Technology enables sampling of an individual’s microbiome over time to observe changes associated with different illnesses or different diets
There is now a pill-sized device that can non-invasively collect and deliver a sample of gut bacteria taken directly from specific areas of a person’s gastrointestinal (GI) tract. One benefit of this new technology is that it can collect samples from the upper digestive system. Although not ready for clinical use, this is the kind of technology that would enable microbiologists and clinical laboratory scientists to add more microbiome assays to their test menu.
Researchers at Stanford University, Envivo Bio, and the University of California, Davis (UC Davis) have developed a vitamin capsule-sized device—dubbed CapScan—that can measure the microbial, viral, and bile acid profiles contained in the human intestines as it passes through on its way to being expelled.
Currently, scientists rely on stool samples to collect similar data as they are easy to gather and readily available. However, stool samples may not provide the most accurate analysis of the various microorganisms that reside in the human gut.
“Measuring gut metabolites in stool is like studying an elephant by examining its tail,” said Dari Shalon, PhD, Founder and CEO at Envivo Bio, one of the authors of the study, in a UC Davis news release. “Most metabolites are made, transformed, and utilized higher up in the intestines and don’t even make it into the stool. CapScan gives us a fuller picture of the gut metabolome and its interactions with the gut microbiome for the first time.” Shalon is the inventor of the CapScan device.
This demonstrates how technological advancements are giving scientists new diagnostic tools to guide selection of therapies and to monitor a patient’s progress.
Microbiologists will take a special interest in this published study because, once confirmed by further studies, it would provide microbiology laboratories and clinical labs with a new way to collect samples. In clinical laboratories throughout the country, handling fecal specimens is considered an unpleasant task. Once cleared for clinical use, devices like CapScan would be welcomed because the actual specimen would be contained within the capsule, making it a cleaner, less smelly specimen to handle than conventional fecal samples.
“This capsule and reports are the first of their kind,” said Oliver Fiehn, PhD, Professor of Molecular and Cell Biology at UC Davis, in a news release. “All other studies on human gut microbiota focused on stool as a surrogate for colon metabolism. However, of course, the fact is that 90% of human digestion happens in the upper intestine, not the colon.” Clinical laboratories have long worked with stool samples to perform certain tests. If CapScan proves clinically viable, labs may soon have a new diagnostic tool. (Photo copyright: UC Davis.)
Collecting Small Intestine Microbiota
Human digestion occurs mostly in the small intestine where enzymes break down food particles so they can later be absorbed through the gut wall and processed in the body. Stool samples, however, only sample the lower colon and not the small intestine. This leaves out vital information about a patient.
“The small intestine has so far only been accessible in sedated people who have fasted, and that’s not very helpful,” Oliver Fiehn, PhD, Professor of Molecular and Cell Biology at UC Davis and one of the study authors, said in the news release.
According to their Nature paper, to perform their research the team recruited 15 healthy adults to participate in the study. Each participant swallowed four CapScan “pills,” either twice daily or on two consecutive days. The pills were designed to respond to different pH (potential of hydrogen) levels.
Each pill’s pH-sensitive outer coating enables scientists to select which area of the intestinal tract to sample. The outer coating dissolves at a certain point as it travels from the upper intestine to the colon. When this happens, a one-way valve gathers miniscule amounts of biofluids into a tiny, inflatable bladder. Once full, the bladder seals shut and the CapScan continues its journey until it is recovered in the stool. The researchers then genetically sequenced the RNA from the collected samples.
The scientists discovered that the microbiome varied substantially at distinctive sections of the GI tract. When compared to collected stool samples, the researchers determined that traditional stool sampling could not capture that variability.
“There’s enormous potential as you think about how the environment is changing as you go down the intestinal tract,” Kerwyn Huang, PhD, Professor of Bioengineering and of Microbiology and Immunology at Stanford, one of the authors of the study, told Drug Discovery News. “Identifying how something like diet or disease affects the variation in the individual microbiome may even provide the potential to start discovering these important health associations.”
The genetic sequencing also revealed which participants had taken antibiotics within one to five months before the study because their data was so incongruous with the other participants. Those individuals had distinctive differences in their microbiome and bile acid composition, which illustrates that antibiotics can potentially affect gut bacteria even months after being taken.
