Gut Microbiome Linked to Colorectal Cancers

Just in case you were wondering how important your gut’s probiotic bacteria are – how about colorectal cancer, one of the most lethal cancers?

Genome research – that is, sequencing the DNA of an organism to delineate its vast combination of nucleotides – has made major advances over the past decade since the human genome was established. Since then researchers have found an even more fascinating version of our body’s genome – the composite genome of our bacteria: Our microbiome.

This composite genome of our bacteria typically focuses upon the gut’s microorganisms. The gut’s composition is sequenced just as our own cell’s DNA is sequenced. But instead of our cells, what is sequenced is the DNA of these microorganisms.

The composite of the DNA sequences of the microorganisms in our gut is our microbiome. The microbiome reveals a map of sorts – but of the various species of bacteria that inhabit our guts. Ones microbiome is typically DNA-sequenced by analyzing a feces sample or by collecting and analyzing intestinal tissues.

Microbiomes differ between people

It turns out that there are different types of microbiomes in humans. Depending on our ancestry and our diet, we might have a microbiome that has more of some species than others.

As the research has advanced, these microbiome composites are being linked with disease conditions. In other words, some species of gut bacteria create a higher risk of certain types of disorders.

Such is the case for the most obvious of conditions: Colon and rectum cancers – collectively called colorectal cancer.

Colorectal cancer is a leading cause of cancer death

Colorectal cancer is big. Over eight percent of cancer deaths are from colorectal cancers.
According to the U.S. National Cancer Institute’s 2012 data, over 1.1 million people in the U.S. have colon cancer, and each year more than 130,000 new cases are diagnosed. Basically, this comes down to almost 5 percent of the entire population.

Colorectal cancer is no laughing matter either. About 35 percent of those diagnosed with colorectal cancer will not live past five years after being diagnosed. Survival rates go down when the diagnosis is caught later.

Enzymes linked with colorectal cancer

In the early 1980s, Dr. Barry Goldin, a professor at the Tufts University School of Medicine, led a series of studies that found that certain diets promoted a group of cancer-causing enzymes. These cancer-causing enzymes included beta-glucuronidase, nitroreductase, azoreductase, and steroid 7-alpha-dehydroxylase. The enzymes were linked with cancer in previous studies.

This research was confirmed by Swedish research teams led by Dr. Gunnar Johansson in the 1990s established that colon cancer was linked to an increase in certain types of enzymes. In addition to the ones mentioned, Dr. Johansson found beta-glucosidase, and sulphatase also implicated in colorectal cancers.

Dr. Johansson’s and Dr. Goldin’s extensive research eventually established that these enzymes were produced by certain types of microorganisms. The more of certain microorganisms there were in the gut, the more of these enzymes were produced, and with them came the greater likelihood of a diagnosis of colon cancer.

Gut bacteria linked to colorectal cancer

In 2014, research from the British Columbia Cancer Agency established the link between particular gut microbes and colorectal cancers. The researchers conducted DNA microbiome sequencing of 130 people with colorectal cancer and compared their microbiome with 130 healthy people of the same ages – referred to as a matched controls.

The researchers found among the microbiome a greater number of bacteria in the Fusobacterium, Leptotrichia and Campylobacter species. They also found these microbes were linked with high levels of the interleukin-8 cancer cytokine.

Particular to species, they also found a high occurrence of the bacteria Campylobacter showae along with the Fusobacterium nucleatum bacteria among the cancer patients.

The link between colorectal cancer and Fusobacterium nucleatum was also established a year earlier by the same researchers after sequencing the microbiome of 99 patients.

Since then other bacteria have been linked to colorectal cancers, including Bacteriodes fragilis and some strains of E. coli. Each of these was also linked to what researchers have referred to as “gene virulence.” That is, somehow these bacteria have the ability to mess with the genetic information of the healthy cells of the colon. This has been linked with the production of enzymes as found in previous research.

New bacteria implicated in recent research

University of Minnesota researchers continued this microbiome-cancer research by sequencing the tumor gut tissues of 44 colorectal cancer patients and compared these with the gut tissues of 44 healthy control subjects.

This research found the species of Fusobacterium as found in previous research, but also found a family of species called Providencia. They also found Candidatus Portiera species.

