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Duke University Study Suggests the Human Body Starves Gut Bacteria to Produce Beneficial Results

Human microbiota is linked to many diseases but could hold the key for advanced clinical laboratory tests and targeted precision medicine therapies Study of the human microbiome continues to provide understanding and knowledge regarding gut bacteria and its many benefits, and incites development into new clinical laboratory tests. However, a new study reveals that our bodies might also put gut bacteria under stress leading to better health. Traditionally, scientists believe the human gut is a...

Researchers Discover Link between Gut Bacteria and the Effectiveness of Certain Cancer Drugs; Knowledge May Lead to New Types of Clinical Laboratory Tests

Microbiome is once again leading scientists toward a new understanding of how human gut bacteria can impact the efficacy and side-effects of certain cancer therapies

Anatomic pathology researchers already know that a person’s genetics can affect the results of cancer treatments. Now it is becoming clear that a patient’s microbiome—which includes gut bacteria—may also impact the efficacy of particular cancer treatments. A recent study showed that gut bacteria can be used to determine whether a cancer drug will work for a certain individual and also if the patient might suffer side effects from certain cancer treatments.

Working with this knowledge, diagnostic test companies may possibly develop new clinical laboratory tests designed to help physicians better diagnose and treat cancer patients. This, in turn, advances personalized medicine and treatments for chronic diseases tailored to patients’ specific physiologies and conditions. This is a healthcare trend where medical laboratories can expect to play a critical role.

Gut Bacteria as Important as Genetics in Cancer Treatments

A recent article published in the journal Nature: npj Biofilms and Microbiomes, outlined a correlation between gut bacteria and side effects of irinotecan (sold as Camptosar), a drug used to treat metastatic colorectal cancer.

Libusha Kelly, PhD, Assistant Professor in the Departments of Systems and Computational Biology, and Microbiology and Immunology, led researchers from the Albert Einstein College of Medicine located in Bronx, N.Y., in conducting the study.

“We’ve known for some time that people’s genetic makeup can affect how they respond to a medication,” noted Kelly in an Einstein news release. “Now, it’s becoming clear that variations in one’s gut microbiome—the population of bacteria and other microbes that live in the digestive tract—can also influence the effects of treatment.”

Irinotecan is administered intravenously to colorectal cancer patients in an inactive form and is metabolized to an active form by liver enzymes. The drug is later converted back to an inactive form by other liver enzymes and the addition of a Glucuronidase chemical group. The irinotecan then enters the intestine for expulsion by the body.

Taken from the Einstein College of Medicine published study, the graph above illustrates “Two distinct metabolizer phenotypes or ‘metabotypes’ based on % SN-38 formation during a time course incubation of SN-38G with fecal samples from 20 individuals quantified by LC-MS/MS. Participants were sub-grouped into low (n = 16) and high (n = 4) metabolizer phenotypes. All samples were run in triplicate and values are the mean ± sem.” (Graphic copyright: Nature/Albert Einstein College of Medicine.)

However, bacteria residing in the digestive tract of some individuals prevent the medication from metabolizing properly and reactivates the medication, which transforms the irinotecan into a toxic substance that can cause side effects.

To perform the research, Kelly and her team collected fecal samples from 20 healthy individuals and treated those samples with inactive irinotecan. The samples were then examined and categorized by whether or not they were able to metabolize or reactivate the drug.

Identifying Potential for Side Effects in Patients a Powerful Tool for Medical Laboratories

Irinotecan can cause severe diarrhea and dehydration in up to 40% of patients who take the medication. By focusing on the presence of beta-glucuronidase (enzymes that are used to catalyze the breakdown of complex carbohydrates) the researchers found that gut bacteria can also be used to distinguish which patients will encounter side effects from the drug.

“As you can imagine, such patients are already quite ill, so giving them a treatment that causes intestinal problems can be very dangerous,” said Kelly in the news release. “At the same time, irinotecan is an important weapon against this type of cancer.”

Four of the 20 subjects in the study were determined to be high metabolizers. Due to differences in the composition of their microbiomes, the team concluded that the high metabolizers were more likely to experience side effects from irinotecan.

