Resistant Starch has been described as the portion of starch and starch products that resist digestion within the small intestine and are, like other dietary fibres, instead fermented by colonic microbiota. There are many types of resistant starch that exist (RS1- RS4), both in the natural world and modified by man, but all have been shown to have considerable health benefits in relation to colorectal cancer, which in the UK, is the third most common form of cancer. While, resistant starch in itself can improve colonic health by means of increasing faecal bulk, having a mild laxative effect and acting as a prebiotic; it also produces short chain fatty acids as a by- product of its fermentation. One of these short chain fatty acids is butyrate, which not only is the primary source of energy for colonocytes; it also has been shown to have anti- carcinogenic properties. Therefore butyrate has been studied in the prevention of colorectal cancer, in which it has been found to cause cell differentiation and apoptosis in neoplastic cells, arresting their proliferation. Colorectal cancer has been established to occur in the distal colon more commonly, although fermentation of resistant starch, and therefore butyrate production, takes place in the proximal colon. In studying various types of resistant starches and in combination with other dietary fibres, to find the optimum butyrate producing diet, in the distal regions of the colon; there may be an increased possibility of reducing the risk factors and preventing colorectal cancer.
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Pioneering studies by Burkitt (1971) showed a relationship between the incidence of colorectal cancer and the lack of dietary fibre, low stool weight and long transit time (cited in Coleman et al., 2002). The findings that people of different cultures have such varied disease incidence and risk, has led to the hypothesis that dietary factors are important in colorectal carcinogenesis (Waterhouse et al., 1976). More recently Bingham et al. (2003) showed that by doubling the dietary fibre intake, in populations with low to average intake, it could reduce the risk of colorectal cancer by up to 40%. This is because by stimulating bacterial growth there is an increase in stool weight, faster transit time and dilution of colonic contents (Cummings, 1981). This is in accordance with the findings that an African indigenous population, who ate fibre-rich diets, had a much lower incidence of colon cancer compared with a higher incidence associated with those who ate a Western-style diet, of high fat lower fibre. Through other human studies it was found that a large quantity of fibre in the diet is also linked with a lower colorectal cancer rate (Howe et al., 1992).
Dietary fibre is principally comprised of non-starch polysaccharides, although there has been debate as to whether Resistant Starch should be included, due to the lack of a universal method to quantify the various components of dietary fibre. Nevertheless, there had been much anticipation of whether Resistant Starch shared any of the potential colonic health benefits that have been ascribed with dietary fibre. With all this hope of the health benefits of Resistant Starch (Jenkins et al., 2000), its human consumption has indeed been shown to improve colonic health by having a mild laxative effect, softening stools, decreasing faecal pH, increasing luminal short chain fatty acid concentrations, increasing faecal bulk and reducing the accumulation of harmful by-products of protein fermentation (i.e. ammonia (NH3) and phenols) (Birkett el al., 1996; Young and Le Leu, 2004). The increasing of digesta mass results in the dilution of carcinogens; while the decrease in digesta pH inhibits the formation and absorption of carcinogens (e.g. secondary bile acids). Of the short chain fatty acids produced through the fermentation of Resistant Starch, butyrate is used as the preferred respiratory fuel of colonocytes. Through different studies butyrate has been shown to lower luminal pH, have anti- inflammatory properties and prevents the development of abnormal colonic cell populations (i.e. carcogenesis) (Topping and Clifton, 2001). Resistant Starch also has other broader protective mechanisms, associated with dietary fibre, such as alterations of gut microbiota to a more beneficial state and decreasing transit time, which contribute to protective effects against colorectal cancer (McGarr et al., 2005). There have also been animal studies that have shown that Resistant Starch prevented colonic DNA damage in rats that had been fed high protein diets (Toden et al., 2006).
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Starch is a polysaccharide made up of glucose monomers joined together with Î±-1,4 glycosidic bonds to form a linear polymer, known as amylose; or with Î±-1,4 and Î±-1,6 glycosidic bonds to form a larger branched polymer, known as amylopectin (Figure 1). Starch is formed in the leaves of all green photosynthesising plants and is an important carbohydrate in the human diet, providing the major source of dietary calories and found in many staple foods such as rice, potatoes, bread, pasta, wheat and maize. There are two crystalline forms of starch, A and B, which contain different relative proportions of amylose and amylopectin. Type A starches are 23-29 glucose units in chain length and are found in cereals, whereas type B have chain lengths 30- 44 glucose units and are found in tubers and amylose-rich starches. A third type, C, found in legumes, appears to be a mixture of A and B forms, which resists digestion as do type B (Topping and Clifton, 2001).
