Probiotics and Colorectal cancer

Colorectal cancer increasingly seems likely to be caused by a variety of factors including an inbalance of the bacteria in the intestine, and a surfeit of yeasts and microbes.

However, in normal daily life, even though there are many factors that weigh against you, colon cancer prevention - indeed preventing cancer in general - can be helped significantly by taking Probiotics. 

A variety of strains of bacteria available in various ´probiotics´ exist to help you top up levels of beneficial bacteria in your intestine, enhancing your immune system, killing microbes, releasing vitamins from your food, helping to excrete toxic chemicals from the body, and even killing cancer cells. They can help you prevent cancer, and they can help you beat cancer if you already have it.

Fighting the microbes and yeasts in your gut

In icon Issue 3 2006  we covered the general benefits of probiotics and, in researching the article, we can genuinely say how surprised we were: The amount of top quality research – including well-planned and executed clinical trials – that indicates beneficial bacteria are crucial to very many aspects of our health - was simply amazing. We were not aware of the serious benefits these bacteria bring to our health, and we doubt whether most of our readers - including not just patients but Doctors, nurses and oncologists - have much idea either. 

Colorectal cancer (CRC)

In the UK, colorectal cancer (CRC or bowel cancer) is the third most common cancer for men and the second most common cancer for women. Globally, the picture is similar. Although there were some claims in a CRUK report that a better diet is producing a reduction in this cancer in the UK, we can find little evidence of that in the figures. In fact the truth is that a modern diet, (along with modern lifestyle factors such as smoking, obesity, inactivity and even increasing diabetes levels – all of which have been linked to increased risk), is probably making this cancer a great deal more prevalent. Even more depressing is the fact that mortality from this cancer is rising (Boyle & Langman 2000). One estimate puts the lifetime risk for Europeans of developing this disease at 2% (Cappocaccia et al 2002). In the EU, 6% of men and women may be affected by the age of 75. Western Europeans may be particularly susceptible due to the combination of inherited risk and a diet often high in fat and low in fibre (de Ferlay et al 2001; Gill & Rowland 2002).

There is probably no cancer more logically attributable to diet. Research, carried inicon Cancer Watch recently, from Japan indicated that a doubling of salt consumption doubled risk; other research we have carried indicates red meat consumption and animal fat consumption go hand in hand with risk, as does alcohol intake.

The prime group of sufferers is concentrated in the 60 age group – but then 85 per cent of all cancers are. However a growing number of pregnant women seem to be succumbing and research amongst sufferers has indicated a higher prior incidence of irregular bowel movements and that prior (often chronic) bowel inflammation, Crohn’s disease, severe ulcerative colitis and IBS may be precursors.

Some ‘foods’ are known to reduce risk.  A diet high in natural fibre is shown as a benefit in research, as is a good level of garlic intake (Boston Nurses Study). And here the ‘clues’ become interesting via two routes.

Firstly, since John Vane won his Nobel Prize in 1982 for the finding that aspirin could reduce the level of ‘harmful’ eicosanoids, (localised hormones produced at the cellular level and lasting barely one and a half seconds), a great number of studies have shown that garlic, ginger and long-chain omega 3 also have this effect – not merely salicylin. All seem to reduce ‘bad’ eicosanoids and reduce the effect of a negative enzyme, named Cox-2. One effect of these ‘bad’ eicosanoids is to cause inflammation – you may have heard of prostaglandins - directly or via a carcinogenic bile acid. And inflammation, especially via the formation of polyps, is a precursor to CRC. (Aloe Vera would be a good source of natural anti-inflammatories and is known to be very calming).