The research also demonstrated that beta-glucuronidase enzymes in the gut may adversely interact with some commonplace drugs, such as ibuprofen and other nonsteroidal anti-inflammatory medications (NSAIDs), morphine, and Tamoxifen, a drug that is prescribed mainly to breast cancer patients.

“In these cases, the issue for patients may not be diarrhea,” states Kelly in the news release. “Instead, if gut bacteria reactivate those drugs, then patients might be exposed to higher-than-intended doses. Our study provides a broad framework for understanding such drug-microbiome interactions.”

Microbiome Takes Center Stage in Pathology Research

As Dark Daily previously reported, from extending life to developing more powerful treatments for chronic diseases, the human microbiome is quickly becoming an important subject of research studies. The findings from such studies will trigger advances in precision medicine. And, the clinical laboratory assays developed from this research will give physicians the knowledge needed to select the most appropriate drug therapies and treatments for individual patients.

—JP Schlingman

Related Information:

Gut Bacteria Can Stop Cancer Drugs from Working

Gut Microbiome May Make Chemo Drug Toxic to Patients

Human Microbiome Signatures of Differential Colorectal Cancer Drug Metabolism

Researchers in Two Separate Studies Discover Gut Microbiome Can Affect Efficacy of Certain Cancer Drugs; Will Findings Lead to a New Clinical Laboratory Test?

Attention Microbiologists and Medical Laboratory Scientists: New Research Suggests an Organism’s Microbiome Might Be a Factor in Longer, More Active Lives

Mayo Clinic and Whole Biome Announce Collaboration to Research the Role of the Human Microbiome in Women’s Diseases Using Unique Medical Laboratory Tests

Might Bacteria be Used to Identify Cancer Cells? Some Researchers Using Synthetic Biology and Genetic Engineering Techniques Say ‘Yes’

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 resulting “bacterial biosensors” go on a “sort of molecular manhunt” to find and capture tumor DNA with mutations in the Kirsten Rat Sarcoma virus (KRAS) gene, according to an article published by the National Cancer Institute (NCI) titled, “Could Bacteria Help Find Cancer?

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.

The researchers published their proof-of-concept findings in the journal Science titled, “Engineered Bacteria Detect Tumor DNA.”

Daniel Worthley, PhD

“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. 

CRISPR Aids CATCH Development

Inside Precision Medicine shared these steps toward creation of the CATCH technique:

  • Researchers engineered bacteria using CRISPR.
  • 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.

—Donna Marie Pocius

Related Information:

Could Bacteria Help Find Cancer?

Researchers Engineer Bacteria That Can Detect Tumor DNA

Engineered Bacteria Can Act as Biosensors to Detect Cancer DNA

Engineered Bacteria Detect Tumor DNA

Engineered Bacteria Can Detect Tumor DNA

Scientists Genetically Engineer Bacteria to Detect Cancer Cells

Genetically Engineered Bacteria Can Detect Cancer Cells in a World-First Experiment

Protein Catalyzed Capture Agents

Dey Laboratory Research Finds Bile Acids Affect Gut Motility and the Human Microbiome, Insights That May Lead to New Clinical Laboratory Tests

These new findings may affect how microbiology labs and physicians diagnose and treat several gastrointestinal conditions

Once again, a research effort has teased out new insights into the role the human microbiome plays in our digestive processes. Microbiologist and medical laboratory managers will be interested to learn that, according to the study team, specific microbes have a role in regulating how fast food moves through the digestive tract.

Researchers at the Dey Laboratory in Seattle recently examined the function of microbial bile acid metabolism in gut motility. They determined that “metabolites generated by the gut microbiome regulate gut transit,” according to a new paper published by the Fred Hutchinson Cancer Research Center (Fred Hutch).

“These findings have potential implications for the treatment of gastrointestinal conditions,” noted a Fred Hutch news release. This may mean new clinical laboratory tests to identify these strains of bacteria, along with new therapies for treating patients.