Figure 1: Diagrammatic representation of amylose (left) and amylopectin (right).
Starch is hydrolyzed by the enzyme Î±-amylase which is found, in saliva, in the mouth; and in the duodenum, after being released by the pancreas. Firstly Î±-amylases release maltodextrins that are then hydrolysed to free glucose, by membrane-bound maltases, which is absorbed (Annison and Topping, 1994). Until research by Englyst et al. (1982), showing that starches could be fermented in the large intestine, it was believed that starch was fully digested in the small intestine. This starch was called Resistant Starch (RS) and that by definition is "the sum of starch and products of starch digestion not absorbed in the small intestine of healthy individuals" (Asp, 1996). RS can therefore be thought of as a dietary fibre. Starch digestion and absorption varies because Î±-amylase activity can be directly affected by factors intrinsic to starchy foods including NSP, Î±-amylase inhibitors and the formation of amylose-lipid complexes (Englyst et al., 1992); as well as extrinsic factors such as additives (e.g. phosphorous) (Niba, 2003). Smaller food particles have a larger surface area to volume ratio and are therefore digested more rapidly than larger ones (Annison and Topping, 1994). Encapsulation of the starch granule results in inefficient digestion due to cell wall components and therefore disruption of the cell wall is necessary for unhindered starch digestion (Tovar et al., 1990).
Dietary fibre, as a term to describe all indigestible plant polysaccharides, was first used by Trowell et al. (1976). Although the definition has been refined over the decades it was generally accepted that plant materials, including non starch polysaccharides (NSP), oligosaccharides and lignin, belonged to either soluble or insoluble dietary fibres. However, Mcleary (2003) provided a definition that included RS, which is both soluble and insoluble and can therefore be thought of as a third type of dietary fibre (Phillips et al, 2008). Soluble dietary fibres are those carbohydrates that are nearly completely fermented in the large intestine into physiological active by- products and are therefore referred to as prebiotics. Insoluble dietary fibres are resistant to fermentation by colonic microbiota, and are therefore metabolically inactive, only present as a fibre matrix due to their absorption of water, which increases stool weight. Through its physical presence, dietary fibre offers colonic protection through the dilution and/or the binding of carcinogens and other toxins (Topping and Clifton, 2001).
There are four types of Resistant Starch (RS), RS1- RS4, that are classed on structural consideration and how they are resistant to enzyme digestion (Diagram 1). RS1 is the class of starch that, due to the presence of intact cell walls, is physically inaccessible to digestion. RS2 forms have native starch granules that resist digestion by the composition of ungelatinised granules; this includes high-amylose maize starch (HAMS), which retains its structure during the processing of foods. RS3 is generally formed by the retrogradation of starch granules. RS4 are those starches that have had their digestibility decreased through chemical modification (Lorraine, 2002; Nugent, 2005).
Table 1: Classification of types of resistant starch, food sources, and factors affecting their resistance to digestion in the colon
From Nugent (2005)
Even though all starchy foods naturally contain RS, each different category has diverse physiological effects due to the varying structural compositions and the ways of processing and cooking that they have undergone. The digestibility of RS also varies within individuals and therefore these several factors show why degradation by bacterial fermentation is not uniform, for example in one study 96% of RS2 in green banana was digested but only 89% of RS2 from raw potato was digested (Cummings et al., 1996). RS is not found in large amounts in nature but is produced in the commercial manufacture or domestic preparation of household foods, in particular by the heating and subsequent cooling of starchy foods (Jenkins et al., 2000). In Western diets, the intakes of RS have been recorded as 5 to 10g per day (Brighenti et al., 1998).
