As this therapeutic approach gains regulatory approval, clinical laboratory tests to determine condition of patient’s gut microbiota and monitor therapy will be needed
Some developments in the clinical laboratory industry are less about diagnostic tests and more about novel approaches to therapy. Such is the case with a new carbon bead technology developed by researchers from University College London (UCL) and the Royal Free Hospital intended to remove harmful bacteria toxins from the gut before they leak to the liver. The macroporous beads, which come in small pouches, are delivered orally and could be utilized in the future to treat a number of diseases.
Why is this relevant? Once a new treatment is accepted for clinical use, demand increases for a clinical laboratory test that confirms the therapy will likely work and to monitor its progress.
In collaboration with Yaqrit, a UK-based life sciences company that develops treatments for chronic liver disease, the UCL and Royal Free Hospital scientists engineered the carbon beads—known as CARBALIVE—to help restore gut health. They measured the technology’s impact on liver, kidney, and brain function in both rats and mice.
“The influence of the gut microbiome on health is only just beginning to be fully appreciated,” said Rajiv Jalan, PhD, Professor of Hepatology at UCL in a press release. “When the balance of the microbiome is upset, ‘bad’ bacteria can proliferate and out-compete the ‘good’ bacteria that keeps the gut healthy.
“One of the ways [the ‘bad’ bacteria] do this is by excreting endotoxin, toxic metabolites, and cytokines that transform the gut environment to make it more favorable to them and hostile to good bacteria,” he continued. “These substances, particularly endotoxin, can trigger gut inflammation and increase the leakiness of the gut wall, resulting in damage to other organs such as the liver, kidneys, and brain.”
“I have high hopes that the positive impact of these carbon beads in animal models will be seen in humans, which is exciting not just for the treatment of liver disease but potentially any health condition that is caused or exacerbated by a gut microbiome that doesn’t work as it should,” said Rajiv Jalan, PhD (above), Professor of Hepatology, University College London, in a press release. “This might include conditions such as irritable bowel syndrome (IBS), for example, which is on the rise in many countries.” Though not a clinical laboratory diagnostic test, new therapies like CARBALIVE could be a boon to physicians treating patients with IBS and other gastrointestinal conditions.
Developing the Carbon Beads
The team discovered CARBALIVE is effective in the prevention of liver scarring and injury in animals with cirrhosis when ingested daily for several weeks. They also found a reduced mortality rate in test animals with acute-on-chronic-liver-failure (ACLF).
After achieving success with CARBALIVE in animals, the researchers tested the technology on 28 cirrhosis patients. The carbon beads proved to be safe for humans and had inconsequential side effects.
“In cirrhosis, a condition characterized by scarring of the liver, it is known that inflammation caused by endotoxins can exacerbate liver damage,” Jalan explained. “Part of the standard treatment for cirrhosis is antibiotics aimed at controlling bad bacteria, but this comes with the risk of antibiotic resistance and is only used in late-stage disease.”
The beads, which are smaller than a grain of salt, contain an exclusive physical structure that absorbs large and small molecules in the gut. They are intended to be taken with water at bedtime as harmful bacteria is more likely to circulate through the body at night which could result in damage. The carbon beads do not kill bacteria, which decreases the risk of antibiotic resistance. They eventually pass through the body as waste.
“They work by absorbing the endotoxins and other metabolites produced by ‘bad’ bacteria in the gut, creating a better environment for the good bacteria to flourish and helping to restore microbiome health,” said Michal Kowalski, M.Sc.Eng, Director and VP of Operations at Yaqrit, in the UCL news release.
“This prevents these toxins from leaching into other areas of the body and causing damage, as they do in cirrhosis,” he added. “The results in animal models are very positive, with reduction in gut permeability, liver injury, as well as brain and kidney dysfunction.”
Additional Research
The researchers plan to perform further clinical trials in humans to determine if the carbon beads are effective at slowing the progression of liver disease. If the benefits that were observed in lab animals prove to be compelling in humans, the technology may become an invaluable tool for the treatment of liver disease and other diseases associated with poor microbiome health in the future.
According to the American Liver Foundation, 4.5 million adults in the US have been diagnosed with liver disease. However, it is estimated that 80 to 100 million adults have some form of fatty liver disease and are unaware of it. Liver disease was the 12th leading cause of death in the US in 2020 with 51,642 adults perishing from the disease that year.
