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

Mouth diseases and tooth loss may be caused by oral microbiome alterations

Chronic periodontitis is a prevalent inflammatory disease of the tissue around and supporting the teeth and is the leading cause of tooth loss in the United States. Scientists at the University of Florida recently published a study in Applied and Environmental Microbiology that studied the oral microbiome of 25 healthy individuals and 25 individuals with chronic periodontitis, in order to determine if there are any consistent microbial differences between the groups.

In the study, they found that patients with periodontal disease had an altered oral microbiome with microbial communitites that were more homogeneous than healthy individuals’.  They were able to identify two specific groups of bacteria, Fusobacterium and Porphyromonas, that were associated with periodontitis and another two groups of bacteria, Rothia and Streptococcus, that were prevalent in the majority of the healthy sites without periodontitis.  The scientists also identified several genes that were involved with various biological activities that were enriched in the oral microbiome of healthy individuals.

This study provides more insight into the possible microbial causes of chronic periodontitis, which is common among adults in the United States. While this study is limited because of its small sample size and its lack of diversity among severity of chronic periodontitis disease, it is still a great starting point for further inquiry into the disease. The scientists also compared their work to previous studies utilizing Human Microbiome Project (HMP) participants, though the HMP only included healthy individuals and excluded individuals with periodontal disease.  Further research could lead to the discovery of better ways to both treat and prevent the disease by altering the microbial communities of our mouth.