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Colonic microbiota metabolise the remaining, undigested carbohydrates (i.e. RS and NSP, dietary fibres) in the large intestine, which provides the majority of enzymatic substrate for saccharolytic colonic bacteria, which use it for characteristic anaerobic fermentation producing short chain fatty acids (SCFA), including acetate, propionate and butyrate (Bauer-Marinovic et al., 2006). RS is therefore digested by bacterial amylases and the glucose produced is then further metabolised, via the formation of pyruvate, into SCFAs and gases, including CO2, H2 and CH4. Absorption of SCFA in the large intestine results in the eventual digestion and absorption of RS energy in the colon (Sharma et al., 2008). There are a variety of reactions and metabolic process involved in fermentation, in which anaerobic microbial breakdown of organic matter yields metabolisable energy. This is used for microbial growth and maintenance and also other metabolic end products used by the host (Macfarlane and Gibson, 1995).
A number of factors determine the production of SCFAs in the colon, including the number and types of microbiota present, substrate source and gut transit time. Due to fermentation, and thus SCFA production, primarily taking place in the proximal colon, the pH increases distally along the colon (Wong et al., 2006). Therefore, it is thought that dietary interventions that raise the levels of SCFAs in the colon are beneficial against colonic neoplasia, which is why SCFAs are used as markers of fermentation levels and colonic health. The length of transit time influences the concentration and types of SCFAs in the colon because a longer transit allows further protein breakdown and an increased SCFA pool due to the contribution by amino acid fermentation (MacFarlane and MacFarlane, 2003).
Short chain fatty acids
The three principle SCFAs produced as a result of colonic fermentation of RS; acetate, propionate and butyrate, have important roles in the maintaining a healthy bowel, which includes increasing colonic blood flow, maintaining a low colonic pH and improving mineral and water absorption (Topping and Clifton, 2001). These effects come about because the major SCFA have an ability to stimulate and enhance colonic muscular contraction, which raises muscular tone and large bowel oxygenation and nutrient transport (Bird et al., 2000). Although SCFA concentrations have been shown to be similar in the proximal and distal colon (Macfarlane et al., 1995), it does not reflect that fermentation is uniform throughout the colon but rather the likely relative absorption by the colonic mucosa. The caecum and the ascending colon are the regions in which there is the greatest fermentation rate of RS, mirroring the supply of carbohydrate in the diet (Topping and Clifton, 2001). SCFA levels fall during passage through the colon, due to their uptake and utilisation by colonocytes and bacteria (Nugent, 2005), with higher levels in the caecum and proximal colon and lower levels in the sigmoid colon, which correlate with the pattern of pH during fermentation. Within the large intestine there are variations in the pH levels during fermentation, with a pH range of 5.4 - 5.9 in the caecum and the ascending colon, which increases to pH 6.2 in the transverse colon and finally ranging from pH 6.6 - 6.9 in the descending colon (Nardgaard, 1998). This pH trend is due to the decreasing rate of SCFA production and the uptake and utilisation of SCFA by colonocytes.
Various data shows that colonic SCFA production is in the order of acetate > propionate â‰¥ butyrate, with a respective molar ratio of approximately 60:20:20 (Cummings, 1981). However various polysaccharides produce different SCFA, for example starch fermentation primarily yields acetate, propionate and butyrate, whilst pectin and xylan fermentation yields acetate only as the main product (Englyst et al., 1987). It has also been shown, both in vitro and in animal studies, that RS produces more butyrate than NSP (Noakes et al., 1996, Ferguson et al., 2000). A study in which 53 Australians consumed a mean total starch intake of 131g (within a typical Western diet), of which 5g was RS, determined that those with the highest RS intakes had the highest faecal butyrate concentration and therefore potentially reduced risk of colorectal cancer (Birkett et al. 1997). Therefore, RS can increase the production of total SCFA and also of the individual concentrations of acetate, propionate and butyrate (Ferguson et al., 2000). The various types of RS also show discrepancies in the increase in the production of the three main SCFA, as shown by Cummings et al. (1996), in which RS2 is reported to have increased the concentration of butyrate in humans, whilst RS3 did not. Within the same type of RS there have been marked differences; potato starch, unlike HAMS, was found to enhance the proportion of butyrate, with both sources of substrate classified as RS2 (Ferguson et al., 2000). However, not all published studies on the effects of RS on humans have shown the same effect on butyrate production (Hylla et al., 1998). This could be due to the type and quantity of RS used and the background dietary fibre, which may affect the location of the fermentation of RS. Even within the same RS type there have been discrepancies in findings; where Thorup et al. (1995) had observed a decrease in ACF using RS2 from potato starch, Young et al. (1996) found an increase in the incidence and size of tumours, also using RS2 from potato starch.