Omega-3 and vitamin D have both been shown to directly reduce the production of this bile acid (produced most frequently by the excesses of animal fats and alcohol). The vitamin D factor may explain why there is some research indicating that dairy, milk and calcium products can reduce risk. Vitamin D and calcium have a strong biochemical inter-relationship in the body. It is more likely that the calcium is having an effect through altering levels of vitamin D. (You can get your vitamin D  through sunshine, fish oils or supplementation – see icon issue 2 2006 for a complete review on this essential cancer fighting vitamin)

Secondly, as we have reported before, one theory of CRC is the negative presence of ‘yeasts’. In icon Cancer Watch we have covered recent US research about microbes as the cause of CRC. Microbes, yeasts, viruses are all parasites and can produce toxins whilst draining you of key nourishment.

We have covered Gerald Green’s theories and anti-yeast diets before (Click here  for full details). Garlic can act as a natural ‘killer’ to a number of yeasts and harmful microbes and Gerald suggests garlic along with a number of other natural ‘foodstuffs’ from Caprylic acid to Pau D’arco and the use of ………….Probiotics.

Which takes us full circle.  And so here in Part II of our in-depth look into the serious use of Probiotics we asked Linda Thomas, PhD FIFST (Science Manager at Yakult UK Ltd.) to tell us about this vital element that seems so often to be overlooked in the prevention of cancer and especially Colorectal Cancer.

Diet and CRC

Everything we eat passes through our digestive systems, so it is no surprise that diet can affect our risk of developing any type of gut cancer.  However, this is very hard to prove. There is no one cause for cancer, and it is particularly difficult to prove any relationship between diet (consisting of many foods) and cancer. In 1992, a large, long term European prospective study (EPIC: the European Prospective Investigation of Cancer) was set up, involving 10 countries and 521,486 people who will each be followed for at least 10 years.  So far, this has reported that a diet high in fibre reduces CRC risk, whereas a diet high in red or processed meat increases CRC risk. The EPIC study has also concluded that a high intake of fish may reduce risk, but this trend was less clear and seemed to vary between countries. A further finding was that a diet high in milk and cheese and high levels of calcium in the diet may reduce risk? but it was also shown that a diet high in fat was a general cancer risk. Similar conclusions have been drawn from epidemiological data (see below Gonzalez 2006)

Dr Tony Leeds, a principal investigator and senior lecturer in nutritional sciences at King’s College London, comments: ´Most of the changes needed to reduce colorectal cancer risk are changes that reduce risks of other major degenerative problems such as cardiovascular disease.  The risk reduction approach includes controlling overweight and obesity, moderating alcohol and red meat intake, and increasing intake of fruit and vegetable consumption.  There is evidence too for regularisation of bowel function by increasing intake of cereal foods and physical activity.  Most healthy diet and lifestyle advice given by health professionals now includes these recommendations´.

What are probiotics again?

Probiotics and prebiotics were recently reviewed in icon. Before we look at their particular relevance to CRC, perhaps we should refresh our memories.

The general concept of probiotics is a very old one. In Genesis 18:8 we are told: ‘Abraham owed his longevity to the consumption of sour milk’. In 1907, Eli Metchnikoff (the Russian Nobel prize winner) attributed the healthy longevity of Bulgarian peasants to their consumption of naturally fermented yogurts containing many Lactobacillus species. Yogurts we eat today are not necessarily probiotic unless labelled as such, since they are normally made with just two species of bacteria (Lactobacillus bulgaricus and Streptococcus thermophilus) and the particular strains may not survive the digestive process. In 1996, the first probiotic food appeared in the UK: a fermented milk drink (Yakult). This was developed over 70 years ago in Japan. Now an almost bewildering array of probiotic products is available – drinks, yogurts, capsules, powders, etc. Many published research papers have increased the body of evidence supporting the health benefits associated with certain probiotic strains. 

So, what exactly is a probiotic?

Probiotics are ‘live microbial food ingredients that, when administered in adequate amounts, confer a health benefit on a host’ (WHO/FAO 2002).

Most probiotics are species of lactobacilli and bifidobacteria, but importantly probiotics must:

• Grow and be active in the lower intestines (even for just a few days). To do this they must survive and pass through the stomach (the acidity of which kills most bacteria)
• Have a proven health effect (i.e. one that has been shown in clinical trials)
• Improve the balance of bacteria in the gut, so that the activities of beneficial bacteria outweigh those that may be harmful
• Be properly identified and named strains (i.e. not just a species, which consists of many strains). These strains must be safe to eat, and the probiotics must stay alive and remain stable before being eaten or drunk.

