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.
“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.
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.
“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.
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.
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.
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
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 (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
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?”
By analyzing ancient poop, researchers have discovered how much the human microbiome has changed over the past millennium, what may have brought about the change, and how those changes formed today’s human microbiome
Two thousand year-old human poop has yielded new insights into the evolution of the microbial cells (microbiota) inhabiting today’s human gut—collectively known as the human microbiome—that could help pathologists and clinical laboratories better understand diseases that may be linked to gut bacteria.
A recent study conducted by an international team of scientists reveals that the gut bacteria of today’s humans may have been altered by the onset of modern processed foods, sanitation, and the use of antibiotics.
In “Reconstruction of Ancient Microbial Genomes from the Human Gut,” published in the journal Nature, the researchers wrote, “In this study, we establish that palaeofaeces [Paleofeces in the US] with well-preserved DNA are abundant sources of microbial genomes, including previously undescribed microbial species, that may elucidate the evolutionary histories of human microbiomes. Similar future studies tapping into the richness of palaeofaeces will not only expand our knowledge of the human microbiome but may also lead to the development of approaches to restore present-day gut microbiomes to their ancestral state.”
Ancient Poop Is a ‘Time Machine’ into the Human Microbiome
To perform the research for this study, scientists analyzed Deoxyribonucleic acid (DNA) from eight preserved, fossilized feces (coprolites) to gain insight into the gut bacteria of ancient communities. The samples used in the research were originally found in rock formations in Utah and Mexico and were preserved by dryness and stable temperatures. The coprolites were between 1,000 and 2,000 years old.
“These paleofeces are the equivalent of a time machine,” Justin Sonnenburg, PhD, Associate Professor, Microbiology and Immunology at Stanford University and co-author of the study, told Science. Tiny bits of food found in the coprolites indicated that the diet of the ancient people included:
The dried-out poop samples were first radiocarbon dated. Then, tiny fragments of the coprolites were rehydrated which allowed researchers to recover longer DNA strands than those found in previous, similar studies. This study compared the microbiome of the ancient populations to that of present-day individuals. The authors of the study suggest that during the past millennium, the human microbiome has lost dozens of bacterial species and has become less diverse.
Other research studies have linked lower diversity among gut bacteria to higher rates of modern diseases, such as diabetes, obesity, and allergies, Science noted.
“We really wanted to be able to go back in time and see when those changes [in the modern gut microbiome] came about, and what’s causing them,” Archeological Geneticist Christina Warinner, PhD, Assistant Professor of Anthropology at Harvard University and one of the authors of the study, told Science. “Is it food itself? Is it processing, is it antibiotics, is it sanitation?” Warinner is the Sally Starling Seaver Assistant Professor at the Radcliffe Institute, and a group leader in the Department of Archaeogenetics at the Max Planck Institute for Evolutionary Anthropology and affiliated with the faculty of biological sciences at the Friedrich Schiller University in Jena, Germany. (Photo copyright: The Game Changers.)
Ancient versus Modern Microbiome
The ancient microbiomes lacked markers for antibiotic resistance and included dozens of bacterial species that were previously unknown. According to the study, “a total of 181 of the 498 reconstructed microbial genomes were classified as gut derived and had extensive DNA damage, consistent with an ancient origin, and 39% of the ancient genomes offered evidence of being newly discovered species.”
The scientists also discovered that the gut bacteria of present-day people living in non-industrialized societies is more like that of the ancient people when compared to present-day humans living in industrialized societies. But there are still vast differences between the ancient and the modern microbiome.
For example, a bacteria known as Treponema is virtually unknown in the microbiome of current humans, even those living in non-industrialized societies. However, according to Kostic, “They’re present in every single one of the paleofeces, across all the geographic sites. That suggests it’s not purely diet that’s shaping things,” he told Science.
What Can Clinical Laboratories Learn from Ancient Poop?
The ancient poop study scientists hope that future research on coprolites from the past will reveal more information regarding when shifts in the microbiome occurred and what events or human activities prompted those changes.
Research on the human microbiome has been responsible for many discoveries that have greatly impacted clinical pathology and diagnostics development.