It has been shown that a lower, and hence acidic, pH is linked with protection from colorectal cancer (Walker et al., 1986). A decrease in pH indirectly influences the composition of the colonic microbiota, such as reducing the pathogenic clostridia bacteria, and reduces the ammonia absorption by the protonic dissociation of ammonia to NH4+, which is less diffusible (Wong et al., 2006). A lower luminal pH can also influence many other beneficial processes, including preventing the conversion of primary bile acids into secondary bile acids (Macfarlane and Cummings, 1991). There is also a decrease in the activity of bacterial enzymes such as Î²- glucoronidase, which causes the deconjugation and reactivation of potential mutagens (Muir et al. 1998). The drop in colonic pH is caused by the accumulation of SCFA and this reduces the solubility of free bile acids, which may decrease the potential tumour promoter activity that secondary bile acids can cause (Grubben et al., 2001). Secondary bile acids have a cytotoxic effect on colonic mucosa that leads to a compensatory increase in their proliferation. The hyper- proliferative mucosa has an enhanced sensitivity to mutagenic substances and is associated with an increased risk of colorectal cancer (Van Munster and Nagengast, 1993). An increased colonic acidification, of which is below a pH 6.5, inhibits colonic bacterial enzyme 7 Î±-dehydroxylase, which converts primary bile acids into secondary bile acids; deoxycholic and iithochoic acids (Van Munster et al. 1994). In the presence of deoxycholic acid there is an increased production of phosphatidylcholine diacylglycerol (DAG) in the human fermentation system (Morotomi et al. 1990). DAG increases the affinity of protein kinase C (PKC) for calcium, rendering it active at physiological levels and phosphorylating various target organs. Phorbol esters, which mimic DAG (in that they also activate PKC) are known to be tumour promoters but are not degraded (Bingham, 1997). Furthermore, decreasing colonic pH increases calcium availability for it to bind to free bile acids and fatty acids (Wargovich et al., 1984).
It has been noted that secondary bile acids show involvement, as a promoting agent, in the adenoma- carcinoma sequence of colorectal cancer. Christl et al. (1997) conducted a study, carried out in vitro, that found that at pH 6, there was significantly more primary bile acids that remained with a lesser production of secondary bile acids, and that at pH 7 total bile acid concentration was lower. This indicated that there is an inhibition of bacterial breakdown of primary to secondary bile acids, when starch is simultaneously fermented. Showing one of the mechanisms in which RS has the potential protective factor against colorectal disease, by the fact that the reduction of pH is explained by the SCFA production. In humans consuming a low RS diet, the colon has a neutral pH 7.2 Â± 0.2. However, with an acidic environment there is healthy bacterial proliferation and inhibition of pathogenic bacteria (Le Leu et al., 2002).
In a low pH, alkaline toxic compounds degrade, which inhibits their absorption into the body (Bird et al., 2000). High faecal concentrations of NH3 and phenols maybe detrimental to colonic health because phenols (e.g. phenol and p-cresol), which are a product of bacterial metabolism of aromatic amino acids, are promoters of skin cancer and have been show to aid the development of bowel and bladder cancer (Macfarlane and Cummings, 1991). In rodent models it has been shown that NH3, the major end product of bacterial metabolism of nitrogenous substances, is a promoter of carcinogenesis (Tsujii et al., 1992).This has also been supported in patients with uterosigmoidostomies who have high concentrations of luminal ammonia have an increased risk of tumours developing distal to the site of ureteric implantation (Tank et al., 1973).
Out of the three main SCFA, butyrate is the one that is the most interesting due to its protective effects against colorectal cancer (Whitehead et al., 1986). It is the primary energy source for cells of the caeco- colonic epithelium and is preferred to glucose and glutamine as a major substrate for maintenance-energy producing pathways for the colonocyte, therefore sparing pyruvate and suggesting that there is a hierarchy of oxidation substrates (Roediger, 1982). 70-90% of butyrate is metabolised by colonocytes, with butyrate oxidation making up 70% of colonic mucosa oxygen consumption (Cook and Sellin, 1998). However, butyrate has apparent opposing effects on colonic tumour cell lines, known as the "butyrate paradox", inducing a differentiation of a range of tumour cell types and thereby leading neoplastic colonocytes to acquire phenotypes more consistent with normal mature cells (Whitehead et al., 1987). The production of butyrate by fermentation is also associated with reduced rate of aberrant crypt foci (ACF) formation, which can be used as markers for carcogenesis of colorectal cancer (Coleman et al., 2002), and also of tumour mass, provided that there is fermentation within the distal colon (Le Leu et al., 2007). Perrin et al. (2001) also showed that fibres that gave a stable production of butyrate from proximal to distal colon resulted in a decreased rate of aberrant crypt foci formation.