Researchers Use Multiple ‘Omics’ Approach
The researchers used “multiomics” to analyze the samples. They identified the presence of 2,000 metabolites and found associations between metabolites and diet.
According to the Envivo Bio website, the CapScan allows for the regional measurement of:
“Overall, this device can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease,” Fiehn said in the press release.
Future of Collecting Gut Bacteria
Using CapScan is a non-invasive procedure that makes it possible to sample an individual’s microbiome once, or to monitor it over time to observe changes associated with different illnesses or diets. Since it takes time for the device to pass through the digestive system, it is not a rapid test, but initial studies show it could be more accurate than traditional clinical laboratory testing.
“This technology makes it natural to think about sampling from many places and many times from one person, and it makes that straightforward and inexpensive,” Huang said.
Advancements in technology continue to provide microbiology and clinical laboratories with new, innovative tools for diagnosing and monitoring diseases, as well as guiding therapy selection by medical professionals. Though more research and clinical studies are needed before a device like the CapScan can be commonly used by medical professionals, it may someday provide a cutting-edge method for collecting microbiome samples.
Research could lead to new microbiome assays that clinical laboratories could use to identify genetic and other health conditions in developing baby
It would seem to be common sense, but now a study conducted by the Broad Institute of MIT and Harvard confirms that a pregnant mother’s microbiome has an effect on the development of her baby’s own gut microbiota. These findings could create opportunities for clinical laboratories to help in diagnosing a broader range of health conditions by testing the gut bacteria of pregnant mothers.
The Broad Institute’s study suggests the mother’s gut microbiome helps form the baby’s gut bacteria not only during pregnancy and birth, but into the baby’s first year of life as well.
“This study helps us better understand how the rich community of microbes in the gut initially forms and how it develops during infancy,” said Tommi Vatanen, PhD, a co-first author on the study who is now a researcher and associate professor at the University of Helsinki, in a Broad Institute news release. “The microbiome is very dynamic and develops along with other systems, so there’s a lot going on in the first years of life.”
“We’ve shown that the maternal microbiome plays an important role in seeding the infant microbiome, and that it’s not a one-time event, but a continuous process,” said gastroenterologist and senior study author Ramnik Xavier, MD, of the Broad Institute. Clinical laboratories and microbiologists may soon have new tools for testing a mother’s microbiome during pregnancy. (Photo copyright: Maria Nemchuk, Broad Institute.)
Study Highlights Physiological Connection Between Mother and Child
This study, according to the Broad Institute news release, is the “first to uncover large-scale horizontal gene transfer events between different species of maternal and infant gut bacteria.” The researchers also found that the bacteria in the mother’s microbiome “donate” genes that go into the bacteria of her unborn child. The mother’s genes help the baby in other ways as well during pregnancy and after birth.
“Benign bacteria in the maternal gut share genes with the child’s intestinal microbes during early life, potentially contributing to immune and cognitive development,” states the news release, adding, “The microbiomes of the mother and baby change during pregnancy and the first year of life … some bacteria in the mother’s gut donate hundreds of genes to bacteria in the baby’s gut. These genes are involved in the development of the immune and cognitive systems and help the baby to digest a changing diet as it grows.”
The study also sheds light on a baby’s unique metabolites (chemicals produced by bacteria) and how they connect with the mother’s microbiome.
“This is the first study to describe the transfer of mobile genetic elements between maternal and infant microbiomes,” gastroenterologist Ramnik Xavier, MD, Core Institute Member, Director of the Immunology Program, and Co-Director of the Infectious Disease and Microbiome Program at the Broad Institute, told Neuroscience News.
“Our study also, for the first time, integrated gut microbiome and metabolomics profiles from both mothers and infants and discovered links between gut metabolites, bacteria, and breastmilk substrates,” he added.
Researchers Use Multiomics
The human microbiome influences health in many ways. For several years, Broad Institute scientists have been trying to better understand the human microbiome and the role it plays in diseases like type 1 diabetes, cancer, and inflammatory bowel disease.
According to the organization’s website, the scientists recently began using multiomics techniques in their research that include:
Xavier and his colleagues were particularly interested in the development of the microbiome during the first year of the baby’s life.
