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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

King’s College London Study Identifies Six Distinct ‘Types’ of COVID-19 Illness, Each with a Distinct ‘Cluster’ of Symptoms

The KCL researchers’ new models for predicting which patients will need hospitalization and breathing support may be useful for pathologists and clinical laboratory scientists

One more window into understanding the SARS-CoV-2 coronavirus may have just opened. A British study identified six distinct “clusters” of symptoms that the research scientists believe may help predict which patients diagnosed with COVID-19 will require hospitalization and respiratory support. If further research confirms these early findings, pathologists and medical laboratory managers may gain new tools to diagnose infections faster and more accurately.

Researchers from King’s College London (KCL) analyzed data gathered from the COVID Symptom Study App, a mobile-device application developed by health science company ZOE in collaboration with scientists and physicians at KCL and Massachusetts General Hospital, as well as:

Launched in March in the United Kingdom and extended to the United States and Sweden, the app has attracted more than four million users who track their health and potential COVID symptoms on a daily basis.

Increased Accuracy in Predicting COVID-19 Hospitalizations

On July 17, 2020, the Centers for Disease Control and Prevention (CDC) published “Symptom Profiles of a Convenience Sample of Patients with COVID-19—United States, January–April 2020,” which identifies cough, fever, and shortness of breath as the most typical symptoms of COVID-19. However, the KCL study takes those findings a step further.

KCL researchers identified six distinct “types” of COVID-19, each distinguished by a particular cluster of symptoms. They include headaches, muscle pains, fatigue, diarrhea, confusion, loss of appetite, shortness of breath, and more. The researchers also found that COVID-19 disease progression and outcome also vary significantly between people, ranging from mild flu-like symptoms or a simple rash to severe or fatal conditions.

Using app data logged by 1,600 users in March and April, the researchers developed an algorithm that combined information on age, gender, body mass index (BMI), and pre-existing conditions with recorded symptoms from the onset of the illness through the first five days. The researchers then tested the algorithm using a second independent dataset of 1,000 users, logged in May.

In a news release, the KCL researchers identified the six clusters of symptoms as:

  • Flu-like with No Fever: Headache, loss of smell, muscle pains, cough, sore throat, chest pain, no fever.
  • Flu-like with Fever: Headache, loss of smell, cough, sore throat, hoarseness, fever, loss of appetite.
  • Gastrointestinal: Headache, loss of smell, loss of appetite, diarrhea, sore throat, chest pain, no cough.
  • Severe Level One, Fatigue: Headache, loss of smell, cough, fever, hoarseness, chest pain, fatigue.
  • Severe Level Two, Confusion: Headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, confusion, muscle pain.
  • Severe Level Three, Abdominal and Respiratory: Headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, confusion, muscle pain, shortness of breath, diarrhea, abdominal pain.

Using the data, the researchers were able to more accurately predict—78.8% versus 69.5%—which of the six symptom clusters placed patients at higher risk of requiring hospitalization and breathing support (ventilation or additional oxygen) than with prediction models based on personal characteristics alone. For example, nearly 50% of the patients in cluster six (Severe Level Three, Abdominal and Respiratory) ended up in the hospital, compared with 16% of those in cluster one (Flu-like with No Fever).

Claire Steves, MD, PhD a Clinical Senior Lecturer at King’s College London
“These findings have important implications for care and monitoring of people who are most vulnerable to severe COVID-19,” Claire Steves, MD, PhD (above left), Clinical Senior Lecturer at King’s College London, said in the KCL news release. “If you can predict who these people are at day five, you have time to give them support and early interventions, such as monitoring blood oxygen and sugar levels, and ensuring they are properly hydrated—simple care that could be given at home, preventing hospitalizations and saving lives.” (Photo copyright: King’s College London.)

According to the Zoe website, the ongoing research is led by:

The researchers published their study findings at medRxiv, titled, “Symptom Clusters in COVID-19: A Potential Clinical Prediction Tool from the COVID Symptom Study App.” The study has not yet undergone peer review.

Encouraging Everyone to Use the COVID-Symptom Study App

The study points out that—broadly speaking—people with cluster four, five, or six COVID-19 symptoms tended to be older and frailer and were more likely to be overweight and have pre-existing conditions, such as diabetes or lung disease, than those with cluster one, two, or three symptoms.

Carole Sudre, PhD a research fellow at King's College London
“Our study illustrates the importance of monitoring symptoms over time to make our predictions about individual risk and outcomes more sophisticated and accurate,” said lead researcher Carole Sudre, PhD (above), a Research Fellow at King’s College London and the study’s lead researcher, in the KCL news release. “This approach is helping us to understand the unfolding story of this disease in each patient so they can get the best care.” (Photo copyright: University College London.)

Tim Spector, FMedSci, Head of the Department of Twin Research and Genetic Epidemiology, and Professor of Genetic Epidemiology at King’s College London, encourages everyone to download the COVID Symptom Study app and help increase the data available to researchers.

“Data is our most powerful tool in the fight against COVID-19,” Spector said in the KCL news release. “We urge everyone to get in the habit of using the app daily to log their health over the coming months, helping us to stay ahead of any local hotspots or a second wave of infections.”

As the body of knowledge surrounding COVID-19 grows, clinical laboratory professionals would be well advised to remain informed on further research regarding not only the potential for COVID-19 variants to exist, but also the evolving guidance on infection prevention and testing.

—Andrea Downing Peck

Related Information:

Six Distinct ‘Types’ of COVID-19 Identified

Symptom Clusters in COVID19: A Potential Clinical Prediction Tool from the COVID Symptom Study App

Symptom Profile of a Convenience Sample of Patients with COVID-19–United States, January-April 2020

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