Apoptosis is an important regulatory process that protects against the development of tumours and it is suggested that it is a better predictor of cancer outcome than cell proliferation in carcinogen induced animal models (Bedi et al., 1995). It removes cells with genomic instability providing an innate cellular defence against carcinogenesis. One of the mechanisms in which butyrate may be thought of as being protective against colorectal cancer is by inhibiting histone deacetylase and therefore enhancing the apoptosis of genetically damaged cells, through a histone hyperacetylation- mediated pathway (Hinnebusch et al., 2002). At physiological concentration, it has also been shown to inhibit proliferation and also induce differentiation of colon cancer cells in vitro, which, in part, may explain the correlation between high fibre diets and the low incidence of colorectal cancer (Young et al., 2005). Butyrate works as an anti-proliferative agent by stopping cell growth in early G1 phase of the cell cycle, by inducing p21WAFI/Cip1 protein (an inhibitor of cyclin D1) and mRNA levels (Chai et al., 2000). At the G1 blockage of the cell cycle there would be DNA checkpoint-mediated repair, however the inhibition of histone deacetylase alters both gene expression and decreases the accessibility of chromatin to DNA repair enzymes, and therefore induces differentiation (Kruh et al., 1994). The apoptosis is caused through the hyperacetylation of histones (H3 and H4) that result in a more open form of DNA, which prevents mutations occurring that would likely happen with a high turnover of cells (Grunstein, 1997). A study by Boffa et al. (1992) showed that luminal butyrate levels are inversely proportional with colonic cell proliferation and positively associated with histone acetylation. These findings are backed up by the demonstration that an RS3 diet, in an animal model, could be preventative of tumour development in vivo, by enhanced apoptosis and decreased cell proliferation, which included the involvement of enhanced removal of damaged cells and increased repair efficiency. These effects were therefore ascribed to the RS3 that was used, as it provided a stable and increased butyrate supply for the colonic mucosa (Bauer- Marinovic et al., 2006). Bajka et al. (2008) also found that in their animal model, colonic exposure to SCFA resulted in a strong negative correlation with DNA damage and therefore higher colonocyte apoptosis with HAMS, which would elevate levels of butyrate. Conversely, in a study conducted by Le Leu et al. (2002), there was no change in the acute apoptotic response to a genotoxic carcinogen between a RS (HAMS) and RS- free diet, suggesting that HAMS did not offer any protection against colorectal cancer via the regulation of acute apoptotic response. However, as was stated, only a modest concentration of RS was used, and that to see a positive result would require higher concentrations of RS. Those in vivo studies that show no protection with known butyrate producing fibres, might relate to the heterogeneity of the fibre and of the basal diet, the chosen biomarker, animal model and stage of colon carcinogenesis (Perrin et al., 2001).
The large intestine is an environment with a complex network of interactions formed between colonic mucosa, intestinal microbiota and their fermentation products, mucus from colonocytes and alimentary components including bile acids. Mucus has an important role to play in the protection and immunology of providing the right environment for colonic microbiota and contains mucins, which are high molecular mass glycoproteins that are responsible for the physical properties of intestinal mucus (Forstner, 1978). Butyrate affects the expression of MUC genes, which code for the protein core of mucins and therefore its composition, as well as mucin production (Fontaine et al., 1996).
Inhibiting nuclear factor-kappaB (NF-ÎºB) signalling has been shown to have potential implications in a therapeutic role against cancers (Sethi et al., 2008). There is evidence that butyrate has an inhibitory effect on proinflammatory cytokine induced NF-ÎºB activation and therefore this represents the prospective efficacy that RS could have in treatment of colorectal cancer (Andoh et al. 2003).