“The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiomes and their metabolites,” the researchers wrote in Cell. “Here, we tracked the co-development of microbiomes and metabolomes from late pregnancy to one year of age using longitudinal multiomics data.”
The researchers deployed bacterial DNA sequencing from stool samples of 70 mother and child pairs.
They found “hundreds of genes” in the infant gut bacterial genome that originated in the mother. According to the scientists, this suggests a mother does not transfer her genes all at once during childbirth. Instead, it likely occurs in an “ongoing” gene transfer from mother to baby through the baby’s first year of life, the news release explains.
Here are details on the study findings, according to Neuroscience News:
Genes associated with diet were involved in the “mother-to-infant interspecies transfer of mobile genetic elements.”
Infant gut metabolomes were less diverse than maternal metabolomes.
Infants had 2,500 unique metabolites not detected in the mothers.
Infants that received baby formula had distinct metabolites and cytokine signatures as compared to those receiving breast milk.
A link between pregnancy and an increase in steroid compounds could be due to impaired glucose tolerance in mothers.
“We also found evidence that prophages—dormant bacteriophages (viruses that reside on bacterial genomes)—contribute to the exchange of mobile genetic elements between maternal and infant microbiomes,” Xavier told Neuroscience News.
Research Could Lead to New Clinical Laboratory Assays
Microbiologists and clinical laboratory scientists are gaining a deeper understanding of the role gut bacteria play in many aspects of human life. But how a mother’s microbiome influences a baby’s development during and after birth is particularly intriguing.
“We’ve shown that the maternal microbiome plays an important role in seeding the infant microbiome, and that it’s not a one-time event, but a continuous process,” said Xavier in the Broad Institute news release. “This may be yet another benefit of prolonged bonding between mother and child, providing more chances for these beneficial gene transfer events to occur.”
Pediatricians, microbiologists, and clinical laboratories may one day have new microbiome assays to help identify a broad range of health conditions in mothers and infants and explore gut bacteria’s effects on a baby’s developing health.
As scientists gain new insights into the human microbiome and how it influences our health, microbiology labs may gain new diagnostic biomarkers
In a study that took more than five years to complete, researchers from Stanford University have successfully created the first synthetic microbiome model from scratch. The goal of the study was to create a baseline microbiome model so that future studies will have a better understanding of which clinical laboratory tests and medical interventions could be useful for treating specific ailments and improving patient care.
To create their synthetic human microbiome, the Stanford researchers combined 119 species of bacteria, The New York Times reported, adding that “the new synthetic microbiome can even withstand aggressive pathogens and cause mice to develop a healthy immune system, as a full microbiome does.”
According to the National Institute of Health (NIH), the human gut contains trillions of microbes, and no two people share the exact same microbiome composition. This complex community of microbial cells influences human physiology, metabolism, nutrition and immune function, and performs a critical role in overall health.
The Stanford scientists believe researchers now have a common microbiome foundation for future microbial studies.
“We were looking for the Noah’s Ark of bacteria species in the human gut, trying to find the ones that were almost always there in any individual,” said Michael Fischbach, PhD, Associate Professor in the Departments of Bioengineering and Microbiology and Immunology at Stanford University. Future microbial studies that use Stanford’s synthetic human microbiome may develop improved clinical laboratory tests and microbiome therapies. (Photo copyright: Stanford University.)
Creating the ‘Human Community One’ Microbiome
The researchers began their study by examining the gut bacteria makeup of adults involved in the Human Microbiome Project (HMP), an NIH initiative created to sequence the full microbial genomes of more than 300 adults.
The scientists then selected bacterial strains that were present in at least 20% of the HMP individuals. They focused on 104 bacterial species that they grew in individual stocks, and then mixed them into one combined culture to create what they named “Human Community One” (hCom1).
The researchers had to ensure that the final mixture had the stability to maintain a balance where no single species overpowered the rest and could perform all the actions of a natural microbiome.
After being satisfied that the bacterial strains could coexist in a lab situation, the scientists set out to determine if their community would colonize in the gut. To do this, they introduced hCom1 to germ-free mice that are designed to have no natural microbiome.
When transplanted into the mice, the researchers discovered hCom1 was an extremely stable ecosystem, with 98% of the species taking root in the guts of the mice, and the levels of each bacterial species remaining constant over a two-month period.