According to BMC Public Health, globally there were 2.05 million new cases of liver cirrhosis diagnosed in 2019. In that year, 1.47 million people around the world died from the disease.
More research and clinical studies are needed before this novel technology can be used clinically. When and if that happens, the demand for clinical laboratory tests that measure microbiome deficiencies and monitor patient progress during therapy will likely be high.
New technology could enable genetic scientists to identify antibiotic resistant genes and help physicians choose better treatments for genetic diseases
Genomic scientists at the Icahn School of Medicine at Mount Sinai Medical Center in New York City have developed what they call a “smart tweezer” that enables researchers to isolate a single bacterium from a patient’s microbiome in preparation for genetic sequencing. Though primarily intended for research purposes, the new technology could someday be used by clinical laboratories and microbiologists to help physicians diagnose chronic disease and choose appropriate genetic therapies.
The researchers designed their new technology—called mEnrich-seq—to improve the effectiveness of research into the complex communities of microorganisms that reside in the microbiomes within the human body. The discovery “ushers in a new era of precision in microbiome research,” according to a Mount Sinai Hospital press release.
“Imagine you’re a scientist who needs to study one particular type of bacteria in a complex environment. It’s like trying to find a needle in a large haystack,” said the study’s senior author Gang Fang, PhD (above), Professor of Genetics and Genomic Sciences at Icahn School of Medicine at Mount Sinai Medical Center, in a press release. “mEnrich-seq essentially gives researchers a ‘smart tweezer’ to pick up the needle they’re interested in,” he added. Might smart tweezers one day be used to help physicians and clinical laboratories diagnose and treat genetic diseases? (Photo copyright: Icahn School of Medicine.)
Addressing a Technology Gap in Genetic Research
Any imbalance or decrease in the variety of the body’s microorganisms can lead to an increased risk of illness and disease.
In researching the microbiome, many scientists “focus on studying specific types of bacteria within a sample, rather than looking at each type of bacteria present,” the press release states. The limitation of this method is that a specific bacterium is just one part of a complicated environment that includes other bacteria, viruses, fungi and host cells, each with their own unique DNA.
“mEnrich-seq effectively distinguishes bacteria of interest from the vast background by exploiting the ‘secret codes’ written on bacterial DNA that bacteria use naturally to differentiate among each other as part of their native immune systems,” the press release notes. “This new strategy addresses a critical technology gap, as previously researchers would need to isolate specific bacterial strains from a given sample using culture media that selectively grow the specific bacterium—a time-consuming process that works for some bacteria, but not others. mEnrich-seq, in contrast, can directly recover the genome(s) of bacteria of interest from the microbiome sample without culturing.”
Isolating Hard to Culture Bacteria
To conduct their study, the Icahn researchers used mEnrich-seq to analyze urine samples taken from three patients with urinary tract infections (UTIs) to reconstruct Escherichia coli (E. Coli) genomes. They discovered their “smart tweezer” covered more than 99.97% of the genomes across all samples. This facilitated a comprehensive examination of antibiotic-resistant genes in each genome. They found mEnrich-seq had better sensitivity than standard study methods of the urine microbiome.
They also used mEnrich-seq to selectively examine the genomes of Akkermansia muciniphila (A. muciniphila), a bacterium that colonizes the intestinal tract and has been shown to have benefits for obesity and Type 2 diabetes as well as a response to cancer immunotherapies.
“Akkermansia is very hard to culture,” Fang told GenomeWeb. “It would take weeks for you to culture it, and you need special equipment, special expertise. It’s very tedious.”
mEnrich-seq was able to quickly segregate it from more than 99.7% of A. muciniphila genomes in the samples.
Combatting Antibiotic Resistance Worldwide
According to the press release, mEnrich-seq could potentially be beneficial to future microbiome research due to:
Cost-Effectiveness: It offers a more economical approach to microbiome research, particularly beneficial in large-scale studies where resources may be limited.
Broad Applicability: The method can focus on a wide range of bacteria, making it a versatile tool for both research and clinical applications.
Medical Breakthroughs: By enabling more targeted research, mEnrich-seq could accelerate the development of new diagnostic tools and treatments.
“One of the most exciting aspects of mEnrich-seq is its potential to uncover previously missed details, like antibiotic resistance genes that traditional sequencing methods couldn’t detect due to a lack of sensitivity,” Fang said in the news release. “This could be a significant step forward in combating the global issue of antibiotic resistance.”