There are further ways in which butyrate could be administered to achieve protective health benefits against colorectal cancer. In animal models, butyrate was given as gastroresistant, slow release pellets and was recorded to increase apoptosis in the colonic epithelium, providing additional evidence of its beneficial effects (Caderni et al., 1998). It has also been suggested that butyrate enemas, in a long term therapy, could be useful in reducing the risk of colorectal cancer in patients with ulcerative colitis (D'Argenio et al., 1996). Scheppach et al. (1992) reported that with a direct infusion of butyrate into the colon there was remission of distal ulcerative colitis. A study by Bonnotte et al. (1998), showed that butyrate can enhance the sensitivity of colon carcinoma cell lines to Fas- mediated apoptosis, which gives implications that it could be used as an adjuvant with chemotherapy and immunotherapy in colorectal cancer. Finally, adding large amounts of butyrate to drinking water or food has unfortunately shown no protective effects against carcinogenesis, in an animal model (Freeman, 1986).
Resistant Starch as a Prebiotic
Prebiotics are non- digestible foods, including RS, which act as growth substrates that are directed specifically at potentiating the growth and activity of bacteria naturally residing in the colon (Gibson and Roberfroid, 1995). Probiotics are live preparations of a single or combination of bacterial species that have beneficial health properties when ingested. Two specific species of colonic microbiota, Bifidobacterium and Lactobacillus (a strain of lactic acid bacteria, LAB) have been associated with health benefits and have resulted in the sciences of probiotics and of prebiotics (Wong et al., 2006). Probiotics need continuous ingestion for them to have any sustained effect, but also need to be able to colonise a site in the large intestine, which can be facilitated by prebiotics. The combination of prebiotics with probiotics is known as synbiotics, in which there is a synergistic interaction between the two (Topping et al, 2003). Experimental findings have shown a potential protective effect of LAB against the development of colorectal cancer. RS has a number of prebiotic effects such as the growth of beneficial microbiota and the inhibition of specific bacterial enzymes (e.g. Î²- glucoronidase). These effects take place due to the fermentation product butyrate, and it is the activity of butyrate that has the beneficial impact on colonic bacteria (Young and Le Leu, 2004). Fermentation of RS and other dietary fibres enhance the formation of LAB and therefore show more evidence of their health benefits in protection against colorectal cancer (Wollowski et al., 2001).
Glutathione transferase is an important species of enzyme that is involved in the detoxification of both electrophillic products and compounds associated with oxidative stress; of which glutathione transferase Ï€ is the most abundant type in colonocytes. It has been indicated that butyrate increases glutathione transferase Ï€ in colonocytes, and may enhance its expression in colonic tissue, therefore acts as a prebiotic factor, from RS acting as a prebiotic and hence may be an important mechanism against colorectal cancer (Csordas, 1995).
Epidemiological studies on Resistant Starch
It was shown that low risk populations, such as South African Blacks eat low fibre but high starch diets, whereas higher risk populations, such as South African Whites have relatively high NSP and low starch intakes (O'Keefe et al., 1999). This may explain why the incidence of colorectal cancer in South African Blacks is much lower than in whites (Walker and Burkitt, 1976). Black households cook maize porridge, which is one of their staple foods, only once a day due to limited access to energy sources. Therefore it is then eaten cold and so has more RS available due to the heating and cooling processes, which may give explanation as to the difference in colorectal cancer rates (Ahmed et al., 2000).
Although there have been many promising findings, some studies have reported unexpected results. A study by Muir et al. (1998), had twelve Australian (therefore high risk) subjects eat a high-starch, higher RS diet that is similar to a diet which might be eaten in China, where colorectal cancer is rare. The results found that only one outcome was favourable; a lower faecal pH, and that the less favourable outcomes included lower faecal bulk, lower SCFA concentrations, slower transit time and higher faecal NH3 and phenol concentrations. These unanticipated results might be because the increase in RS was not high enough to see an effect. It also might be the case that it would take a longer period of time for there to have been an effect as there have been observations that sufficient time for colonic microbiota and its environment to adapt is necessary before changes in SCFAs are observed and therefore other physiological effects (Topping and Clifton, 2001). Another factor could have been that the Chinese diet had lower concentrations of insoluble NSP which would have contributed to the negative results and therefore the digestion and metabolism of fermentable substrates occurred higher in the colon, where they are less detectable (Muir et al., 1998).
