Americans swap foods with Africans and their microbiomes follow – fiber, fat and cancer risk

Phuto pap and porridge, a traditional South African, high fiber, meal.

Despite having similar genetic backgrounds, African Americans are thirteen times more likely to develop colon cancer than rural South Africans.  Indeed, environmental factors, rather than genetics, are thought to be the major factor in developing colon cancer, because recent immigrants’ children’s risk is more similar to where they are living than to their parents’ homeland.  This environmental risk could be primarily caused by a number of factors, such as antibiotic use or drug use, but many scientists believe that diet, and its influence on the microbiome, is primarily responsible.  As it turns out, rural Africans eat much more fiber (almost 5x more) and much less fat (almost 3x less) than African Americans, and these differences have drastic effects on the microbiomes of their hosts.  Not only are the most abundant bacterial species different, but the major metabolites vary greatly as well.  Scientists from the University of Pittsburgh came up with the clever idea of swapping the foods of rural South Africans and African Americans, to investigate how this dietary intervention would affect each group’s microbiomes and risk for colon cancer.  They published the results of their study in Nature Communications last week.

The researchers studied 20 middle aged African American men and 20 middle aged rural South African men.  They each had their microbiomes and colons studied for two weeks while eating their normal diets, and then again for two weeks after swapping diets.  Initially, the Americans had microbiomes dominated by Bacteroides and the Africans by Prevotella.  After the diet though, they noticed a rapid shift in these populations, and it corresponded to an increase in colonic inflammation for the Africans and decrease in the Americans.  In addition, an increase in butyrate, the short chained fatty acid (SCFA) that is thought to be beneficial to health, followed the fiber diet as well, and a decrease was associated with eating the high fat diet; this makes sense, as butyrate is produced as a metabolite of fiber fermentation by the microbiome.  Interestingly, prior to the diet change a top-level analysis of all the metabolic end products of the microbiome showed that Africans produced more of every single one studied except for choline, which is related to heart disease.  Many of the metabolites studied, including choline, followed their diet switch, and were produced according to the food eaten, rather than the person eating it.  Perhaps most importantly, secondary bile acids, which are produced by the microbiome and may be carcinogenic and an important cause of colon cancer, followed the diet as well.  Africans, who produced much fewer secondary bile acids than Americans while consuming their regular diet, had a 400% increase in production after the diet switch, and vice versa for the Americans, who had a 70% decrease.

This study really illustrates the importance of diet on the output of the microbiome.  These metabolites can directly influence our health, and may be more important to our well-being than the bacteria that produce them.  According to this study, it appears that eating more veggies and less fat, something that parents have been saying for a long time, fits in with our understanding of the microbiome.  As Erica Sonnenburg said in our podcast 3 weeks ago, “Feed your microbiome at every meal!”

New study may lead to microbiome-based colon cancer diagnostic

Colorectal carcinoma, or colon cancer, is one of the most common cancers and a leading cause of death among the elderly. The cancer is often caused when adenomas, benign tumors, transform into malignant tumors called adenocarcinomas. The gut microbiome has been long implicated in colorectal cancer however it is not yet clear how the microbiome integrates with other risk factors that may lead to this cancer in patients. A study published in Nature Communications studied various risk factors that may influence this progression into colon cancer. 

The scientists collected stool samples from 156 individuals including healthy individuals as well as those with colorectal adenomas or carcinomas and sequenced the microbial DNA. They identified specific bacteria that were different in patients with adenomas or carcinomas and healthy individuals. For example, Bifidobacterium was deficient in those with benign or malignant tumors as well as other bacteria that are signatures of a healthy microbiome.  This showed that the microbiome was different between patients with the cancer and those without.

The scientists also studied whether they could use the microbiome as a diagnostic tool for identifying patients with carcinomas. Using the data they collected of bacteria in the guts of patients with  and without tumors, they came up with a set of markers that could detect the presence of carcinomas. They also specifically investigated whether this could be done for adenomas, which are harder to screen for than carcinomas but important to identify at an early stage in order to intervene before they mutate into carcinomas. This was also successful, though further investigations would most likely be needed to identify adenomas. 

In addition, the researchers looked at what impact diet had on the microbiome of patients with and without carcinomas and adenomas.  They found that those individuals eating higher levels of red meat had carcinoma enriched bacterial communities in their gut and those eating fruits and vegetables had lower levels of carcinoma enriched bacteria.

Continued research into the role that specific risk factors like smoking, diet, and obesity have on the microbiome will help us better understand how these factors influence the onset of this cancer. In the future, it may be possible to utilize the microbiome as a diagnostic tool for the identification of either colorectal adenomas or carcinomas, or even to help develop new microbiome based therapies for colorectal cancer. 

Microbiome bacteria help cancer cells evade the immune system

Optical microscope image of bacteria from the genus Fusobacteria.

