluble and insoluble components have different and synergic advantages. The insoluble fibre is mainly responsible for the increase in stool bulk, important for reducing transit time and diluting carcinogens in the lumen by means of both reducing exposure to carcinogens and lowering secondary bile acid production ^[5]. The soluble fibre, instead, seems to be implicated in the wellbeing of microbiota through fibre fermentation which, in turn, is able to promote the production of short-chain fatty acids (SCFA) and which, by lowering the colonic pH, might inhibit pathogenic microorganisms and increase the absorption of some nutrients ^[13]. In addition, experimental studies have shown that butyrate, SCFA, has anti-proliferative effects, promotes colon motility and induces apoptosis ^[14]. The consequent reduction in cholesterol, and insulin resistance, seem to inherently reduce the risk of colorectal cancer. Furthermore, dietary fibre intake seems to also promote the eubiosis of the gut microbiota ecosystem ^[15]. On the contrary, dysbiosis (increased number of harmful bacteria in the gut) seems to be associated with an increased release of enterotoxins that alter the immune system, inducing the production of pro-inflammatory cytokines responsible for the disease status ^[16], including colorectal cancer ^[17].

Considering the beneficial effects of both dietary fibre components, and based on the suggestion provided by Food and Agriculture Organization (FAO) and World Health Organization (WHO) stating that the above mentioned distinction should be overcome as solubility does not always predict physiological effects [60], we did not perform a separate analysis among soluble and insoluble fibre. Indeed, the potential role of fibre in preventing colorectal adenoma and then cancer could be attributed to all of the mentioned mechanisms, mainly on account of the dietary fibre heterogeneity in chemical composition, physicochemical properties, and solubility. On the other hand, selectively focusing on one of the two components and consequently on a particular food source might lead to a reduction in diet variety. In light of this, international healthy dietary guidelines consider dietary fibre as a single entity [61] and recommend satisfying the daily dietary fibre intake of at least 30 g, derived from a varied and balanced diet, rich in plant-based foods, such as wholegrains, legumes, non-starchy vegetables and fruit [62], as the Mediterranean diet advocates [63]. Nevertheless, in our society, the increased rate of colorectal adenoma (and cancer) can be attributed, among the others, to unhealthy lifestyles, including the so-called Western diet. This dietary pattern is characterized on one hand by a high intake of refined grains, sugars, salt, saturated and trans-fatty acids mainly due to a high consumption of ultra-processed food [64,65], and on the other hand by a low intake of dietary fibre. In this respect, previous studies showed that a low intake of fibre along with a high consumption of typical western diet food increase the risk of dysbiosis, which in turn can be responsible for a lower production in SCFA [66,67].

Considering the beneficial effects of both dietary fibre components, and based on the suggestion provided by Food and Agriculture Organization (FAO) and World Health Organization (WHO) stating that the above mentioned distinction should be overcome as solubility does not always predict physiological effects ^[18], we did not perform a separate analysis among soluble and insoluble fibre. Indeed, the potential role of fibre in preventing colorectal adenoma and then cancer could be attributed to all of the mentioned mechanisms, mainly on account of the dietary fibre heterogeneity in chemical composition, physicochemical properties, and solubility. On the other hand, selectively focusing on one of the two components and consequently on a particular food source might lead to a reduction in diet variety. In light of this, international healthy dietary guidelines consider dietary fibre as a single entity ^[19] and recommend satisfying the daily dietary fibre intake of at least 30 g, derived from a varied and balanced diet, rich in plant-based foods, such as wholegrains, legumes, non-starchy vegetables and fruit ^[20], as the Mediterranean diet advocates ^[21]. Nevertheless, in our society, the increased rate of colorectal adenoma (and cancer) can be attributed, among the others, to unhealthy lifestyles, including the so-called Western diet. This dietary pattern is characterized on one hand by a high intake of refined grains, sugars, salt, saturated and trans-fatty acids mainly due to a high consumption of ultra-processed food ^[22][23], and on the other hand by a low intake of dietary fibre. In this respect, previous studies showed that a low intake of fibre along with a high consumption of typical western diet food increase the risk of dysbiosis, which in turn can be responsible for a lower production in SCFA ^[24][25].

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