Discovery highlights how ongoing microbiome research points to new opportunities that can lead to development of more effective cancer screening clinical laboratory tests
New research from the Fred Hutchinson Cancer Center in Seattle once again demonstrates that the human microbiome plays a sophisticated role in many biological processes. Microbiologists and anatomic pathologists who diagnose tissue/biopsies will find this study’s findings intriguing.
This breakthrough in colon cancer research came from the discovery that a “subspecies” of a common type of a bacteria that resides in the mouth and causes dental plaque also “shields tumor cells from cancer treatment,” according to NBC News.
The scientists inspected colorectal cancer (CRC) tumors and found that 50% of those examined featured a subspecies of Fusobacterium nucleatum (F. nucleatum or Fn) and that this anaerobic bacterium was “shielding tumor cells from cancer-fighting drugs,” NBC News noted. Many of these tumors were considered aggressive cases of cancer.
“The discovery, experts say, could pave the way for new treatments and possibly new methods of screening,” NBC News reported.
“Patients who have high levels of this bacteria in their colorectal tumors have a far worse prognosis,” Susan Bullman, PhD (above), who jointly supervised the Fred Hutch research team and who is now Associate Professor of Immunology at MD Anderson Cancer Center, told NBC News. “They don’t respond as well to chemotherapy, and they have an increased risk of recurrence,” she added. Microbiologists and clinical laboratories working with oncologists on cancer treatments will want to follow this research as it may lead to new methods for screening cancer patients. (Photo copyright: Fred Hutchinson Cancer Center.)
Developing Effective Treatments
Susan Bullman, PhD, Associate Professor of Immunology at MD Anderson Cancer Center, who along with her husband and fellow researcher Christopher D. Johnston, PhD, Assistant Professor at Fred Hutchinson Cancer Center, jointly supervised an international team of scientists that examined the genomes of 80 F. nucleatum strains from the mouths of cancer-free patients and 55 strains from tumors in patients with colorectal cancer, according to the National Institutes of Health (NIH). The NIH funded the research.
The researchers targeted a subspecies of F. nucleatum called F. nucleatum animalis (Fna) that “was more likely to be present in colorectal tumors. Further analyses revealed that there were two distinct types of Fna. Both were present in mouths, but only one type, called Fna C2, was associated with colorectal cancer” the NIH wrote in an article on its website titled, “Gum Disease-related Bacteria Tied to Colorectal Cancer.”
“Tumor-isolated strains predominantly belong to Fn subspecies animalis (Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (Fna C1 and Fna C2). Of these, only Fna C2 dominates the CRC tumor niche,” the Fred Hutch researchers wrote in their Nature paper.
“We have pinpointed the exact bacterial lineage that is associated with colorectal cancer, and that knowledge is critical for developing effective preventive and treatment methods,” Johnston told the NIH.
How Bacteria Got from Mouth to Colon Not Fully Understood
Traditionally, F. nucleatum makes its home in the mouth in minute quantities. Thus, it is not fully understood how these bacteria travel from the mouth to the colon. However, the Fred Hutch researchers showed that Fna C2 could survive in acidic conditions, like those found in the gut, longer than the other types of Fna. This suggests that the bacteria may travel along a direct route through the digestive tract.
The study, which focused on participants over 50, comes at a time when colorectal cancer rates are trending upward. Rates are doubling for those under 55, jumping from 11% in 1995 to 20% in 2019. CRC is the second-leading cancer death and over 53,000 will succumb to the disease in 2024, according to NBC News.
Many of the newer diagnoses are in later stages with no clear reason why, and the Fred Hutch scientists are trying to understand how their findings tie into the increase of younger cases of colon cancer.
Bullman says it will be important to look at “whether there are elevated levels of this bacterium in young onset colorectal cancer, which is on the rise globally for unknown reasons,” she told NBC News.
Possibility of More Effective Cancer Screening
There is hope that scientists equipped with this knowledge can develop new and more effective screening and treatment options for colon cancer, as well as studying the microbiome’s impact on other diseases.
