Although it is a non-specific procedure that does not identify specific health conditions, it could lead to new biomarkers that clinical laboratories could use for predictive healthcare
Researchers from the Mayo Clinic recently used artificial intelligence (AI) to develop a predictive computational tool that analyzes an individual’s gut microbiome to identify how a person may experience improvement or deterioration in health.
Dubbed the Gut Microbiome Wellness Index 2 (GMWI2), Mayo’s new tool does not identify the presence of specific health conditions but can detect even minor changes in overall gut health.
Built on an earlier prototype, GMWI2 “demonstrated at least 80% accuracy in differentiating healthy individuals from those with any disease,” according to a Mayo news release. “The researchers used bioinformatics and machine learning methods to analyze gut microbiome profiles in stool samples gathered from 54 published studies spanning 26 countries and six continents. This approach produced a diverse and comprehensive dataset.”
“Our tool is not intended to diagnose specific diseases but rather to serve as a proactive health indicator,” said senior study author Jaeyun Sung, PhD (above), a computational biologist at the Mayo Clinic Center for Individualized Medicine: Microbiomics Program in the news release ease. “By identifying adverse changes in gut health before serious symptoms arise, the tool could potentially inform dietary or lifestyle modifications to prevent mild issues from escalating into more severe health conditions, or prompt further diagnostic testing.” For microbiologists and clinical laboratory managers, this area of new knowledge about the human microbiome may lead to multiplex diagnostic assays. (Photo copyright: Mayo Clinic.)
Connecting Specific Diseases with Gut Microbiome
Gut bacteria that resides in the gastrointestinal tract consists of trillions of microbes that help regulate various bodily functions and may provide insights regarding the overall health of an individual. An imbalance in the gut microbiome is associated with an assortment of illnesses and chronic diseases, including cardiovascular issues, digestive problems, and some cancers and autoimmune diseases.
To develop GMWI2, the Mayo scientists provided the machine-learning algorithm with data on microbes found in stool samples from approximately 8,000 people collected from 54 published studies. They looked for the presence of 11 diseases, including colorectal cancer and inflammatory bowel disease (IBS). About 5,500 of the subjects had been previously diagnosed with one of the 11 diseases, and the remaining people did not have a diagnosis of the conditions.
The scientists then tested the efficacy of GMWI2 on an additional 1,140 stool samples from individuals who were diagnosed with conditions such as pancreatic cancer and Parkinson’s disease, compared with those who did not have those illnesses.
The algorithm gives subjects a score between -6 and +6. People with a higher GMWI2 score have a healthier microbiome that more closely resembles individuals who do not have certain diseases.
Likewise, a low GMWI2 score suggests the individual has a gut microbiome that is similar to those who have specific illnesses.
Highly Accurate Results
According to their study, the researchers determined that “GMWI2 achieves a cross-validation balanced accuracy of 80% in distinguishing healthy (no disease) from non-healthy (diseased) individuals and surpasses 90% accuracy for samples with higher confidence,” they wrote in Nature Communications.
Launched in 2020, the original GMWI (Gut Microbiome Wellness Index) was trained on a much smaller number of samples but still showed similar results.
The researchers tested the enhanced GMWI2 algorithm across various clinical schemes to determine if the results were similar. These scenarios included individuals who had previous fecal microbiota transplants and people who had made dietary changes or who had exposure to antibiotics. They found that their improved tool detected changes in gut health in those scenarios as well.
“By being able to answer whether a person’s gut is healthy or trending toward a diseased state, we ultimately aim to empower individuals to take proactive steps in managing their own health,” Sung said in the news release.
The Mayo Clinic team is developing the next version of their tool, which will be known as the Gut Microbiome Wellness Index 3. They plan to train it on at least 12,000 stool samples and use more sophisticated algorithms to decipher the data.
More research and studies are needed to determine the overall usefulness of Mayo’s Gut Microbiome Wellness Index and its marketability. Here is a world-class health institution disclosing a pathway/tool that analyzes the human microbiome to identify how an individual may be experiencing either an improvement in health or a deterioration in health.
The developers believe it will eventually help physicians determine how patients’ conditions are improving or worsening by comparing the patients’ microbiomes to the profiles of other healthy and unhealthy microbiomes. As this happens, it would create a new opportunity for clinical laboratories to perform the studies on the microbiomes of patients being assayed in this way by their physicians.
Findings could lead to new therapies and clinical laboratory biomarkers for detecting and defeating antibiotic-resistant bacteria
Once again, new research shows that human gut bacteria (microbiota) may be useful in fighting antibiotic-resistant bacterial infections. The study findings could provide new therapeutics and clinical laboratory biomarkers for diagnosing and treating severe gastrointestinal disorders.