More research and clinical trials are needed before mEnrich-seq can be used in the medical field. The Icahn researchers plan to refine their novel genetic tool to improve its efficiency and broaden its range of applications. They also intend to collaborate with physicians and other healthcare professionals to validate how it could be used in clinical environments.
Should all this come to pass, hospital infection control teams, clinical laboratories, and microbiology labs would welcome a technology that would improve their ability to detect details—such as antibiotic resistant genes—that enable a faster and more accurate diagnosis of a patient’s infection. In turn, that could contribute to better patient outcomes.
Though they are a mystery, once solved, Obelisks could lead to new biomarkers for clinical laboratory testing
Microbiologists and clinical laboratories know that human microbiota play many important roles in the body. Now, scientists from Stanford University have discovered an entirely new class of “viroid-like” lifeforms residing inside the human body. The researchers detected their presence in both the gut microbiome and saliva samples. Most interesting of all, the researchers are not sure what the lifeforms actually are.
The Stanford researchers, led by PhD student Ivan Zheludev, called the new discovery “Obelisks” due to their RNA structures, which are short and can fold into structures that resemble rods.
The scientists believe the Obelisks went undetected until now in the human microbiome due to their compact genetic elements, which are only around 1,000 characters or nucleotides in size. A typical human DNA structure consists of around three billion nucleotides.
In an article they published on the biology preprint server bioRxiv titled, “Viroid-like Colonists of Human Microbiomes,” the Stanford researchers wrote, “Here, we describe the ‘Obelisks,’ a previously unrecognized class of viroid-like elements that we first identified in human gut metatranscriptomic data. … Obelisks comprise a class of diverse RNAs that have colonized and gone unnoticed in human and global microbiomes.”
The researchers discovered that Obelisks “form their own distinct phylogenetic group with no detectable sequence or structural similarity to known biological agents.”
This is yet another example of how researchers are digging deeper into human biology and finding things never before identified or isolated.
“I am really impressed by the approach. The authors were really creative,” computational biologist Simon Roux, PhD (above) of the Department of Energy (DEO) Joint Genome Institute at Lawrence Berkeley National Laboratory told Science in response to the Stanford researcher’s published findings. “I think this [work] is one more clear indication that we are still exploring the frontiers of this viral universe. This is one of the most exciting parts of being in this field right now. We can see the picture of the long-term evolution of viruses on Earth start to slowly emerge.” How these findings might eventually spark new biomarkers for clinical laboratory testing remains to be seen. (Photo copyright: Berkeley Lab.)
Researchers Bewildered by Obelisks
In their study, “Zheludev and team searched 5.4 million datasets of published genetic sequences and identified almost 30,000 different Obelisks. They appeared in about 10% of the human microbiomes the team examined,” Science reported.
The Stanford researchers found that various types of Obelisks seem to inhabit different areas of the body. In one dataset, the Obelisks were found in half of the oral samples.
The function of Obelisks is unknown, but their discovery is bewildering experts.
Rod-like secondary structures encompassing the entire genome, and
Open reading frames coding for a novel protein superfamily, which the researchers dubbed “Oblins.”
At least half of the genetic material of the Obelisks was taken up by these Oblins. The researchers suspect those proteins may be involved in the replication process of the newly-discovered lifeforms.
The Oblins are also significantly larger than other genetic molecules that live inside cells and they do not have the genes to create protein shells that RNA viruses live within when they are outside of cells.
“Obelisks, therefore, need some kind of host. The researchers managed to identify one: A bacterium called Streptococcus sanguinis that lives mostly in dental plaque in our mouths. Exactly which other hosts obelisks inhabit is yet another mystery, as are what they do to their host and how they spread,” Vice reported.
“While we don’t know the ‘hosts’ of other Obelisks, it is reasonable to assume that at least a fraction may be present in bacteria,” the researchers noted in their bioRxiv paper.
Researchers are Stumped
The Stanford scientists were unable to identify any impact the Obelisks were having on their bacterial hosts—either negative or positive—or determine how they could spread between cells.
“These elements might not even be ‘viral’ in nature and might more closely resemble ‘RNA plasmids,’” they concluded in their paper.
The Stanford scientists are uncertain as to where or what the hosts of the Obelisks are, but they suspect that at least some of them are present in bacteria. However, Obelisks do not appear to be similar to any biological agents that could provide a link between genetic molecules and viruses.