“We colonized germ-free mice with hCom1 and found that it was stable over time. Its species span six orders of magnitude of relative abundance: from ~10% to less than one in 1,000,000,” Michael Fischbach, PhD, Associate Professor in the Departments of Bioengineering and Microbiology and Immunology at Stanford University and one of the authors of the study, explained on Twitter.
Based on a theory called colonization resistance, the team then introduced a human fecal sample to hCom1 to ensure that all vital microbiome functions would be performed by one or more species. Colonization resistance is the phenomenon where the normal gut microbiome protects itself against invasion by new and often harmful microorganisms. This theory hypothesizes that any bacterium introduced into an existing colony will only survive if it can fill a niche that is not already occupied.
Creating a Second New Microbiome
Some researchers involved in the project were skeptical that introducing human fecal matter to hCom1 would work. They believed it would overtake the synthetic microbiome model.
“The bacterial species in hCom1 had lived together for only a few weeks,” Fischbach explained in a Stanford press release. “Here we were introducing a community that had coexisted for a decade. Some people thought they would decimate our colony.”
However, the scientists found that hCom1 thrived with only about 10% of the cells in the final community originating from the fecal transplant. A few of the original bacterial species died off and approximately 20 new bacterial species were able to successfully colonize hCom1. They ultimately catalogued 119 bacterial strains present in the colony after the transplant and dubbed the new microbiome “Human Community Two” (hCom2).
To further prove the functionality of their synthetic microbiome, the team then introduced an Escherichia coli (E. coli) sample to mice colonized with hCom2 and found that they were able to resist infection.
“Mice colonized by hCom2 look normal immunologically, have similar microbiome-derived metabolites, and exert colonization resistance against E. coli,” said Fischbach on Twitter, “There are improvements to make, but we think hCom2 (in its current form) is a good model system of the microbiome.”
Future Microbial Studies
The Stanford team hopes its synthetic microbiome model will allow researchers around the world to have a common foundation for future studies and provide them with the ability to create engineered microbiome-based therapies.
“We built this consortium for the broader research community,” said Fischbach in the press release. “We want to get this into as many hands as possible to have an impact on the field.”
While direct links to new clinical laboratory tests and microbiome therapies have not yet been established, research like the Stanford study demonstrates the increasing value of the human microbiome as a source of diagnostic information that can guide decisions on better ways to treat patients.
One key finding of interest to clinical laboratory scientists is that this research study indicates that the human microbiome may more closely correlate with blood markers of metabolic disease than the genome of individuals
In the search for more sensitive diagnostic biomarkers (meaning the ability to detect disease with smaller samples and smaller quantities of the target biomarker), an international team of researchers has teased out a finding that a panel of multiple biomarkers in the human microbiome is more closely correlated with metabolic disease than genetic markers.
The team also discovered that the foods an individual ate had a more powerful impact on their microbiomes than their genes. The study participants included several sets of identical twins. The researchers found that identical twins shared only about 34% of the same gut microbes. People who were unrelated shared 30% of the same gut microbes.
This is a fascinating insight for pathologists and microbiologists involved in the study of the human microbiome for use in development of precision medicine clinical laboratory testing and drug therapies.
Microbiome Markers for Obesity, Heart Disease, and More
The study began in 2018, when an international team of researchers analyzed the gut microbiomes, diets, and blood biomarkers for cardiometabolic health obtained from 1,100 mostly healthy adults in the United Kingdom (UK) and the United States (US). They collected blood samples from the participants before and after meals to examine blood sugar levels, hormones, cholesterol, and inflammation levels. Sleep and activity levels also were monitored. Participants had to wear a continuous glucose monitor for two weeks during the research period.
The scientists discovered that the composition of a healthy gut microbiome is strongly linked to certain foods, food groups, nutrients, and diet composition. They identified markers for obesity, impaired glucose tolerance, and cardiovascular disease in the gut bacteria.
“When you eat, you’re not just nourishing your body, you’re feeding the trillions of microbes that live inside your gut,” genetic epidemiologist Tim Spector, MD, FmedSCi, told Labroots. Spector is a professor of genetic epidemiology at King’s College London and one of the authors of the study.