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 findings of this study are another step forward in understanding the composition and functions of gut bacteria. The study of the microbiome could prove to be a growth area for clinical laboratories and microbiology labs as well. It is probable that soon, labs will be performing more microbiome testing to help with the diagnosis, and treatment selection and monitoring of patients.
Following the raid, the company’s co-founders resigned
from the board of directors
Microbiome testing company, uBiome, a biotechnology developer that offers at-home direct-to-consumer (DTC) test kits to health-conscious individuals who wish to learn more about the bacteria in their gut, or who want to have their microbiome genetically sequenced, has recently come under investigation by insurance companies and state regulators that are looking into the company’s business practices.
CNBC
reported that the Federal Bureau of
Investigation (FBI) raided the company’s San Francisco headquarters in
April following allegations of insurance fraud and questionable billing
practices. The alleged offenses, according to CNBC, included claims that
uBiome routinely billed patients for tests multiple times without consent.
Becker’s
Hospital Review wrote that, “Billing documents obtained by The Wall Street
Journal and described in a June 24 report further illustrate uBiome’s
allegedly improper billing and prescribing practices. For example, the
documents reportedly show that the startup would bill insurers for a lab test
of 12 to 25 gastrointestinal pathogens, despite the fact that its tests only
included information for about five pathogens.”
Company Insider Allegations Trigger FBI Raid
In its article, CNBC stated that “company insiders”
alleged it was “common practice” for uBiome to bill patients’ insurance
companies multiple times for the same test.
“The company also pressured its doctors to approve tests
with minimal oversight, according to insiders and internal documents seen by CNBC.
The practices were in service of an aggressive growth plan that focused on
increasing the number of billable tests served,” CNBC wrote.
FierceBiotech reported that, “According to previous
reports, the large insurers Anthem, Aetna, and Regence BlueCross BlueShield
have been examining the company’s billing practices for its physician-ordered
tests—as has the California Department of Insurance—with probes focusing on
possible financial connections between uBiome and the doctors ordering the
tests, as well as rumors of double-billing for tests using the same sample.”
Becker’s Hospital Review revealed that when the FBI
raided uBiome they seized employee computers. And that, following the raid,
uBiome had announced it would temporarily suspend clinical operations and not
release reports, process samples, or bill health insurance for their services.
The company also announced layoffs and that it would stop
selling SmartJane and SmartGut test kits, Becker’s reported.
uBiome Assumes New Leadership
Following the FBI raid, uBiome placed its co-founders Jessica
Richman (CEO) and Zac
Apte (CTO) on administrative leave while conducting an internal
investigation (both have since resigned from the company’s board of directors).
The company’s board of directors then named general counsel, John Rakow, to be interim CEO,
FierceBiotech
reported.
John Rakow (center) is shown above with uBiome co-founders Jessica Richman (lower left) and Zac Apte (lower right). In a company statement, Rakow stressed that he believed in the company’s products and ability to survive the scandal. His belief may be based on evidence. Researchers have been developing tests based on the human microbiome for everything from weight loss to predicting age to diagnosing cancer. Such tests are becoming increasingly popular. Dark Daily has reported on this trend in multiple e-briefings. (Photo copyrights: LinkedIn/uBiome.)
After serving two months as the interim CEO, Rakow resigned
from the position. The interim leadership of uBiome was then handed over to
three directors from Goldin
Associates, a New York City-based consulting firm, FierceBiotech
reported. They include:
SmartFlu: a nasal microbiome swab that detects bacteria and viruses associated with the flu, the common cold, and bacterial infections.
What Went Wrong?
Richman and Apte founded uBiome in 2012 with the intent of
marketing a new test that would prove a link between peoples’ microbiome and their
overall health. The two founders initially raised more than $100 million from
venture capitalists, and, according to PitchBook,
uBiome was last valued at around $600 million, Forbes
reported.
Nevertheless, as a company, uBiome’s future is uncertain. Of
greater concern to clinical laboratory leaders is whether at-home microbiology
self-test kits will become a viable, safe alternative to tests traditionally performed
by qualified personnel in controlled laboratory environments.