Prebiotics are food ingredients that stimulate the growth of beneficial bacteria, including probiotics. Prebiotics are not digested in the stomach or upper intestines, so they reach the large intestine (or colon) to feed the beneficial bacteria there. Harmful bacteria that may also be in the colon cannot use prebiotics as an energy source, so a diet high in prebiotics will favour the growth of beneficial bacteria in the colon. Prebiotics are available naturally in certain foods: the Allium group of plants (onions, garlic, shallots, leeks), asparagus, chicory, and Jerusalem artichokes, and to a lesser extent in beans and pulses and some cereals such as oats. Inulin is a pure form of the sugar fructose, that is the basis of many prebiotic carbohydrates, and is often used as a prebiotic supplement in certain food products.

To confuse things further, the combination of both is called a synbiotic.

Why should probiotics/prebiotics influence cancer risk? 

It has been thought for some time that the gut microflora could be involved in causing CRC. Certain bacterial species in the colon produce harmful substances that are almost certainly linked to cancer.  Beneficial bacteria may prevent the growth of these organisms, and some beneficial species even produce anti-carcinogenic substances. Since probiotics modify the balance of gut bacteria in favour of beneficial bacteria, it seems more than a possibility that probiotics might help reduce CRC risk.  Experts think this is probably due to a combination of several different mechanisms (as shown in the table).

What are the probiotic effects that may reduce cancer risk?

Preventing damage to the chromosomes of the gut cells

If you are thinking of buying a probiotic, you might like to look at the Natural Selection Product of Choice. You can do this by  clicking here

Probiotic bacteria grow and are active in the colon, and so compete with harmful bacteria for food and space and help suppress them. Some probiotics also produce antibacterial agents. Species of Lactobacillus and Bifidobacterium produce lactic acid and similar short chain fatty acids; this makes the gut lumen more acidic and unfavourable to the growth of harmful bacteria. Dietary fibre, including prebiotics, supports the growth of lactobacilli and bifidobacteria. This will increase levels of butyric acid in the gut - a compound important for the growth and regulation (including programmed death) of colon cells.

Epidemiological studies show a link between CRC risk and high fat diets and this is thought to be due to raised levels of bile acids (which help digest the fat) in the colon. These salts are released into the small intestine, and also re-absorbed there, but some may pass into the colon. The breakdown products of bile may have a cytotoxic effect on the cells lining the colon, increasing cell proliferation and possibly cancer. Probiotic modulation of the intestinal microflora may affect the activity of one of the enzymes (7a-dehydroxylase) forming these toxic products, but probiotics may also reduce the toxicity of bile salts by binding to them.

To summarise, at the molecular level, probiotics may help by:

• suppressing the activities of enzymes associated with carcinogen formation (e.g. ?-glucuronidase, nitroreductase)
• binding to mutagens
• stimulating the activity of beneficial enzymes that inactivate carcinogens (e.g. glutathione S transferase).
• forming conjugated linoleic acid, a compound with anti-inflammatory properties that may inhibit development of cancer.
• Increasing levels of butyric acid in the colon: an important energy source and growth regulator for colon cells.

Probiotics can also help support and stimulate the immune system indirectly and directly. This may partly explain the results of a study in Japan, which reported anti-cancer effects outside the colon. The particular probiotic helped prevent the recurrence of bladder tumours, a protective effect that was thought to be due to the combination of the probiotic reducing levels of toxic substances excreted via the bladder but also by stimulation of the immune system, in particular the activity of natural killer (NK) cells (innate immune cells that are thought to be involved in cancer protection) (Aso et al 1995).

How do scientists show probiotic involvement in helping to reduce cancer risk?