A few weeks ago Kris Campbell wrote about the microbiome’s association with colorectal cancer.  This association is complex, but perhaps critically important, and last week a new study reinforced this connection.  Researchers, primarily from Israel, published results in Cell Immunity that showed common microbiome bacteria are protecting cancer cells by helping the cancer cells evade the immune system.

The researchers noticed that a type of bacteria, Fusobacterium nucleatum, which is normally found in the oral microbiome and is a cause of periodontal disease, can be found in high concentrations around colorectal tumors.  In addition, these same bacteria had been linked to various microbiome associated diseases, such as preterm birth and rheumatoid arthritis.  They suspected that these bacteria may somehow be protecting the cancer cells from the immune system, so they performed a series of experiments to find out.

The scientists grew cancer cells in the presence and absence of the F. nucleatum and then exposed these cancers to immune system cells that are designed to attack cancers.  They noticed that those cancer cells that had been grown with the bacteria were naturally protected from these immune cells.  Through a series of tests they discovered that the bacteria produce a protein called Fap2 that naturally bound with the immune cells and essentially deactivated them (technically speaking, Fap2 bound to the Natural Killer cells’ TIGIT inhibitory receptors).  Interestingly, this TIGIT receptor is nearly ubiquitous across many types of immune system cells, which means that this bacteria, and others like it, may be especially good at protecting themselves and other cancer cells from our bodies’ natural defenses.

It may be surprising for our readers to hear that bacteria are sometimes used to destroy cancer cells, like in the case of bladder cancer, but this paper shows a more dichotomous relationship between the microbiome and cancer.  While some bacteria may be helpful in killing cancers others may be helping them grow.  Either way, one thing is clear, the microbiome and cancers are intimately related, and learning about the microbiome should lead to advanced therapies for treating cancers.

Gut microbiota reveal better ways of detecting (and preventing) colorectal cancer

Editors note:  The AMI is thrilled to have a guest blog post today from Kristina Campbell, a very talented science writer who specializes in the microbiome.  She writes for the Gut Microbiota for Health Experts Exchange, and blogs as The Intestinal Gardener.  Our readers can also keep up with her on Twitter,  @bykriscampbell.  

By Kristina Campbell

Scientists are starting to develop an idea of how colorectal carcinoma (CRC) arises. It all starts with bacteria in the digestive tract: possibly a strain of Bacteroides fragilis or the infamous Escherichia coli. Whether the bacteria are new to the body, or resided there all along, doesn't matter. The bacteria somehow get a green light to start producing chemical agents that damage the genetic information in the body's cells. The damaged cells rapidly divide. Soon enough, polyps (also called adenomas) appear in the colon. These polyps can become cancerous.

Currently, there's a gap in CRC detection methods. This is a problem that's directly connected with patient mortality: if CRC is detected at an early stage, survival rate is more than 80%. But if it's left until a late stage, it's less than 10%.

The two standard ways to detect this cancer are a fecal occult blood test (FOBT) and a colonoscopy. FOBT – which tests for traces of blood in the stool – has limited sensitivity for CRC. It's only a rough guide, since it misses many cases. Colonoscopy is the most effective method of diagnosis, but it's far from perfect because it's invasive and costly.

New research shows that the microbiota might lead to better CRC detection. Iradj Sobhani and colleagues recently published an intriguing paper in Molecular Systems Biology called ‘Potential of fecal microbiota for early-stage detection of colorectal carcinoma'. They took fecal samples from healthy people and those with confirmed CRC, and used metagenomic sequencing to find out how they differed.

They found that the fecal samples held clues that were missing from FOBT. Using both methods together, they increased the sensitivity of colon cancer detection 45% (as compared with FOBT alone). Used effectively in the clinic, this could save thousands of lives each year.

Sobhani said he and his colleagues are working on a clinical tool to help patients make use of this information. In a recent interview, he said, "Now we know a panel of some 18-20 [relevant] bacteria and we are trying to make an easy and simple tool to identify these bacteria. We can, I hope, in a very short future time, make low-cost tools to identify the bacterial phenotype usually found in patients with colon cancer."

A smaller study from the Schloss lab found a similar result: enhanced CRC detection using information from FOBT and a fecal sample, as well as body mass index, age, and race (which are known risk factors for colon cancer).

Schloss said that one kind of bacteria in particular piqued his interest. "We’re trying to better understand [why] Fusobacterium seems to be popping up in a lot of these stories. How does Fusobacterium get from the mouth to the gut? Everybody has it in their mouth. But not everybody has it in the gut. So what’s breaking down there? Does it have a role in disease?"

The Sobhani study went beyond CRC detection to factors that might be involved in prevention. The researchers looked at the bacterial genes in the guts of those with CRC and asked, "What can these bacteria do well?" In other words, they looked at the bacterial functions as indicated by their genes.