The scientists found that a diet rich in nutrient-dense, whole foods was more beneficial to a healthy gut microbiome, which can be an indicator of good health. Individuals who ate minimally processed foods, such as vegetables, nuts, eggs, and seafood were more likely to have healthy gut bacteria than individuals who consumed large amounts of highly processed foods, like juices and other sweetened beverages, processed meats, and refined grains and foods that were high in added sugars and salt.
“It goes back to the age-old message of eating as many whole and unprocessed foods as possible,” Sarah Berry, PhD, a nutrition scientist at King’s College London and a co-author of the study told The New York Times. “What this research shows for the first time is the link between the quality of the food we’re eating, the quality of our microbiomes, and ultimately our health outcomes,” she added.
The researchers concluded that heavily processed foods tend to contain very minimal amounts of fiber, a macronutrient that helps promote good bacteria in the gut microbiome and leads to better metabolic and cardiovascular health.
They found that people who had healthy blood sugar levels following a meal had higher levels of good bacteria called Prevotella copri, a genus of gram-negative bacteria, and Blastocystis, a genus of single-celled heterokont parasites, present in their guts. These bacteria are associated with lower levels of visceral fat, which accumulates around internal organs and increases risk of heart disease.
These “good” microbes also are affiliated with lower levels of inflammation, better blood sugar control, and lower spikes in blood fat and cholesterol levels after meals.
“We were surprised to see such large, clear groups of what we informally call ‘good’ and ‘bad’ microbes emerging from our analysis,” Nicola Segata, PhD (above), told News Medical. Segata is a professor and principal investigator at the Computational Metagenomics Lab at the University of Trento in Italy, and co-author of the study. “It is also exciting to see that microbiologists know so little about many of these microbes that they are not even named yet. This is now a big area of focus for us, as we believe they may open new insights in the future into how we could use the gut microbiome as a modifiable target to improve human metabolism and health,” he added. Pathologists and clinical laboratory scientists who read Dark Daily are already familiar with the plethora of ways the human microbiome is being studied for use in diagnostic testing and drug therapy. (Photo copyright: University of Trento.)
The study also found that different people have wildly varying metabolic responses to the same foods, partially due to the types of bacteria residing in their gut microbiome. The consumption of some foods is better for overall health than other foods, but there is no definitive, one-size-fits-all diet that works for everyone.
“What we found in our study was that the same diet in two different individuals does not lead to the same microbiome, and it does not lead to the same metabolic response. There is a lot of variation,” Andrew Chan, MD, Professor of Medicine at Harvard Medical School, told The New York Times. Chan is also Chief of the Clinical and Translational Epidemiology Unit at Massachusetts General Hospital and co-author of the study.
Small Changes in Diet, Big Impact to Health
The team is now planning a clinical trial to test whether changes in diet can alter levels of good and bad microbes in the gut. If proven to be true, such information could help clinicians design personalized nutritional plans that would enable individuals to improve their gut microbiome and their overall health.
“As a nutritional scientist, finding novel microbes that are linked to specific foods, as well as metabolic health, is exciting,” Berry told News Medical. “Given the highly personalized composition of each individual’s microbiome, our research suggests that we may be able to modify our gut microbiome to optimize our health by choosing the best foods for our unique biology.
“We think there are lots of small changes that people can make that can have a big impact on their health that might be mediated through the microbiome,” Berry told The New York Times.
More research and clinical trials are needed before diagnostic tests that use microbiome biomarkers to detect metabolic diseases can be developed. But these early research findings are a sign to pathologists and clinical laboratory managers that microbiome-based assays may come to play a more significant role in the early detection of several metabolic diseases.
Research could lead to clinical laboratory tests in service of precision medicine therapies to reduce a person’s susceptibility to being targeted by blood-sucking insects
Ever wonder why some people attract mosquitoes while others do not? Could biting insects pick their victims by smell? Scientists in California believe the answers to these questions could lead to new precision medicine therapies and clinical laboratory tests.
The research revealed evidence that some blood-sucking insects may identify their prey by homing in on the “scent” of chemicals produced by bacteria located in the skin microbiome of animals and humans.
This is yet another example of research into one area of the human microbiome that might someday lead to a new clinical laboratory test, in this case to determine if a person is more likely to attracts biting insects. If there were such a test, precision medicine therapies could be developed that change an individual’s microbiome to discourage insects from biting that individual.