Professor Ian Rowland, (Professor of Human Nutrition at the University of Ulster), is one of the world’s leading experts on diet and cancer prevention, with a particular interest in probiotics.  This is what he has to say:

‘Studies using cultures of human colon cells grown in flasks show that probiotics can interfere with the action of cancer forming substances. When probiotics have been given to laboratory rats, they have decreased the level of gene damage (an important event in cancer) and reduced the numbers of tumours induced in the colon. There are only a few studies in humans because of the difficulties in studying the effects of diet on human cancer. However, in the few studies that have been done, probiotics - sometimes in combination with prebiotics - have shown effects suggesting that they may reduce the risk of colon cancer.’

Real proof of probiotic benefit must come from ‘double-blind, placebo-controlled, human volunteer studies’. These are trials in which one set of people consumes the probiotic and another set of patients consumes a placebo: a product looking and tasting exactly the same as the probiotic but with no activity because it has no bacteria. None of the volunteers know which they are taking. Even better, neither do the doctors and nurses involved in the trial. Someone else ‘de-codes’ the results after the trial has finished. This is all to ensure the trial is completely objective and the results can be trusted. This can be done relatively easily in probiotic trials.

The main problem with all cancer trials is that they involve high numbers of patients over many years.  Another problem is there is no generally accepted scientific way of measuring the risk of developing cancer or the progression of carcinogenesis. Biomarkers are used instead, but these may not necessarily be a true indication of cancer risk or progression. The following biomarkers have been used:

• those relating to the health, correct growth and division of the cells lining the colon
• those that measure levels of carcinogenic or other harmful substances in the faeces (a marker for colon levels)
• those that are markers of the immune system, the bulk of which is located in the gut.

To give one example – the work of Belgian scientists who used biomarkers to measure levels of two toxic metabolites (p-cresol and ammonia) in the faeces of healthy volunteers. These are compounds formed by microbial fermentation of protein in the colon. The results showed that consuming either a probiotic (species of Lactobacillus and Bifidobacterium) or a prebiotic (oligofructose-enriched inulin), resulted in reduced levels of these compounds (de Preter et al 2006). 

What evidence is there?

CRC progresses along a well-defined adenoma-carcinoma sequence, with histological changes associated with alterations in various genes. Different strains may act at different stages before or during cancer development and the extent of any protection may vary according to the probiotic (Commane et al 2005). There is, as yet, no concrete evidence for probiotics in prevention of cancer - but there are some encouraging results for specific probiotic strains – particularly for Lactobacillus or Bifidobacterium.

Studies have shown probiotics may:

• prevent DNA damage for cells in test tube studies and in animals
• prevent early changes in the colon tissue
• suppress tumours in animals
• may have some protection in humans

More human trials need to be done but here are two examples of the few studies published: 

An unusually large study over 4 years followed 400 patients who had previously had colorectal tumours. Their diet was supplemented with either wheat bran, a Lactobacillus casei probiotic powder, both, or neither. The most positive results from the study were for the group taking the probiotic. Although the incidence of new tumours in this group was no less compared to the control group, the rate of development of the tumours was significantly slower (Ishikawa et al 2005).

Studies have looked at people eating a diet high in fried ground beef, which is known to increase levels of mutagenic amines. Lower mutagen levels in the urine and the faeces were found to be associated with consumption of Lactobacillus probiotic species (Hayatsu & Hayatsu 1993; Lidbeck et al 1992).

At the moment, a large EU-funded project (SYNCAN) is running. This is looking at the effects of probiotics (Lactobacillus and Bifidobacterium) and/or inulin-based prebiotics in various experimental models as well as human volunteers. In a trial conducted at the University of Ulster, 80 volunteers were recruited. Half had been treated for CRC and half had been diagnosed with intestinal polyps: intestinal growths that can become cancerous if left untreated (http://www.synca.be/; van Loo et al 2006). During the study, biopsies were taken before and after a course of a drink containing probiotic bacteria and a prebiotic. The effects of this synbiotic intervention were determined by comparing the extent of cell damage and cell proliferation (how rapidly the cells grow). The results showed no difference for the group of patients who had previously been treated for cancer but there was evidence of some benefit for patients with intestinal polyps.