And so, Obelisks are a true mystery—one the Stanford researchers may one day solve. If they do, new biomarkers for clinical laboratory testing may not be far behind.
Study findings could lead to new clinical laboratory testing biomarkers designed to assess for male infertility
Clinical laboratories are increasingly performing tests that have as their biomarkers the DNA and enzymes found in human microbiota. And microbiologists and epidemiologists know that like other environments within the human body, semen has its own microbiome. Now, a study conducted at the University of California, Los Angeles (UCLA) has found that the health of semen microbiome may be linked to male infertility.
The UCLA researchers discovered a small group of microorganisms within semen that may impair the sperm’s motility (its ability to swim) and affect fertility.
A total of 73 individuals were included in the study. About half of the subjects were fertile and already had children, while the remaining men were under consultation for fertility issues.
“These are people who have been trying to get pregnant with their partner, and they’ve been unsuccessful,” Sriram Eleswarapu, MD, PhD, a urologist at UCLA and co-author of the study, told Scientific American. “This latter group’s semen samples had a lower sperm count or motility, both of which can contribute to infertility.”
“There is much more to explore regarding the microbiome and its connection to male infertility,” said Vadim Osadchiy, MD (above), a resident in the Department of Urology at UCLA and lead author of the study, in a UCLA news release. “However, these findings provide valuable insights that can lead us in the right direction for a deeper understanding of this correlation.” Might it also lead to new biomarkers for clinical laboratory testing for male infertility? (Photo copyright: UCLA.)
Genetic Sequencing Used to Identify Bacteria in Semen Microbiome
Most of the microbes present in the semen microbiome originate in the glands of the male upper reproductive tract, including the testes, seminal vesicles and prostate, and contribute various components to semen. “Drifter” bacteria that comes from urine and the urethra can also accumulate in the fluid during ejaculation. Microbes from an individual’s blood, or his partner’s, may also aggregate in semen. It is unknown how these bacteria might affect health.
“I would assume that there are bacteria that are net beneficial, that maybe secrete certain kinds of cytokines or chemicals that improve the fertility milieu for a person, and then there are likely many that have negative side effects,” Eleswarapu told Scientific American.
The scientists used genetic sequencing to identify different bacteria species present within the semen microbiome. They found five species that were common among all the study participants. But men with more of the microbe Lactobacillus iners (L. iners) were likelier to have impaired sperm motility and experience fertility issues.
This discovery was of special interest to the team because L. iners is commonly found in the vaginal microbiome. In females, high levels of L. iners are associated with bacterial vaginosis and have been linked to infertility in women. This is the first study that found a negative association between L. iners and male fertility.
The researchers plan to investigate specific molecules and proteins contained in the bacteria to find out whether they slow down sperm in a clinical laboratory situation.
“If we can identify how they exert that influence, then we have some drug targets,” Eleswarapu noted.
Targeting Bacteria That Cause Infertility
The team also discovered that three types of bacteria found in the Pseudomonas genus were present in patients who had both normal and abnormal sperm concentrations. Patients with abnormal sperm concentrations had more Pseudomonas fluorescens and Pseudomonas stutzeri and less Pseudomonas putida in their samples.
According to the federal National Institute of Child Health and Human Development (NICHD), “one-third of infertility cases are caused by male reproductive issues, one-third by female reproductive issues, and the remaining one-third by both male and female reproductive issues or unknown factors.” Thus, learning more about how the semen microbiome may be involved in infertility could aid in the development of drugs that target specific bacteria.
“Our research aligns with evidence from smaller studies and will pave the way for future, more comprehensive investigations to unravel the complex relationship between the semen microbiome and fertility,” said urologist Vadim Osadchiy, MD, a resident in the Department of Urology at UCLA and lead author of the study, in a UCLA news release.
More research is needed. For example, it’s unclear if there are any links between the health of semen microbiome and other microbiomes that exist in the body, such as the gut microbiome, that cause infertility. Nevertheless, this research could lead to new biomarkers for clinical laboratory testing to help couples who are experiencing fertility issues.
Collected data could give healthcare providers and clinical laboratories a practical view of individuals’ oral microbiota and lead to new diagnostic assays
When people hear about microbiome research, they usually think of the study of gut bacteria which Dark Daily has covered extensively. However, this type of research is now expanding to include more microbiomes within the human body, including the oral microbiome—the microbiota living in the human mouth.