On the prevention side, researchers have seen that in mice the addition of Fna “appeared to cause precancerous polyps to form, one of the first warning signs of colorectal cancer, though Bullman added that this causation hasn’t yet been proven in humans.” NBC reported.
Future research may find that screening for Fna could determine if colorectal tumors will be aggressive, NIH reported.
“It’s possible that scientists could identify the subspecies while it’s still in the mouth and give a person antibiotics at that point, wiping it out before it could travel to the colon,” Bullman told NBC News. “Even if antibiotics can’t successfully eliminate the bacteria from the mouth, its presence there could serve as an indication that someone is at higher risk for aggressive colon cancer.”
There is also the thought of developing antibiotics to target a specific subtype of bacteria. Doing so would eliminate the need to be “wiping out both forms of the bacteria or all of the bacteria in the mouth. Further, it’s relevant to consider the possibility of harnessing the bacteria to do the cancer-fighting work,” NBC noted.
“The subtype has already proven that it can enter cancer cells quite easily, so it might be possible to genetically modify the bacteria to carry cancer-fighting drugs directly into the tumors,” Bullman told NBC News.
Further studies and research are needed. However, the Fred Hutch researchers’ findings highlight the sophistication of the human microbiome and hint at the potential role it can play in the diagnosis of cancer by clinical laboratories and pathology groups, along with better cancer treatments in the future.
Half of the genes identified were found to be singletons, unique to specific individuals, offering the possibility of developing precision medicine therapies targeted to specific patients, as well as clinical laboratory tests
Microbiologists and other medical laboratory scientists may soon have more useful biomarkers that aid in earlier, more accurate detection of disease, as well as guiding physicians to select the most effective therapies for specific patients, a key component of Precision Medicine.
The scientists also found that more than half of the bacterial genes examined occurred only once (called “singletons”) and were specific to each individual. A total of 11.8 million of these singletons came from oral samples and 12.6 million of them derived from gut samples, a Harvard news release noted.
In a paper published in Cell Host and Microbe the researchers state, “Despite substantial interest in the species diversity of the human microbiome and its role in disease, the scale of its genetic diversity, which is fundamental to deciphering human-microbe interactions, has not been quantified.”
To determine this quantity, the researchers conducted a meta-analysis of metagenomes from the human mouth and gut among 3,655 samples from 13 unique studies. Of their findings, they wrote, “We found staggering genetic heterogeneity in the dataset, identifying a total of 45,666,334 non-redundant genes (23,961,508 oral and 22,254,436 gut) at the 95% identity level.”
The scientists also found that while genes commonly found in
all the samples seemed to drive the basic functions of a microbe’s survival,
the singletons perform more specialized functions within the body, such as
creating barriers to protect the micro-organisms from external onslaughts and
helping to build up resistance to antibiotics.
“Some of these unique genes appear to be important in solving evolutionary challenges,” said Braden Tierney, a PhD student at Harvard Medical School and one of the authors of the study, in the news release. “If a microbe needs to become resistant to an antibiotic because of exposure to drugs, or suddenly faces a new selective pressure, the singleton genes may be the wellspring of genetic diversity the microbe can pull from to adapt,” he concluded.
‘More Genes in the Human Microbiome than Stars in the
Universe’
According to their published paper, the team of microbiologists and bioinformaticians pinpointed more than 46 million bacterial genes contained within 3,655 Deoxyribonucleic acid (DNA) samples. They identified 23,961,508 non-redundant genes in the oral samples and 22,254,436 non-redundant genes in the intestinal samples.
While similar research in the past has targeted bacteria in
either the gut or the mouth, the scientists believe their study is the first
that analyzed DNA collected from both areas simultaneously.
The graphic above, taken from the Harvard Medical School study, illustrates the ratio of singleton vs. non-singleton bacteria contained in human microbiome. The sheer amount of diversity seems to have impressed the scientists. “There may be more genes in the collective human microbiome than stars in the observable universe, and at least half of these genes appear to be unique to each individual,” the Harvard news release states. This diversity could lead to new precision medicine treatments and clinical laboratory diagnostics. (Graphic copyright: Harvard Medical School.)