Gut motility (aka, Peristalsis) is the term used to describe the movement of food from the time it enters via the mouth until it leaves the body. This movement, the researchers found, is regulated by interactions between diet, the enteric nervous system (ENS) and the gut microbiota via processes that include bile acid metabolism.

Sex, Diet, and Lifestyle All Affect Treatment for Gastrointestinal Diseases

The Dey Laboratory researchers also discovered that sex was a significant variable in determining transit times with males having larger pro-motility effects.

In “Microbiome-encoded Bile Acid Metabolism Modulates Colonic Transit Times,” the Dey Laboratory researchers noted that previous studies have shown higher motility and varying bile acid profiles between men and women. They published their study in iScience, an open-access Cell Press journal.

“Our results suggest that strategies for treating or preventing gastrointestinal diseases may need to be tailored to sex and to biogeography of the gut,” they wrote. “While targeting the microbiome and the ENS is justified, our observation of significant transcriptional responses to defined interventions in a highly controlled gnotobiotic setting also highlights challenges to clinical translation.”

The researchers concluded that:

  • Gut microbiome-generated bile acids regulate colonic transit via TGR5 protein.
  • Lithocholic acid (LCA) had the largest colonic pro-motility effect.
  • Bile acids exert sex-biased effects on gut transit times.
  • Enteric nervous system (ENS) transcriptional responses are regional- and microbiome-specific.

“The human experience—which reflects the aggregate effects of the innumerable dietary ingredients that we consume daily, the hugely diverse metabolically dynamic microbes that inhabit our guts, our own digestive processes, and the interactions of all of the above that result in thousands of gut metabolites—entails significantly more complex and variable transcriptional responses to environmental cues,” the Dey Laboratory scientists concluded.

Dey Lab graphic

To perform their research, the scientists developed both high and low BSH (bile salt hydrolase) bacterial communities for germ-free mice, which are known to exhibit slower gut motility and less complex bile acid profiles than colonized animals. (See graphic above taken from the Dey Laboratory published paper.)

The spice turmeric and dyes were added to the diets of the mice to track gut motility. The mice that were given the BSH-high microbiota had higher fecal concentrations of unconjugated bile acids than those given the BSH-low form of the microbiota. The mice given the BSH-high version also experienced faster transit times, according to the researchers’ iScience paper.

The researchers also concluded that the BSH-high group had greater fecal concentrations of lithocholic acid (LCA) which indicates variations in bile acid metabolism might affect gut transit.

When the scientists infused bile acids directly into mouse colons, variable acids reacted differently with LCA having the fastest transit times. The researchers hypothesized that LCA might signal through a bile receptor known as TGR5 which blocked the effects of LCA on colonic transit times. TGR5, also called G protein-coupled bile acid receptor, functions as a cell surface receptor for bile acids.

The Dey Laboratory team developed a method to measure expression changes in ENS genes and found that neither BSH activity nor gut transit phenotypes were major drivers of gene expression changes. They found that the location of the gut segment, or biogeography, was the leading contributor to ENS signature variance between samples.

Neelendu Dey, MD

“We expected to see shared host transcriptional responses in mice harboring communities with similar metabolic profiles. However, we did not see this for the most part,” explained gastroenterologist Neelendu Dey, MD (above), a physician/scientist and Assistant Professor, Clinical Research Division, at Fred Hutchinson Cancer Research Center, in the press release. “If anything, shared responses were regional, and these signatures did not cluster by BSH/motility phenotypes.” (Photo copyright: Seattle Cancer Care Alliance.)

The scientists “identified consortium-specific transcriptional changes in genes involved in ENS signaling, development, maintenance, and bile acid metabolism, and these differed across regions of the GI tract. Together these findings indicate that ENS transcriptional responses are regional and microbiome-specific,” according to the Fred Hutch press release.

“This remains a confusing part of the story for us—how is it that we can see predictable host motility responses when colonizing the guts of gnotobiotic mice with phenotypically defined communities, but the middle-man (the host enteric nervous system) appears to have such varied responses?” the Dey Laboratory researchers noted in the press release.