CDC reports more than 93-million US adults are obese, and health issues related to obesity include heart disease, stroke, type 2 diabetes, and cancers
In recent years, the role of the human microbiome in weight loss or weight gain has been studied by different research groups. There is keen interest in this subject because of the high rates of obesity, and diagnostic companies know that development of a clinical laboratory test that could assess how an individual’s microbiome affects his/her weight would be a high-demand test.
This is true of a study published this year in Mayo Clinic Proceedings. Researchers at Mayo Clinic looked at obese patients who were in an active lifestyle intervention program designed to help them lose weight. It was determined that gut microbiota can have a role in both hindering weight loss and supporting weight loss.
Gut Microbiota More Complicated than Previously Thought
The Mayo researchers determined “an increased abundance of Phascolarctobacterium was associated with [successful weight loss]. In contrast, an increased abundance of Dialister and of genes encoding gut microbial carbohydrate-active enzymes was associated with failure to [lose] body weight. A gut microbiota with increased capability for carbohydrate metabolism appears to be associated with decreased weight loss in overweight and obese patients undergoing a lifestyle intervention program.”
How do bacteria impede weight loss? Vandana Nehra, MD, Mayo Clinic Gastroenterologist and co-senior author of the study, explained in a news release.
“Gut bacteria have the capacity to break down complex food particles, which provides us with additional energy. And this is normally is good for us,” she says. “However, for some individuals trying to lose weight, this process may become a hindrance.”
Put another away: people who more effectively metabolized carbohydrates were the ones who struggled to drop the pounds, New Atlas pointed out.
Vandana Nehra, MD (left), and Purna Kashyap, MBBS (right), are Mayo Clinic Gastroenterologists and co-senior authors of the Mayo study. “While we need to replicate these findings in a bigger study, we now have an important direction to pursue in terms of potentially providing more individualized strategies for people who struggle with obesity,” Nehra noted in the news release. Thus, precision medicine therapy for obese individuals could be based on Mayo Clinic’s research. (Photo copyright: Mayo Clinic.)
Mayo Study Provides Clues to Microbiota Potential in Weight Loss
The Mayo researchers wanted to know how gut bacteria behave in people who are trying to lose weight.
They recruited 26 people, ranging in age from 18 to 65, from the Mayo Clinic Obesity Treatment Research Program. Fecal stool samples, for researchers’ analysis, were collected from participants at the start of the three-month study period and at the end. The definition of successful weight loss was at least 5% of body weight.
Researchers found the following, according Live Science:
2 lbs. lost, on average, among all participants;
Nine people were successful, losing an average of 17.4 lbs.;
17 people did not meet the goal, losing on average just 3.3 lbs.; and,
More gut bacterial genes that break down carbohydrates were found in stool samples of the unsuccessful weight loss group, as compared to the successful dieters.
The researchers concluded that “An increased abundance of microbial genes encoding carbohydrate-active enzyme pathways and a decreased abundance of Phascolarctobacterium in the gut microbiota of obese and overweight individuals are associated with failure to lose at least 5% weight following a 3-month comprehensive lifestyle intervention program.”
Purna Kashyap, MBBS, Mayo Clinic Gastroenterologist and co-senior author of the study, told Live Science, “The study suggests there is a need to take the microbiome into account in clinical studies (on weight loss), and it also provides an important direction to pursue in terms of providing individualized care in obesity.” The very basis of precision medicine.
Future Weight-Loss Plans Based on Patient’s Microbiota
The Mayo Clinic researchers acknowledged the small sample size and need for more studies with larger samples over a longer time period. They also noted in their paper that Dialister has been associated with oral infections, such as gingivitis, and its role in energy expenditure and metabolism is unclear.
Still, the study suggests that it may soon be possible to give people individualized weight loss plans based on their gut bacteria. Clinical laboratory professionals and pathologists will want to stay abreast of follow-up studies and replication of findings by other research teams. A future medical laboratory test to analyze patients’ microbiomes could help obese people worldwide as well as lab business volume.
