Prebiotic fibres

Prebiotic fibres
A natural source of cancer prevention
Nutraceutical Business & Technology – January/February 2007, p 42-46
With more than 11 million people diagnosed every year, cancer is a leading cause of death worldwide. However, this
disease is largely preventable, according to the World Health Organisation. For example, it is well-known that changing
dietary patterns can contribute to reduce exposure to cancer risk. The identification and reduction of the presence of
carcinogens in our diets are already dealt with by scientists and industrials. On the other hand, other substances could
be used as dietary supplements for their protective action. One candidate is the family of short-chain fructooligosaccharides, soluble dietary fibres that can be added in food for their prebiotic properties.
Figure 1 : scFOS synthesis
Colorectal cancer
According to the World Cancer Research Fund, only 5% of death by cancer are caused by hereditary, genetic factors,
underlying the great impact of our environment and nutrition on the development of such pathology. In the case of
colorectal cancer which presents the highest incidence when we consider both sexes, scientific evidence pointed out that
high intake of cooked red meat is positively correlated with a high risk of colorectal cancer, whereas consumption of fruit
and vegetables, associated with physical activity can probably decrease this risk. Based on an epidemiological study in
rural Africans having a high-fibre based diet, Burkitt first developed the “dietary fibre hypothesis” as a protective factor of
colorectal cancer in 1969. However, other studies provided conflicting results potentially related to the heterogeneity of
the tested fibres and of the basal diet. It has also been suggested that a consumption of more than 30g per day of fibre
1
would be needed to afford protection against colorectal cancer .
Prebiotic fibres
Short-chain Fructo-oligosaccharides (scFOS) are soluble fibres that are already used for food supplementation because
of their nutritional and health benefits. They naturally occur in many vegetables like onion, garlic, wheat, etc but can also
be produced from sucrose. The β1-2 link between the different molecules of glucose and fructose (Figure 1) is not
hydrolysed by digestive enzymes and can only be fermented by certain strains of bifidobacteria and lactobacilli. Thus,
scFOS belong to the family of prebiotic ingredients, which are selectively fermented ingredients that allow specific
changes in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well being
2
and health . ScFOS are one of the most efficient prebiotic ingredients to stimulate the growth of bifidobacteria within the
3
colon. Their bifidogenic effect starts at 2.5g and proportionally increases with the dose up to 10g/day . The modification
of the colonic microflora with the consumption of scFOS leads to higher concentrations of short-chain fatty acids like
butyrate and maintains a slightly acidic pH in the lumen. Through the stimulation of the growth and the fermentative
activities of bifidobacteria, scFOS have demonstrated their efficiency to beneficially improve the colonic environment and
4
improve digestive comfort . Furthermore, prebiotic ingredients are known to act at different levels to reduce the exposure
of the colon to carcinogens and modulate cellular events that are important for cancer prevention.
Mechanism of action through butyrate action
Epithelial cells are normally renewed every 5 to 7 days. This is a process in which butyrate plays an important role via a
direct action on the level of gene expression, involved at different steps of cell cycle. Butyrate stimulates the proliferation
of stem cells near the basis of the crypt in the mucosa, enhances the differentiation of the epithelial cells when they
5
migrate up the crypt . Any disturbance of this cycle may lead to aberrant epithelial cells which are associated with the
6, 7
onset of carcinogenesis .
The development of a cancerous tumour initiates by a hyperproliferation of the intestinal mucosa cells at the level of the
villi, whereas cells should be already differentiated when they migrate from the crypt to the villi. This hyperproliferation of
the cell mucosa leads to the development of early adenoma, which further evolves into advanced adenoma and
carcinoma able to trigger metastatic disease. According to in-vitro experiments, butyrate seems to have a protective
effect by inhibiting the hyperproliferation of cells along the villi and by inducing the apoptosis (cell programmed death) of
7
the adenomic and carcinomic cells .
Reduction in exposure to carcinogens
0
tu
m
or
s
tu
m
or
1
tu
m
or
s
2
tu
m
or
s
3
4
tu
m
or
s
number of mice
In addition to the beneficial impact of higher butyrate concentrations in the colon, scFOS can also impact on carcinogens
exposure of the epithelial mucosa. In animals, they have been shown to reduce polyamines (like putrescine ) faecal
8
concentrations . These polyamines can be provided by the diet or produced from bacterial fermentation occurring in the
distal part of the colon and have
been recognised as potential
carcinogens for the colon.
The metabolism of bile acids by
6
bacterial activities is of great
5
importance when considering
colorectal
cancer.
Bacterial
4
degradation of primary bile acids
3
leads
to
accumulation
of
secondary
bile
acids
(like
2
lithocholic
acid)
that
have
1
demonstrated
capacities
to
Control d
iet
induce cell necrosis or to promote
WB
0
tumour activity during in-vitro and
Sc -FOS
studies with animal models. By
maintaining
slightly
acidic
Diet
conditions
of
pH,
scFOS
consumption may limit the
production of secondary bile
Figure 2 : Effects of dietary fibres on occurrence of colorectal tumours in
acids and reduce colon exposure
mice
to these toxic compounds.