Fusobacterium species were found in 23 of the 44 cases, while Providencia species were found in 28 of the 44 cases.

The Providencia genus includes a number of gram-negative bacteria. These include P. stuartii, and P. burhodogranariea and P. sneebia. But they also include the Enterobacteriaceae family of bacteria, which includes E. coli, Klebsiella species, Enterobacter species and Proteus species.

How can we change our gut bacteria?

When one considers bacteria, there are two central considerations: The first is environment and the second is substrate. Put more simply, different kinds of bacteria like to ferment – or, eat – certain types of food: We call that food substrate.

Let’s use an example: Let’s say that you live in the country and you are inclined to be surrounded by wolves and jackals. What will you do? You will leave out some meats around your house – which will attract the wolves and jackals who love to scavenge for those foods.

But let’s say that you’d rather attract deer and wild horses and perhaps some buffalo to live around your property. What will you do? You will plant some alfalfa – the food that these types of animals like to eat. You’d probably also plant some trees to provide some shade for these animals to have a nice environment to stay in.

In the same way, if we want to develop certain species of bacteria, we can simply eat certain foods – those foods that those species of bacteria like to consume (ferment). Right?

Just consider a study from researchers from the University of Pittsburgh (Ou et al. 2013), who sequenced the microbiome from 24 healthy Africans – 12 African Americans and 12 Native Africans between the age of 50 and 65 years old.

The researchers found that the Native Africans had significantly Prevotella gut microbiota enterotype, while the African Americans had predominantly Bacteroides enterotypes. The African Americans also had significantly fewer total microorganisms.

The researchers also found that the Native Africans also had higher levels of the healthier short-chain fatty acids, while the African Americans had higher levels of secondary bile acids – meaning their intestines were highly acidic compared to the Native Africans.

These relationships have been made with colon cancer: Higher levels of secondary bile acids are linked with higher levels of colon cancer while higher levels of short-chain fatty acids – such as butyrate produced by healthy gut microorganisms – have been linked with lower rates of colon cancer. The researchers concluded:

“Our results support the hypothesis that colon cancer risk is influenced by the balance between microbial production of health-promoting metabolites such as butyrate and potentially carcinogenic metabolites such as secondary bile acids.”

And the difference between the two groups of Africans? Naturally, the African Americans ate predominantly a Western diet, while the Native Africans ate more plant-based foods.

This correlation was confirmed in an earlier study by some of the same University of Pittsburgh researchers. In this study (Ou et al. 2012), 12 African Americans who were examined and determined to be at high-risk of colon cancer were studied and compared to 10 Caucasian Americans (who ate a western high-fat diet), together with 13 Native Africans, who ate primarily a low-fat diet higher in plant-based foods.

The researchers found that the components found high in colon cancer cases – notably secondary colonic bile acids, deoxycholic acid and lithocholic acid and associated enzymes – were higher among both the Caucasian Americans and the African Americans, who both ate a higher-protein, higher-fat Western diet. These were significantly higher than those levels of the Native Africans, who ate a diet of more plant-based foods.

The researchers wrote:

“Our results suggest that the higher risk of colon cancer in Americans may be partly explained by their high-fat and high-protein, low complex carbohydrate diet, which produces colonic residues that promote microbes to produce potentially carcinogenic secondary bile acids and less antineoplastic short-chain fatty acids.”

The intestinal bacteria that produce these cancer-related short-chain fatty acids were related to higher levels of the Bacteroides enterotype.

Just as research by Swedish researcher Dr. Gunnar Johansson in the 1990s established that the enzymes such as beta-glucuronidase, beta-glucosidase, and sulphatase could be reduced within a month of a change to a plant-based diet, research has found that a plant-based diet can change the makeup of our gut bacteria.

Research from the Republic of Korea’s Kyung Hee University (Kim et al. 2013) found that changing one’s diet to a strict plant-based diet for one month dramatically changed the composition of their gut bacteria, along with improvements in blood glucose levels and hypertension symptoms.

The researchers tested six adults who were obese with type 2 diabetes and/or high blood pressure. They tested their gut microbiota initially, and after a month of a strict plant-based diet, they re-tested the subjects.