“Just like no two siblings are genetically identical, no two bacterial strains are genetically identical, either,” said study co-author Chirag Patel, PhD, Assistant Professor of Biomedical Informatics at Harvard’s Blavatnik Institute. “Two members of the same bacterial strain could have markedly different genetic makeup, so information about bacterial species alone could mask critical differences that arise from genetic variation.”
The scientists also endeavored to determine the number of
genes that reside in the human microbiome but found the precise number difficult
to identify. One calculation estimated that number to be around 232 million,
while another suggested the number could be substantially higher.
“Whatever it may be, we hope that our catalog, along with a
searchable web application, will have many practical uses and seed many directions
of research in the field of host-microbe relationships,” stated Patel in the
news release.
New Diagnostics for Clinical Laboratories?
This type of research could have lasting effects on clinical
laboratories. As the volume of data generated by diagnostic testing of microbes
in patients opens new understanding of how these factors affect human disease
and create differences from one individual to another, the increased number of
genes and gene mutations mean that microbiology laboratories will increase
their use of information technology and analytical software tools.
“Ours is a gateway study, the first step on a what will
likely be a long journey toward understanding how differences in gene content
drive microbial behavior and modify disease risk,” said Tierney in the Harvard
news release.
That’s good news, because new biomarkers derived from such
research will help microbiologists and other clinical laboratory scientists
more accurately detect disease and identify the best therapies for individual
patients.
Obesity may be one of several health conditions and diseases where the human microbiome can be harnessed for diagnostic and therapeutic uses
Microbiologists could soon be the front lines in the nation’s fight against obesity and possibly other chronic diseases. New research underway at Vanderbilt University could lead to a host of new clinical laboratory tests that use engineered microbes.
This research is revealing how the human microbiome can be the source of new biomarkers for diagnostic tests and therapeutic drugs. In fact, early research findings point to the possibility that pathologists and clinical laboratories may eventually use the human microbiome in their daily work.
Engineering Bacteria to Battle Obesity
The human microbiome has remained largely unstudied. One reason why this is true is that it has been difficult to recreate, in the laboratory, the optimal conditions to allow these microbes to grow and thrive just as they do in the human body. However, as researchers continue to make new discoveries about this community of micro-organisms, there is optimism that elements of the human microbiome can be used to develop novel medical laboratory tests. (more…)
With $175 Million in Funding, Human Microbiome Project is Making Rapid Progress
Research into the human microbiome is expected to trigger development of new diagnostic tests that will be offered by clinical pathology laboratories. That’s because the organisms that live on us and in us are as unique to individuals as their DNA, and scientists believe these microbes may be just as important to health. Which microbes and how much they matter to the host’s health are the questions a consortium of researchers involved in the Human Microbiome Project (HMP) hope to answer.
This five-year, $157-million project, funded by the National Institutes of Health, will sequence and classify 900 microbes believed to play a role in human health. Analysis of the sequences of the first 178 microbes, which was published in the May 21 issue of Science, held some surprises, particularly in regard to the extent and complexity of microbial diversity. About 90% of their DNA was previously unknown. The study also identified novel genes and proteins that contribute to human health and disease.
Human Microbiome Project is expected to trigger many new molecular diagnostic assays
Meet the human microbiome, considered by some medical researchers to be the newest biomedical frontier. A major effort to map the human microbiome is expected to identify a significant number of new biomarkers that will be useful in both clinical pathology diagnostic tests and therapeutic drug development.
Known as the Human Microbiome Project, the five-year program is funded with $115 million in grants from the National Institutes of Health (NIH). Researchers are well on their way to produce a comprehensive inventory of microbes—bacteria, viruses, yeast and fungi—that live in or on the human body, along with information about their role in disease development or prevention. The overall goal of this international effort is to identify which microbes are harmful and figure out ways to prevent or treat diseases they cause.