Prevention of tumours in animals
The effect of scFOS to stimulate the production of butyrate has been clearly demonstrated in several animal studies
investigating the effect of Sc-FOS on colorectal carcinogenesis. A comparison of the capacity of different fibres to
increase butyrate production confirmed that only fibres promoting a stable production of butyrate in the colon, such as
scFOS, are susceptible to have an effect on the development of colorectal cancer in rats by reducing the number of
9
aberrant crypt foci, considered as precancerous lesions of the colonic epithelium . Another study confirmed the effect of
scFOS to reduce the number of colon tumours. It was observed in Min mice (genetically predisposed to adenomatous
polyposis and sporadic colon cancer) supplemented with scFOS instead of receiving either the wheat bran-enriched or
10
the control diet (Figure 2). This effect seemed to be linked to the interaction between the digestive flora modified by
scFOS and the intestinal immune system. Indeed, after receiving scFOS, mice also showed an increase number of
lymphoid nodules along their intestine.
In Humans
Patients with adenomatous polyps or colon cancer present a modified pattern of colonic fermentation, illustrated by lower
11
butyrate concentrations than in healthy subjects . The daily consumption of scFOS modifies the profile of the colonic
microflora as well as its fermentative activities. In patients with small adenomas, the consumption of 10g of scFOS per
day can help to enhance the production of butyrate and increase its concentration until values observed in healthy
12
patients .
As mentioned above, a wide range of bacterial enzymatic activities is able to generate potentially carcinogenic
metabolites. For example, β-glucuronidase is one of the most important enzyme that releases toxic aglycones in the
colon. In humans, likely due to an increased proportion of bifidobacteria and lactobacilli, scFOS have been shown to
significantly reduce the activity of β-glucuronidase enzyme after eight days of supplementation at 10g per day, whereas
13
high-risk diets for colorectal cancer have generally shown an increase of this activity compared to low-risk diets .
Considering this effect, ScFOS have also been shown to influence the metabolism of bile acids in the colon.
Furthermore, epidemiological studies highlighted higher concentrations of secondary bile acids in populations at high risk
of developing colorectal cancer. In humans, scFOS were shown to increase faecal concentrations of primary bile acids
12
while decreasing concentration of secondary bile acids (Figure 3).
Figure 3: Effects of scFOS consumption (10g/day) on faecal
concentrations of bile acids
1500
mmol/g DM
1000
500
Primary bile acids
0
Secondary bile acids
M0
M3
Tertiary bile acids
-500
-1000
-1500
time (months)
Through their effect on the gastrointestinal flora, short-chain fructooligosaccharides can beneficially alter the bacterial
metabolism, by increasing the proportion of bifidobacteria and enhancing the production of butyrate in people with low
bifidobacteria or insufficient butyrate production. They can also reduce the exposure of the colon to carcinogens. Thus,
short-chain fructo-oligosaccharides can stand as candidate fibres to be tested in prevention studies for colorectal cancer
or as a nutritional support concomitant to chemical treatment of patients.
References:
1. Fergusson, L.R. and P.J. Harris, The dietary fibre debate: more food for thought - commentary. Lancet, 2003. 361: p.
1487-1488.
2. Gibson, G.R., et al., Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutrition
Research Reviews, 2004. 17(2): p. 259-275.
3. Bouhnik, Y., et al., The Capacity of short-chain fructo-oligosaccharides to Stimulate Fecal Bifidobacteria: A DoseResponse Relationship Study in Healthy Humans. Nutrition Journal, 2006. 5(8).
4. Desvignes, D., et al., Regular consumption of short-chain fructo-oligosaccharides improves digestive comfort of
subjects with minor digestive disorders (FDD). NAFAS, 2005. 3(6): p. 57-58.
5. Smith, J.G., W.H. Yokoyama, and J.B. German, Butyric acid from the diet: actions at the level of gene expression.
Critical Review Food Science Nutrition, 1998. 38(4): p. 259-97.
6. Salminen, S., et al., Functional food science and gastrointestinal physiology and function. British Journal of Nutrition,
1998. 80: p. S147-S171.
7. Scheppach, W., H. Luehrs, and T. Menzel, Beneficial Health effects of low-digestible carbohydrate consumption.
British journal of Nutrition, 2001. 85(suppl 1): p. S23-S30.
8. Hussein, H. and G. Sunvold, Dietary strategies to decrease dog and cat fecal odor components, in Recent Advances
in Canine and Feline Nutrition, G. Reinhart and D. Carey, Editors. 2000, Orange Frazer Press: Wilmington, OH. p.
153-168.
9. Perrin, P., et al., Only fibers promoting a stable butyrate producing colonic ecosystem decrease the rat of aberrrant
crypt foci in rats. Gut, 2001. 48: p. 53-61.
10. Pierre, F., et al., Short-chain fructoligosaccharides reduce the occurence of colon tumors and develop gut-associated
lymphoid tissue in min mice. Cancer Research, 1997. 57: p. 225-228.
11. Weaver, G.A., et al., Short chain fatty acid distribution of enema samples from sigmoidoscopy population : an
association of high acetate and low butyrate ratios with adenomateous polyps and colon cancer. Gut, 1988. 29: p.
1539-1543.
12. Boutron-Ruault, M.C., et al., Effects of a 3-mo consumption of short-chain fructo-oligosaccharides on parameters of
colorectal carcinogenesis in patients with or without small large colorectal adenomas. Nutrition and Cancer, 2005.
53(2): p. 160-168.
1
13. Rafter, J., et al., PASSCLAIM _Diet-related cancer. European Journal of Nutrition, 2004. 43(0): p. ii47-ii84.