Then, the clinical laboratory test would have value because it helped diagnose a health condition that is treatable.
Curiosity regarding why mosquitoes seem to gravitate towards some humans over others was the original catalyst for the UCSD Medical School research. “You know when you go to a barbeque and your friend is getting bombarded by mosquitos, but you’re fine? There is some research to support the idea that the difference in mosquito attraction is linked to your skin microbiome—the unique community of bacteria living on your skin,” said Holly Lutz, PhD (above), first author of the UCSD study. “Keeping in mind that some people are more attractive to mosquitoes than others, I wondered what makes insects attracted to some bats but not others.” Lutz’s research could lead to clinical laboratory tests that drive precision medicine therapies to alter human skin microbiomes and make people less attractive to biting insects. (Photo copyright: The Field Museum of Natural History.)
Biting Flies Prefer Specific Bats
“In these caves, I’d see all these different bat species or even taxonomic families roosting side by side. Some of them were loaded with bat flies, while others had none or only a few,” Lutz said in Phys.org. “And these flies are typically very specific to different kinds of bats—you won’t find a fly that normally feeds on horseshoe bats crawling around on a fruit bat. I started wondering why the flies are so particular. Clearly, they can crawl over from one kind of bat to another, but they don’t really seem to be doing that.”
The researchers suspected that the bacteria contained in the skin microbiomes of individual bats could be influencing which bats the flies selected to bite. The bacteria produce a distinctive odor which may make certain bats more attractive to the flies.
The type of fly assessed for the study are related to mosquitoes and most of them are incapable of flight.
“They have incredibly reduced wings in many cases and can’t actually fly,” Lutz explained. “And they have reduced eyesight, so they probably aren’t really operating by vision. So, some other sensory mechanisms must be at play, maybe a sense of smell or an ability to detect chemical cues.”
To test their hypothesis, the research team collected skin and fur samples from the bodies and wings of a variety of bat species located in various caves around Kenya and Uganda. They collected their samples at 14 field sites from August to October in 2016. They then examined the DNA of the bats as well as the microbes residing on the animals’ skin and searched for the presence of flies.
“The flies are exquisitely evolved to stay on their bat,” said Carl Dick, PhD, a professor of biology at Western Kentucky University and one of the study’s authors. “They have special combs, spines, and claws that hold them in place in the fur, and they can run quickly in any direction to evade the biting and scratching of the bats, or the efforts by researchers to capture them,” he told Phys.org.
“You brush the bats’ fur with your forceps, and it’s like you’re chasing the fastest little spider,” Lutz said. “The flies can disappear in a split second. They are fascinatingly creepy.”
Genetic Sequencing DNA of Bat Skin Bacteria
After collecting their specimens, the researchers extracted DNA from the collected bacteria and performed genetic sequencing on the samples. They created libraries of the bacteria contained in each skin sample and used bioinformatics methods to identify the bacteria and compare the samples from bats that had flies versus those that did not.
“How the flies actually locate and find their bats has previously been something of a mystery,” Dick noted. “But because most bat flies live and feed on only one bat species, it’s clear that they somehow find the right host.”
The scientists discovered that different bat families did have their own distinctive skin microbiome, even among samples collected from different locations. They found that differences in the skin microbiomes of certain bats does contribute to whether those bats have parasites. But not all their questions were answered.
“We weren’t able to collect the actual chemicals producing cue—secondary metabolites or volatile organic compounds—during this initial work. Without that information, we can’t definitively say that the bacteria are leading the flies to their hosts,” Lutz said.
Next Steps
“So, next steps will be to sample bats in a way that we can actually tie these compounds to the bacteria. In science, there is always a next step,” she added.
This research illustrates that there may be a reason why certain animals and humans tend to be more attractive to insects than others. It is also possible that an individual’s skin microbiome may explain why some people are more prone to mosquito and other types of insect bites.
More research and clinical studies on this topic are needed, but it could possibly lead to a clinical laboratory test to determine if an individual’s skin microbiome could contribute to his or her potential to being bitten by insects. Such a test would be quite beneficial, as insects can carry a variety of diseases that are harmful to humans.
Perhaps a precision medicine therapy could be developed to alter a person’s microbiome to make them invisible to blood-sucking insects. That would be a boon to regions of the world were diseases like malaria are spread by insect bites.