Antibiotic-resistant bacterial infections often appear in patients with chronic intestinal conditions and in those with long-term antibiotic use. Enterobacteriaceae is a large family of gram-negative bacteria that includes more than 30 genera and over 100 species.
“Despite two decades of microbiome research, we are just beginning to understand how to define health-promoting features of the gut microbiome,” said Marie-Madlen Pust, PhD, a computational postdoctoral researcher at the Broad Institute and co-first author of the paper, in the news release.
“Part of the challenge is that each person’s microbiome is unique. This collaborative effort allowed us to functionally characterize the different mechanisms of action these bacteria use to reduce pathogen load and gut inflammation,” she added.
The researchers identified a way to treat patients infected by antibiotic-resistant strains of bacteria that does not involve antibiotics. Should further research validate these early findings, this could be a viable approach to treating patients with this condition.
“Microbiome studies can often consist of analyzing collections of genetic sequences, without understanding what each gene does or why certain microbes are beneficial,” said Ramnik Xavier, MD (above), director of Broad Institute’s immunology program, co-director of the infectious disease and microbiome program, and co-senior author on the study, in a news release. “Trying to uncover that function is the next frontier, and this is a nice first step towards figuring out how microbial metabolites influence health and inflammation.” Clinical laboratories that test for intestinal conditions caused by antibiotic resistance will want to follow the Broad Institute’s research. (Photo copyright: Broad Institute.)
Suppressing Growth of Antibiotic-resistant Bacteria
To perform their research, the scientists isolated about 40 strains of bacteria from the stools of five healthy fecal donors. They then used those stool samples in fecal microbiota transplants to treat mice that had been infected with either Escherichia coli (E. coli) or Klebsiella, both forms of Enterobacteriaceae. The scientists tested different combinations of the 40 strains and identified 18 that suppressed the growth of Enterobacteriaceae.
“Antibiotic-resistant Enterobacteriaceae such as E. coli and Klebsiella bacteria are common in hospitals, where they can proliferate in the gut of patients and cause dangerous systemic infections that are difficult to treat. Some research suggests that Enterobacteriaceae also perpetuates inflammation in the intestine and infection by other microbes,” the Broad Institute news release notes.
The researchers discovered that Klebsiella changed the gene expression in carbohydrate uptake and metabolism in the Klebsiella-infected mice that were treated with the 18 beneficial strains. The gene expression included the downregulating of gluconate kinase and transporter genes, which revealed there is increased competition among gut bacteria for nutrients.
When combined, these 18 strains alleviated inflammation in the guts of the treated mice by depriving the harmful gut bacteria of carbohydrates. This non-antibiotic approach also prevented harmful bacteria from colonizing in the gut.
“In partnership with the Broad’s Metabolomics Platform, led by senior director and study co-author Clary Clish, PhD, they analyzed samples from pediatric patients with ulcerative colitis, looking for the presence of alternate gluconate pathway genes of gut microbes and fecal gluconate levels. They found higher levels of gluconate linked to more gluconate-consuming Enterobacteriaceae in samples from pediatric patients with ongoing inflammation, indicated by high levels of the protein calprotectin,” the study authors wrote in Nature.
“Together, the findings suggest that Enterobacteriaceae processes gluconate as a key nutrient and contributes to inflammation in patients. But when a gut microbiome includes the 18 helpful strains, they likely compete with Enterobacteriaceae for gluconate and other nutrient sources, limiting the proliferation of the harmful bacteria,” the scientists concluded.
Promising New Bacterial Therapies
This research could ultimately lead to the development of fecal microbiota transplants for individuals to eradicate antibiotic-resistant bacteria in a more objective and specific manner, with fewer side effects than current treatments.
“Harnessing these activities in the form of live bacterial therapies may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant Enterobacteriaceae infection,” the scientists wrote in Nature.
According to the news release, they plan to continue research to “uncover the identity and function of unknown metabolites that contribute to gut health and inflammation.” The team hopes to discover how different bacteria compete with each other, and to develop microbial therapeutics that improve gut microbiome and curb bacterial infections.
More studies are needed to prove the efficacy of this type of fecal bacterial treatment. However, this research demonstrates how using nano processes enabled by new technologies to identify the actual work of proteins, RNA, and DNA in the body cheaply, faster, and with greater precision, will open doors to both therapeutic and diagnostic clinical laboratory biomarkers.