“It suggests that gut motility phenotypes that appear similar may in fact represent (when we look under the hood) diverse host physiologic phenotypes that we are just beginning to understand,” they added.

The results of this study could have potential implications for the precision medicine diagnosis and treatment of gastrointestinal illnesses.

Blue Poop Challenge

Earlier this year, people were encouraged to participate in the “blue poop challenge” conducted by research company ZOE Global Limited (ZOE) to determine how long it takes food to travel through the body.

ZOE is also known for collaborating with King’s College London, and Guy’s and St Thomas’ Hospitals to create the COVID Symptom Tracker mobile app (now known as the COVID Symptom Study).

For the Blue Poop Challenge, individuals are asked to eat blue muffins and then report on the company’s website as to how long it took for the blue dye to appear in their stools.

The purpose of this ongoing study is to reveal pertinent information about an individual’s gut health and microbiome.

Since 2010, Dark Daily has reported on dozens of research studies and innovative developments involving human microbiome and gut bacteria and their critical importance in the development of clinical laboratory testing, drug therapies, and precision medicine.

In “University of Utah and Sloan Kettering Institute Study Sheds Light on How the Body Recognizes ‘Good’ from Bad Bacteria in the Microbiome,” we reported on research being conducted at the University of Utah and the Sloan Kettering Institute (SKI) which found that early in life intestinal microorganisms “educate” the thymus to develop T cells.

These studies’ findings could lead to improved immune system therapeutics and associated clinical laboratory tests.

“All of this suggests the potential in the future for clinical laboratories and microbiologists to do microbiome testing in support of clinical care,” said Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report.

More research is needed in these areas. But gut bacteria and the human microbiome are an integral part of our health and wellbeing. It is worth keeping an eye on new developments in those fields of study.

JP Schlingman

Related Information

Keeping Regular: Gut Bacteria Modulate Transit Time via Bile Acids

Microbiome-encoded Bile Acid Metabolism Modulates Colonic Transit Times

Does the Viral Blue Poop Challenge Really Tell You Anything about Gut Health?

The Blue Poop Challenge Could Tell You Important Info about Your Gut Health—Here’s How It Works

University of Utah and Sloan Kettering Institute Study Sheds Light on How the Body Recognizes ‘Good’ from Bad Bacteria in the Microbiome

University of Utah and Sloan Kettering Institute Study Sheds Light on How the Body Recognizes “Good” from Bad Bacteria in the Microbiome

Researchers found that early in life intestinal microorganisms “educate” the thymus to develop T cells; findings could lead to improved immune system therapeutics and associated clinical laboratory tests

Researchers at the University of Utah and the Sloan Kettering Institute (SKI)—the experimental research division of the Memorial Sloan Kettering Cancer Center (MSKCC) in New York—have uncovered new insights into how the immune system learns to distinguish between harmful infectious bacteria and “good” bacteria in the microbiome that occupies the gastrointestinal tract.

The researchers published their findings in Nature. They used engineered mice as the test subjects and say the study could lead to a greater understanding of human conditions such as Type 1 and Type 2 diabetes and inflammatory bowel disease (IBD). In turn, this new knowledge could lead to new diagnostic tests for clinical laboratories.

“From the time we are born, our immune system is set up so that it can learn as much as it can to distinguish the good from the bad,” Matthew Bettini, PhD, Associate Professor of Pathology said in a University of Utah news release.

Does Gut Bacteria ‘Educate’ the Immune System?

The researchers were attempting to learn how the body develops T cells specific to intestinal microorganisms. T cells, they noted, are “educated” in the thymus, an organ in the upper chest that is key to the adaptive immune system.

“Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection,” they wrote in their study. “Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen, while limiting inflammatory anti-commensal responses.”

Matthew Bettini, PhD and Gretchen Diehl, PhD

Matthew Bettini, PhD (left), Associate Professor of Pathology at the University of Utah, co-authored the study along with Gretchen Diehl, PhD (right), an immunologist at Sloan Kettering Institute. The team also included researchers from the Baylor College of Medicine in Houston and the Washington University School of Medicine in St. Louis. “Our studies make clear that there is a window in which gut microbiota have access to the immune education process. This opens up possibilities for designing therapeutics that can influence the trajectory of the immune system during this early time point,” Bettini said in the University of Utah news release. (Photo copyright: University of Utah/Sloan Kettering Institute.)