Professor Rowland again:

‘There is a lot of evidence from studies on cell cultures and in animals that probiotics, prebiotics and combinations of the two can exert anticancer effects. Until recently, there has been little work conducted in humans. However a paper soon to be published … reports a study conducted as part of the European Union funded ´SYNCAN´ Project. In this experiment volunteers were fed a mixture of pro and prebiotics, or placebo, for 8 weeks and a wide range of indicators of colon cancer risk were measured. Those subjects on the pro and prebiotics had less DNA damage and a lower rate of cell proliferation in biopsies taken from their colons. Additionally pro/prebiotic feeding resulted in improvements in certain characteristics of stool samples that may be indicative of reduced cancer risk’.

Lower levels of chemical associated with cancer were found in the faeces. Professor Rowland concluded:

‘Whilst this evidence is not definitive, the study does suggest that the extensive data showing anticancer activity from experiments in animals and isolated cells may be applicable to humans, and that more studies in human volunteers are warranted.’

Cancer killing chemicals

A final twist came in research covered in Cancer Watch in Autumn 2009, where researchers have shown that beneficial bacteria in the gut can actually cause the release of a cancer cell killing chemical from foodstuffs. That chemical is Sodium Butyrate. You could replicate it´s effects by taking ´Biotin´. But why bother. Beneficial bacteria will also help release biotin from the whole grains you eat.

You really should ensure that your beneficial bacteria are fully represented and part of your cancer prevention, and cancer fightinmg team.

If you are thinking of buying a probiotic, you might like to look at the Natural Selection Product of Choice. You can do this by  clicking here

REFERENCES

1. et al (1995) Preventive effect of a Lactobacillus casei preparation on the recurrence of superficial bladder cancer in a double blind trial. Eur Urol 27: 104-109.
2. Boyle, P & Langman, JS (2000) ABS of colorectal cancer – epidemiology. British Medical Journal 321: 805-808.
3. Cappocaccia, R et al (2002) Measuring cancer prevalence in Europe – the EUROPREVAL project. Ann Oncol 13: 831-839
4. Commane et al (2005) The potential mechanisms involved in the anti-carcinogenic action of probiotics. Mutation Res 1-2:276-289p
5. De Preter, V et al (2006) Effects of Lactobacillus casei Shirota, Bifidobacterium breve, and oligofructose-enriched inulin on the colonic nitrogen-protein metabolism in healthy humans. Am J Physiol Gastrointest Liver Physiol. Sept 21 (Epublication)
6. Ferlay, J et al (2001) Globocan 2000: Cancer incidence, mortality and prevalence worldwide. Versio 1.0 IARC Cancer Base No 5 Lyon, IARC Press
7. Gill, CIR & Rowland, IR (2002) Diet and cancer: assessing the risk. British J Nutrition 88, S73-S87
8. Gonzalez, CA (2006) Nutrition and cancer: the current epidemiological evidence. British J Nutrition 96, Suppl 1: S42-S45.
9. Hayatsu, H & Hayatsu, T (1993) Suppressing effect of Lactobacillus casei administration on the urinary mutagenicity arising from ingestion of fried ground beef in urine. Cancer Lett 73: 173-179.
10. Ishikawa, H et al (2005) Randomized trial of dietary fiber and Lactobacillus casei administration for prevention of colorectal tumours. Int J Cancer 116, 762-767.
11. Lidbeck, A et al (1992) Effect of Lactobacillus acidophilus supplements on mutagen excretion in feces and urine in humans. Microb Ecol Health Dis 5: 59-67
12. Van Loo, J et al (2006) The SYNCAN project: goals, set-up, first results and settings of the human intervention study. Br J Nutr 1: S91-S98.

WHO/FAO Joint Working Group (2002) Guidelines for the evaluation of probiotics in food.

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