One example is coming from Genefitletics, a biotech company based in New Delhi, India. It recently launched ORAHYG, the first and only (they claim) at-home oral microbiome functional activity test available in Asia. The company is targeting the direct-to-consumer (DTC) testing market.
According to the Genefitletics website, the ORAHYG test can decode the root causes of:
“Using oral microbial gene expression sequencing technology and its [machine learning] model, [Genefitletics] recently debuted its oral microbiome gene expression solution, which bridges the gap between dentistry and systemic inflammation,” ETHealthworld reported.
“The molecular insights from this test would give an unprecedented view of functions of the oral microbiome, their interaction with gut microbiome and impact on metabolic, cardiovascular, cognitive, skin, and autoimmune health,” BioSpectrum noted.
“Microbes, the planet Earth’s original inhabitants, have coevolved with humanity, carry out vital biological tasks inside the body, and fundamentally alter how we think about nutrition, medicine, cleanliness, and the environment,” Sushant Kumar (above), founder and CEO of Genefitletics, told the Economic Times. “This has sparked additional research over the past few years into the impact of the trillions of microorganisms that inhabit the human body on our health and diverted tons of funding into the microbiome field.” Clinical laboratories may eventually see an interest and demand for testing of the oral microbiome. (Photo copyright: ETHealthworld.)
Imbalanced Oral Microbiome Can Trigger Disease
The term microbiome refers to the tiny microorganisms that reside on and inside our bodies. A high colonization of these microorganisms—including bacteria, fungi, yeast, viruses, and protozoa—live in our mouths.
“Mouth is the second largest and second most diverse colonized site for microbiome with 770 species comprising 100 billion microbes residing there,” said Sushant Kumar, founder and CEO of Genefitletics, BioSpectrum reported. “Each place inside the mouth right from tongue, throat, saliva, and upper surface of mouth have a distinctive and unique microbiome ecosystem. An imbalanced oral microbiome is said to trigger onset and progression of type 2 diabetes, arthritis, heart diseases, and even dementia.”
The direct-to-consumer ORAHYG test uses a saliva sample taken either by a healthcare professional or an individual at home. That sample is then sequenced through Genefitletics’ gene sequencing platform and the resulting biological data set added to an informatics algorithm.
Genefitletics’ machine-learning platform next converts that information into a pre-symptomatic molecular signature that can predict whether an individual will develop a certain disease. Genefitletics then provides that person with therapeutic and nutritional solutions that can suppress the molecules that are causing the disease.
“The current industrial healthcare system is really a symptom care [system] and adopts a pharmaceutical approach to just make the symptoms more bearable,” Kumar told the Economic Times. “The system cannot decode the root cause to determine what makes people develop diseases.”
Helping People Better Understand their Health
Founded in 2019, Genefitletics was created to pioneer breakthrough discoveries in microbial science to promote better health and increase longevity in humans. The company hopes to unravel the potential of the oral microbiome to help people fend off illness and gain insight into their health.
“Microorganisms … perform critical biological functions inside the body and transform our approach towards nutrition, medicine, hygiene and environment,” Kumar told CNBC. “It is important to understand that an individual does not develop a chronic disease overnight.
“It starts with chronic inflammation which triggers pro-inflammatory molecular indications. Unfortunately, these molecular signatures are completely invisible and cannot be measured using traditional clinical grade tests or diagnostic investigations,” he added. “These molecular signatures occur due to alteration in gene expression of gut, oral, or vaginal microbiome and/or human genome. We have developed algorithms that help us in understanding these alterations way before the clinical symptoms kick in.”
Genefitletics plans to utilize individuals’ collected oral microbiome data to determine their specific nutritional shortcomings, and to develop personalized supplements to help people avoid disease.
The company also produces DTC kits that analyze gut and vaginal microbiomes as well as a test that is used to evaluate an infant’s microbiome.
“The startup wants to develop comparable models to forecast conditions like autism, PCOS [polycystic ovarian syndrome], IBD [Inflammatory bowel disease], Parkinson’s, chronic renal [kidney] disease, anxiety, depression, and obesity,” the Economic Times reported.
Time will tell whether the oral microbiome tests offered by this company prove to be clinically useful. Certainly Genefitletics hopes its ORAHYG test can eventually provide healthcare providers—including clinical laboratory professionals—with a useful view of the oral microbiome. The collected data might also help individuals become aware of pre-symptomatic conditions that make it possible for them to seek confirmation of the disease and early treatment by medical professionals.