They found that the plant-based diet significantly reduced levels of cancer-causing bacteria such as the Enterobacteriaceae (such as E. coli). They had increased levels of healthy species and decreased production of the colon-cancer producing short-chain fatty acids. The month-long diet change also improved fasting glucose levels, hemoglobin A1c levels, reduced triglyceride levels, reduced LDL-cholesterol levels and resulted in weight loss.

The researchers stated that:

“This study underscores the benefits of dietary fiber for improving the risk factors of metabolic diseases and shows that increased fiber intake reduces gut inflammation by changing the gut microbiota.”

Diet and cancer-causing enzymes and the gut bacteria that produce them

Dr. Goldin’s research mentioned above along with others found lower levels of cancer-causing enzymes among those with primarily plant-based diets, while those eating animal-based diets had greater levels of these enzymes. Again, they suspected a group of pathogenic bacteria decades prior to the microbiome research discussed above.

Dr. Goldin and his research teams studied the difference between these enzyme levels with different diets. In one study, the researchers removed animal foods from the diets of a group of people for 30 days. His team found an immediate reduction of steroid 7-alpha-dehydroxylase.

When the probiotic L. acidophilus was supplemented to their diets, this group also showed a significant reduction in beta-glucuronidase and nitroreductase.

In other words, two dietary connections were found regarding these disease-causing enzymes: animal-based diets and a lack of intestinal probiotics. The two are actually related because probiotics thrive in prebiotic-rich plant-based diets and suffer in animal-rich diets.

Other studies have confirmed that plant-based diets result in a reduction of these carcinogenic enzymes produced by pathogenic bacteria. Researchers from Finland’s University of Kuopio (Ling and Hanninen 1992) tested 18 volunteers who were randomly divided into either a conventional omnivore diet or a plant-based diet for one month.

The plant-based diet group followed the month with a return to their original omnivore diet. After only one week on the plant-based diet, the researchers found that fecal urease levels decreased by 66%, cholylglycine hydrolase levels decreased by 55%, beta-glucuronidase levels decreased by 33% and beta-glucosidase levels decreased by 40% in the plant-based diet group. These reduced levels continued through the month of consuming the plant-based diet. Serum levels of phenol and p-cresol – also inflammation-producing endotoxins of pathogenic bacteria – also significantly decreased in the group.

Within two weeks of returning to the omnivore diet, the formerly-plant-based diet group’s pathogenic enzyme levels returned to the higher levels they had before converting to the plant-based diet. After one month of returning to the omnivore diet, serum levels of toxins phenol and p-cresol returned to their previously higher levels prior. Meanwhile, the higher levels of inflammation-producing enzymes remained among the conventional omnivore diet (control) group.

Learn more about the microbiome-friendly diet:

REFERENCES:

Michael B. Burns, Joshua Lynch, Timothy K. Starr, Dan Knights, Ran Blekhman. Virulence genes are a signature of the microbiome in the colorectal tumor microenvironment. Genome Medicine, 2015; 7 (1) DOI: 10.1186/s13073-015-0177-8

Warren RL, Freeman DJ, Pleasance S, Watson P, Moore RA, Cochrane K, Allen-Vercoe E, Holt RA. Co-occurrence of anaerobic bacteria in colorectal carcinomas. Microbiome. 2013 May 15;1(1):16. doi: 10.1186/2049-2618-1-16.

Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, Barnes R, Watson P, Allen-Vercoe E, Moore RA, Holt RA. Fusobacterium nucleatum infection is prevalent in colorectal carcinoma. Genome Res. 2012 Feb;22(2):299-306. doi: 10.1101/gr.126516.111.

Jones ML, Ganopolsky JG, Martoni CJ, Labbé A, Prakash S. Emerging science of the human microbiome. Gut Microbes. 2014;5.

Ou J, Carbonero F, Zoetendal EG, DeLany JP, Wang M, Newton K, Gaskins HR, O’Keefe SJ. Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr. 2013 Jul;98(1):111-20. doi: 10.3945/ajcn.112.056689.

Ou J, DeLany JP, Zhang M, Sharma S, O’Keefe SJ. Association between low colonic short-chain fatty acids and high bile acids in high colon cancer risk populations. Nutr Cancer. 2012;64(1):34-40. doi: 10.1080/01635581.2012.630164.

Portions of this article contain excerpts from The Ancestor’s Diet. Please refer to this book for the list of those earlier scientific references.