This analysis showed some interesting links to diet. Sobhani explained, "Those with colon cancer had largely more meat-metabolizing bacteria] compared to those who have no colon cancer, who have bacteria that show more functions to metabolize vegetables." He added, "Then there are functions involved in the transfer and capture of… minerals."

Whatever made the meat metabolizers more abundant in the colon could turn out to be what caused the cancer in the first place. But it's not clear whether red meat consumption itself accounts for the disease-associated condition of the microbiota, or whether other components of the diet play a role. (Fiber is a prime preventative candidate under investigation.)

A whopping 95% of CRC could be attributable to environmental factors. More research related to the gut microbiota and CRC might one day reveal exactly what those environmental factors are, so we can kick colon cancer to the curb.

References:

Zackular J, Rogers M, Ruffin M and Schloss P. (2014) The Human Gut Microbiome as a Screening Tool for Colorectal Cancer. Cancer Prevention Research doi: 10.1158/1940-6207.CAPR-14-0129

Zeller G, Tap J, Voigt AY, et al. (2014) Potential of fecal microbiota for early-stage detection of colorectal cancer. Molecular Systems Biology doi: 10.15252/msb.20145645

The fungal microbiome may be associated with colon cancer

We don’t write much about the fungal microbiome on this blog, but it may be every bit as important as the bacterial microbiome (and let’s not forget about the archaeal and eukaryotic microbiomes, and virome as well!).   Fungi are not as abundant in the microbiome as bacteria, which is probably why they are not as heavily researched, but they are known to cause diseases.  For example, vaginal yeast infections and oral thrush are caused by fungi belonging to the Candida genus.    

We recently wrote about a study that linked bacterial biofilm formation with colorectal cancer.  In this blog we mentioned that colorectal cancer is likely to have environmental causes.  Researchers from China hypothesized that fungi may be one of these risk factors, so they conducted an experiment to find out.  They recently published their results in Nature Scientific Reports.

The researchers first sampled the microbiomes of 27 patients with various stages of colorectal tumors, in addition to other, healthy areas of those patients’ guts adjacent to the tumors.  They then sequenced the genomes of the samples to determine which fungi existed, and where.  They discovered that fungal diversity was lower on tumors compared to other areas of the colon.  In addition, two known pathogenic fungi, Candida and Phoma existed in higher levels on tumors compared to the adjacent areas.  Finally, they found distinct differences between individuals with advanced and non-advanced tumors.  Those with advanced tumors had a higher abundance of two other known pathogenic fungi, Fusarium, which has been associated with intestinal disease in the past, and Trichoderma, which has been associated with infections of various organs. 

This study did not involve any healthy patient controls, and its sample size was somewhat limited.  Still, the results are intriguing because gut fungi that are known to cause inflammation elsewhere in the body are being found at the site of tumors.  Even if these fungi are not causing the tumors, they could at least be potentially used as a diagnostic or biomarker for tumors.  While we know that some fungi can be dangerous, we note that even specific genera are not always pathogenic, and sometimes they can exist normally in a host and only turn pathogenic at a later time.  Like other aspects of the microbiome, the story is complicated, but we would be willing to bet there is at least one beneficial fungus among us.

Microbiota biofilms and colorectal cancer

Colorectal cancer is the 4th most deadly cancer in the world, and over 1 million people are diagnosed with it each year.  It has very few genetic indicators and it is rapidly growing in prevalence, thus researchers believe it is very likely associated with environmental causes.  An obvious environmental cause would be the microbiome, and researchers from John’s Hopkins helped establish this link with their recent publication in PNAS.  In their article they show that biofilm formation in the colon is tightly correlated with colorectal cancer.

The researchers studied a cohort of people that had colorectal cancer along with healthy people as controls.  In those people with tumors they studied the microbiome of the tumors themselves along with other, distal parts of their colons.  They discovered that the majority of people with tumors, whether benign or malignant, had thick biofilms growing on and even in the tumor.  What’s more, is that the researchers noticed that biofilms were forming all along the colon, even in the distal parts.  Biofilms were not seen in healthy patients, and in some of the patients with tumors. 

Interestingly, the bacteria in the biofilms between different patients did not necessarily correlate, and so it appeared the presence of biofilms, rather than the composition of the biofilm was critical.  Moreover, the biofilms studied decreased the gut permeability, leading to ‘leaky guts’, which we have covered on this blog before.

A normal colon has a mucous layer to prevent any bacteria from infiltrating the underlying epithelial cells.  It is possible that people with decreased mucosal integrity are at risk for bacteria to invade and form these biofilms which may eventually lead to cancer.  In fact, according to this small study, people with biofilm formation in their colon have a 5-fold increase in their likelihood to get colorectal cancer, much higher than any other known indicator.  More research on a larger scale still needs to be performed.  Still though, biofilm detection could be a useful diagnostic for colorectal cancer, and biofilm management could be a target for drugs or probiotics.