Even though epidemiological data regarding the role of dietary fibre in colorectal cancer has been inconclusive, there is a large European study of over half a million subjects, EPIC, which has shown significant risk reduction of colonic neoplasia with an increase of dietary fibre consumption, which includes RS in its definition of dietary fibre (Bingham et al, 2003).
Further investigation of Resistant Starch
As most colorectal cancers occur in the distal portion of the colon, it is of importance to focus fermentation dependent events and thus butyrate production at his site, in order to reduce the incidence of colonic carcinogenesis. However, the fermentation of RS predominantly takes place in the caecum and proximal colon, where substrate availability is greatest, however the presence of other carbohydrates can alter the colonic physiology and therefore where fermentation occurs along the colon (Wong et al., 2006). Due to this fact that RS fermentation occurs rapidly in the proximal colon, it has results of higher butyrate and lower ammonia concentrations predominantly in the proximal regions of the colon. However, with the addition of insoluble NSP, the fermentation of RS can be shifted further distally and therefore maintaining higher butyrate and lower NH3 concentrations in the distal regions. The combination of RS and insoluble NSP is common in human diets and hence these findings are physiological relevant to human (Govers et al., 1999).
When RS was combined with wheat bran it was found that there was a much higher production of SCFAs; in particular butyrate levels (Le Leu et al., 2002). It was shown that the combination of RS with wheat bran was also effective in lowering NH3 and phenol concentrations, primarily through the dilution effects of increased faecal bulk (Muir et al, 2004). Negative results seen, in which a RS diet actually increased the number and size of tumours, were then reversed when RS was combined with wheat bran (Englyst et al, 1987). Work done by Muir et al. (2004) gave the implication that different combinations of RS and other dietary fibres are required for maximum health benefits with regards to colorectal cancer.
Morita et al. (1999) showed that when RS was combined with psyllium, its site of fermentation was pushed further distally along the colon. Govers et al. (1999) reported that when a diet of RS with wheat bran was given the fermentation site was displaced from the caecum to further along the colon, resulting in an increased butyrate concentration and therefore potentially greater colonic protection distally. Further studies are needed to examine whether large amounts of varied types of RS are able to give the same effects of wheat bran in the distal colon.
There have been acylated starches, such as butyrylated HAMS (HAMSB), designed to provide rapid and sustained delivery of SCFA to the colon. In animal studies these have shown to be twice as effective as HAMS in raising colonic SCFA levels of the acid that has been esterified; in the sense that butyrylated SCFA results in a greater increase in butyrate than HAMS. HAMSB is also effective in raising the concentrations of butyrate in the distal colon, which is the common site of colorectal cancers (Clarke et al. 2008).
Resistant Starch, classified as a dietary fibre, seems to confer various colonic health benefits including having a mild laxative effect, softening stools, encouraging the growth of beneficial bacteria and thus acting as a prebiotic, increasing luminal short chain fatty acid concentrations, decreasing faecal pH, increasing faecal bulk and reducing the concentration of toxic and carcinogenic compounds. These effects are partially mediated, if not to a large proportion by the actions of butyrate activity, which is one of the short chain fatty acids produced during the fermentation of Resistant Starch by colonic microbiota.
Le Leu et al. (2002) showed that increases in short chain fatty acids and butyrate levels correlated with an apoptosis in the distal colon, providing evidence that fermentation-related events were responsible for the increase in apoptosis. There was also evidence that supplementation with Resistant Starch in a no- fibre diet resulted in increased faecal bulk and lowered faecal pH. However, with all the various epidemiological studies there has not been shown a direct link between the dietary factors, intermediate markers of risk and the end point of colorectal cancer in humans. However, limitations in knowledge are due to the variabilities observed among studies in which different sources of Resistant Starch are used, the range of subjects used whether they are human or animal and the complications that arise with the reliability of associating the differing results from study to study. Future research is necessary for a better understanding of the relationships between dietary factors, short chain fatty acid production and colonic microbiota, especially in relation to butyrate distribution along the colon and the risk of carcinogenesis.
Resistant Starch has many physical and chemical properties similar to those of dietary fibre and therefore shows promise of physiological benefits and protection against colorectal cancer in humans. Even if Resistant Starches have not shown a clear health benefit in terms of colorectal cancer risk reduction, there are still many physiological advantages with adequate consumption of Resistant Starch, including increased butyrate concentrations and all the benefits that this brings about.