As this therapeutic approach gains regulatory approval, clinical laboratory tests to determine condition of patient’s gut microbiota and monitor therapy will be needed
Some developments in the clinical laboratory industry are less about diagnostic tests and more about novel approaches to therapy. Such is the case with a new carbon bead technology developed by researchers from University College London (UCL) and the Royal Free Hospital intended to remove harmful bacteria toxins from the gut before they leak to the liver. The macroporous beads, which come in small pouches, are delivered orally and could be utilized in the future to treat a number of diseases.
Why is this relevant? Once a new treatment is accepted for clinical use, demand increases for a clinical laboratory test that confirms the therapy will likely work and to monitor its progress.
In collaboration with Yaqrit, a UK-based life sciences company that develops treatments for chronic liver disease, the UCL and Royal Free Hospital scientists engineered the carbon beads—known as CARBALIVE—to help restore gut health. They measured the technology’s impact on liver, kidney, and brain function in both rats and mice.
“The influence of the gut microbiome on health is only just beginning to be fully appreciated,” said Rajiv Jalan, PhD, Professor of Hepatology at UCL in a press release. “When the balance of the microbiome is upset, ‘bad’ bacteria can proliferate and out-compete the ‘good’ bacteria that keeps the gut healthy.
“One of the ways [the ‘bad’ bacteria] do this is by excreting endotoxin, toxic metabolites, and cytokines that transform the gut environment to make it more favorable to them and hostile to good bacteria,” he continued. “These substances, particularly endotoxin, can trigger gut inflammation and increase the leakiness of the gut wall, resulting in damage to other organs such as the liver, kidneys, and brain.”
“I have high hopes that the positive impact of these carbon beads in animal models will be seen in humans, which is exciting not just for the treatment of liver disease but potentially any health condition that is caused or exacerbated by a gut microbiome that doesn’t work as it should,” said Rajiv Jalan, PhD (above), Professor of Hepatology, University College London, in a press release. “This might include conditions such as irritable bowel syndrome (IBS), for example, which is on the rise in many countries.” Though not a clinical laboratory diagnostic test, new therapies like CARBALIVE could be a boon to physicians treating patients with IBS and other gastrointestinal conditions.
Developing the Carbon Beads
The team discovered CARBALIVE is effective in the prevention of liver scarring and injury in animals with cirrhosis when ingested daily for several weeks. They also found a reduced mortality rate in test animals with acute-on-chronic-liver-failure (ACLF).
After achieving success with CARBALIVE in animals, the researchers tested the technology on 28 cirrhosis patients. The carbon beads proved to be safe for humans and had inconsequential side effects.
“In cirrhosis, a condition characterized by scarring of the liver, it is known that inflammation caused by endotoxins can exacerbate liver damage,” Jalan explained. “Part of the standard treatment for cirrhosis is antibiotics aimed at controlling bad bacteria, but this comes with the risk of antibiotic resistance and is only used in late-stage disease.”
The beads, which are smaller than a grain of salt, contain an exclusive physical structure that absorbs large and small molecules in the gut. They are intended to be taken with water at bedtime as harmful bacteria is more likely to circulate through the body at night which could result in damage. The carbon beads do not kill bacteria, which decreases the risk of antibiotic resistance. They eventually pass through the body as waste.
“They work by absorbing the endotoxins and other metabolites produced by ‘bad’ bacteria in the gut, creating a better environment for the good bacteria to flourish and helping to restore microbiome health,” said Michal Kowalski, M.Sc.Eng, Director and VP of Operations at Yaqrit, in the UCL news release.
“This prevents these toxins from leaching into other areas of the body and causing damage, as they do in cirrhosis,” he added. “The results in animal models are very positive, with reduction in gut permeability, liver injury, as well as brain and kidney dysfunction.”
Additional Research
The researchers plan to perform further clinical trials in humans to determine if the carbon beads are effective at slowing the progression of liver disease. If the benefits that were observed in lab animals prove to be compelling in humans, the technology may become an invaluable tool for the treatment of liver disease and other diseases associated with poor microbiome health in the future.
According to the American Liver Foundation, 4.5 million adults in the US have been diagnosed with liver disease. However, it is estimated that 80 to 100 million adults have some form of fatty liver disease and are unaware of it. Liver disease was the 12th leading cause of death in the US in 2020 with 51,642 adults perishing from the disease that year.
According to BMC Public Health, globally there were 2.05 million new cases of liver cirrhosis diagnosed in 2019. In that year, 1.47 million people around the world died from the disease.
More research and clinical studies are needed before this novel technology can be used clinically. When and if that happens, the demand for clinical laboratory tests that measure microbiome deficiencies and monitor patient progress during therapy will likely be high.