Findings Challenge Earlier Assumptions about Microbiota’s Influence on Immunity

The researchers began by seeding the intestines of mice with segmented filamentous bacteria (SFB), which they described as “one of the few commensal microorganisms for which a microorganism-specific T-cell receptor has been identified.” In addition, SFB-specific T cells can be tracked using a magnetic enrichment technique, they wrote in Nature.

They discovered that in young mice, microbial antigens from the intestines migrated to the thymus, resulting in an expansion of T cells specific to SFB. But they did not see an expansion of T cells in adult mice, suggesting that the process of adapting to microbiota happens early.

“Our study challenges previous assumptions that potential pathogens have no influence on immune cells that are developing in the thymus,” Bettini said in the news release. “Instead, we see that there is a window of opportunity for the thymus to learn from these bacteria. Even though these events that shape which T cells are present happen early in life, they can have a greater impact later in life.”

For example, T cells specific to microbiota can also protect against closely related harmful bacteria, the researchers found. “Mice populated with E. coli at a young age were more than six times as likely to survive a lethal dose of Salmonella later in life,” the news release noted. “The results suggest that building immunity to microbiota also builds protection against harmful bacteria the body has yet to encounter.”

According to the researchers, in addition to protecting against pathogens, “microbiota-specific T cells have pathogenic potential.” For example, “defects in these mechanisms could help explain why the immune system sometimes attacks good bacteria in the wrong place, causing the chronic inflammation that’s responsible for inflammatory bowel disease,” they suggested.

Other Clinical Laboratory Research into the Human Microbiome

The research conducted by the University of Utah, Sloan Kettering Institute, and others, adds to a growing understanding of the human microbiome. For example, in “International Study into Ancient Poop Yields Insight into the Human Microbiome, May Produce Useful Insights for Microbiologists,” Dark Daily reported on an international study of 2000-year-old human feces which suggested that the microbiomes of today’s humans may have been modified by modern phenomena such as processed food and sanitation.

And in “Harvard Medical School Study Finds ‘Staggering’ Amounts of Genetic Diversity in Human Microbiome; Might Be Useful in Diagnostics and Precision Medicine,” Dark Daily reported on a study from Harvard Medical School and Joslin Diabetes Center that unveiled a “staggering microbial gene diversity” in the microbiome and the potential for identification of more-useful biomarkers for disease detection.

And a study from the University of Nebraska-Lincoln and the Ocean Road Cancer Institute in Tanzania raised the possibility that bacteria in the cervical microbiome could lead to new tests for cervical cancer. (See Dark Daily, “University Study Suggests Cervical Microbiome Could Be Used by Medical Laboratories as Biomarker in Determining Women’s Risk for Cervical Cancer.”

All of this suggests the potential in the future “for clinical laboratories and microbiologists to do microbiome testing in support of clinical care,” said Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report. Of course, more research is needed in these areas.

“We believe that our findings may be extended to areas of research where certain bacteria have been found to be either protective or pathogenic for other conditions, such as Type 1 and Type 2 diabetes,” Bettini said in the University of Utah news release. “Now we’re wondering, will this window of bacterial exposure and T cell development also be important in initiating these diseases?”

—Stephen Beale

Related Information

How the Body Builds a Healthy Relationship With ‘Good’ Gut Bacteria

Thymic Development of Gut-Microbiota-Specific T Cells

International Study into Ancient Poop Yields Insight into the Human Microbiome, May Produce Useful Insights for Microbiologists

Harvard Medical School Study Finds ‘Staggering’ Amounts of Genetic Diversity in Human Microbiome; Might Be Useful in Diagnostics and Precision Medicine

University Study Suggests Cervical Microbiome Could Be Used by Medical Laboratories as Biomarker in Determining Women’s Risk for Cervical Cancer

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