NCRI 2013

Diet, the microbiome, and colon cancer risk

Dr Stephen O' Keefe - University of Pittsburgh, USA

I’m based at the University of Pittsburgh in Pennsylvania, USA and the work I was presenting here was on examining the question of diet in colon cancer risk and particularly its effect on the microbiota to produce factors that affect mucosal health and proliferation and its advance into cancer.

What specifics have you been looking at?

Epidemiological studies from around the world have provided very good evidence that colon cancer risk is heavily influenced by what you eat. These studies have suggested that your risk can be increased by the amount of meat and fat that you eat and, on the other side, reduced by the amount of fibre, particularly in the form of vegetables and cereals on reducing the risk. We feel that with regard to the colon these effects are probably mediated by the microbiota, they’re not direct effects of food on the mucosa because basically most normal food is absorbed in the upper GI tract but a reside remains that goes through to the colon which is essential for the microbiota health. We know, which is actually quite fascinating, that there’s a symbiotic relationship between the microbiota and the mucosa such that the mucosal cells or epithelia within the colon rely on butyrate rather than glucose as the prime energy source. Butyrate can only be synthesized by the microbiota in response to the dietary residues that go through and that’s probably the explanation of why a high fibre diet is beneficial because it increases fermentation, production of butyrate and suppression of inflammation and cancer risk.

What are the goals of this investigation?

The problem about a lot of dietary studies is that we have to believe what somebody else said that they ate a few days beforehand to analyse what they ate and we know that this is very inaccurate. So what’s original about our study is that we looked at two populations with extreme risk of colon cancer, namely African Americans who have the highest rate of colon cancer in the USA, over 65 per 100,000, and rural Africans in South Africa who have a minimal risk, about less than 5 per 100,000. We know that these two populations have completely different diets and we know that diets, as I’ve just said, influence your risk of colon cancer but is this association or is it cause? So we performed a very unique study design by actually switching the diets of segments of these two populations, twenty African Americans in Pittsburgh and twenty matched Africans, these are healthy, middle-aged subjects, in rural South Africa. Basically we studied them first of all in their background diet when they were eating their usual diet, and then again after dietary switch. We gave the dietary switch for two weeks so the African Americans were given the African diet which is low in fat, low in meat but high in fibre, and we gave the African Americans the African diet which is low in meat, low in fat but high in fibre for two weeks, under lock and key basically. So they were in a metabolic area or in an enclosed environment where all the meals were actually cooked for them and we measured how much they ate and how much they didn’t so we knew exactly what they took. We measured the effect of that on the microbiota through measurements of faecal samples and colonic evacuates. We also measured the effect on colonoscopic differences, so we did a colonoscopy before on their usual diet and then again two weeks later. The results were absolutely dramatic, that within that two week period the microbiota changed dramatically in both groups reciprocally. The importance of this, or the functional significance of this, is that the mucosal biomarkers of cancer risk, and we were specifically looking at Ki-67 staining of proliferative cells, was significantly changed – increased in Africans given a Western diet and reduced in African Americans given the African diet. Plausible mechanisms were that the African diet was associated with high rates of butyrate genesis, and there are specific bacteria in the colon that produce butyrate, and butyrate itself has been shown not only to be the chief energy source for the epithelial cells in the colon but it also controls proliferation and so therefore cancer risk. Indeed, first of all Africans on their own diet had high rates of butyrate genesis and African Americans given the African diet increased their rates of butyrate genesis and reduced their risk markers.

On the other side, if you have a Westernised diet you have a high fat intake and it increases the amount of bile acids produced by the liver, a proportion of which then go into the colon and are not absorbed in the enterohepatic circulation. In the colon they are then converted by specific microbes to secondary bile acids which have been shown to be carcinogenic in experimental studies. So on the other side of it we found that African Americans on the Westernised diet had high rates of secondary bile acid production but when they went on the African diet they were suppressed, and when we gave the Africans the nasty Westernised diet, but very tasty Westernised diet, their secondary bile acid production increased dramatically.

So it ties things very nicely together and what really is intriguing about our study is that it only took two weeks to show these changes which is good news for Westernised populations that you don’t have to wait a generation before your cancer risk changes but if you go out and follow good dietary guidelines now, which means halving your fat and meat intake and increasing your fibre intake, you can expect to modify your microbiota and reduce risk markers of cancer.