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.
Cellular healthcare is an approach that goes beyond clinical laboratory testing to identify the location of specific cancer cells and aid in treatment decisions
Advances in synthetic biology and genetic engineering are leading to development of bacterial biosensors that could eventually aid pathologists and clinical laboratories in diagnosis of many types of cancers.
One recent example comes from researchers at the University of California San Diego (UCSD) who worked with colleagues in Australia to engineer bacteria that work as “capture agents” and bind to tumorous material.
The KRAS gene is associated with colorectal cancer. The researchers named their development the Cellular Assay for Targeted CRISPR-discriminated Horizontal gene transfer (CATCH).
CATCH successfully detected cancer in the colons of mice. The researchers believe it could be used to diagnose cancers, as well as infections and other diseases, in humans as well, according to a UCSD news release.
“If bacteria can take up DNA, and cancer is defined genetically by a change in its DNA, then, theoretically, bacteria could be engineered to detect cancer,” gastroenterologist Daniel Worthley, PhD, a cancer researcher at Colonoscopy Clinic in Brisbane, Australia, told MedicalResearch.com. This research could eventually provide clinical laboratories and anatomic pathologists with new tools to use in diagnosing certain types of cancer. (Photo copyright: Colonoscopy Clinic.)
Tapping Bacteria’s Natural Competence
In their Science paper, the researchers acknowledged other synthetic biology achievements in cellular biosensors aimed at human disease. But they noted that more can be done by leveraging the “natural competence” skill of bacteria.
“Biosensors have not yet been engineered to detect specific extracellular DNA sequences and mutations. Here, we engineered naturally competent Acinetobacter baylyi (A. baylyi) to detect donor DNA from the genomes of colorectal cancer cells, organoids, and tumors,” they wrote.
“Many bacteria can take up DNA from their environment, a skill known as natural competence,” said Rob Cooper, PhD, co-first author of the study and a scientist at US San Diego’s Synthetic Biology Institute, in the news release. A. baylyi is a type of bacteria renowned for success in doing just that, the NCI article pointed out.
This enabled them to explore “free-floating DNA sequences on a genomic level.”
Those sequences were compared to “known cancer DNA sequences.”
A. baylyi (genetically modified) was tested on its ability to detect “mutated and healthy KRAS DNA.”
Only bacteria that had “taken up mutated copies of KRAS … would survive treatment with a specific drug.”
“It was incredible when I saw the bacteria that had taken up the tumor DNA under the microscope. The mice with tumors grew green bacterial colonies that had acquired the ability to be grown on antibiotic plates,” said Josephine Wright, PhD, Senior Research Fellow, Gut Cancer Group, South Australian Health and Medical Research Institute (SAHMRI), in the news release.
Detecting DNA from Cancer Cells In Vitro and in Mice
Findings in vitro and in mice include the following:
The engineered bacteria enabled detection of DNA with KRAS G12D from colorectal cancer cells made in the lab, NCI reported.
When mice were injected with colorectal cancer cells, the researchers’ technology found tumor DNA, Engadget reported.
The study adds to existing knowledge of horizontal gene transfer from bacteria to bacteria, according to UCSD.
“We observed horizontal gene transfer from the tumor to the sensor bacteria in our mouse model of colorectal cancer. This cellular assay for targeted, CRISPR-discriminated horizontal gene transfer (CATCH) enables the biodetection of specific cell-free DNA,” the authors wrote in Science.
“Colorectal cancer seemed a logical proof of concept as the colorectal lumen is full of microbes and, in the setting of cancer, full of tumor DNA,” gastroenterologist Daniel Worthley, PhD, a cancer researcher at Colonoscopy Clinic in Brisbane, Australia, told MedicalResearch.com.
Finding More Cancers and Treatment
More research is needed before CATCH is used in clinical settings. The scientists are reportedly planning on adapting CATCH to multiple bacteria that can locate other cancers and infections.
“The most exciting aspect of cellular healthcare … is not in the mere detection of disease. A laboratory can do that,” wrote Worthley in The Conversation. “But what a laboratory cannot do is pair the detection of disease (a diagnosis) with the cells actually responding to the disease [and] with appropriate treatment.
“This means biosensors can be programmed so that a disease signal—in this case, a specific sequence of cell-free DNA—could trigger a specific biological therapy, directly at the spot where the disease is detected in real time,” he added.
Clinical laboratory scientists, pathologists, and microbiologists may want to stay abreast of how the team adapts CATCH, and how bacterial biosensors in general continue to develop to aid diagnosis of diseases and improve ways to target treatment.
