Tag Archives: Human Microbiota

Rheumatoid arthritis (RA)  is a complex, chronic inflammatory disease that is thought to affect about one percent of …

Rheumatoid arthritis (RA)  is a complex, chronic inflammatory disease that is thought to affect about one percent of the world’s population. RA happens when a person’s own antibodies attack joint tissue, causing painful swelling, stiffness, and redness. Some research has suggested that there is a link between RA and gum disease.

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Gum disease is estimated to affect up to 47 percent of adults, and in the disorder, oral microbes can move to the blood after the gums start to bleed. An increase in disease activity has been observed in RA patients who also have gum disease. Gum disease has been shown to be more common in RA patients who carry a certain type of antibodies, called anti-citrullinated protein antibodies (ACPAs), though ACPAs are often found in the blood of individuals with RA. The presence of ACPAs can often predate the diagnosis of RA by a few years.

A new study investigated the connections between these observations. In this work, the researchers collected blood samples from a small group of ten people with RA, five with and five without gum disease. These samples were collected every week for one year, and the investigators assessed the expression of both human and bacterial genes in those samples.

Certain types of inflammatory immune cells carried gene expression signatures that were associated with the autoimmune flares of arthritis patients who also had periodontal disease, as well as the presence of certain oral bacteria in the blood.

Many of these oral bacteria were chemically altered by deimination; they were citrullinated. Citrullination can change the structure and function of proteins. Although citrullination can be a part of the normal function of tissues, high levels of citrullination have been linked to inflammation.

Citrullination can also create targets for ACPAs; when the normal, unconverted forms of the oral bacteria were incubated with ACPAs, the antibodies did not react, but when the citrullinated oral bacteria were exposed to ACPAs, there was a reaction. ACPAs appear to be bound to oral microbes in RA patients.

The findings have been reported in Science Translational Medicine.

The study noted that the immune response to oral microbes could be influencing RA flares, that oral microbes can trigger a specific antibody reaction in patients with both RA and gum disease, and that RA flares cause varying immune signatures, which could reflect different flare triggers.

It could be that gum disease repeatedly causes the immune system to respond, and as the immune system keeps reacting and repeatedly increasing inflammation, RA may eventually begin to emerge. More work will be needed, however, to fully understand whether gum disease is playing a causative role in the development of RA.

Source: Science Translational Medicine

Carmen Leitch

For many years, there was debate about whether chronic fatigue syndrome was a ‘real’ disorder. It took time, …

For many years, there was debate about whether chronic fatigue syndrome was a ‘real’ disorder. It took time, but patients were eventually validated, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was shown to be a disease that can cause various symptoms including fatigue, pain, cognitive difficulties, sleep problems, gastrointestinal issues, and post-exertional malaise. The causes of ME/CFS are still unclear and there is no way to treat it. But the gut microbiome has been shown to play a crucial role in many aspects of human health and disease, and now scientists have shown that the gut microbiomes of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) differ from those of healthy individuals. Two studies reported in Cell Host & Microbe have outlined these differences, showing that they might be used to diagnose ME/CFS. The gut microbiome may also present a treatment opportunity.

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In one of the studies, researchers assessed the gut bacteria of 106 people with ME/CFS and 91 healthy controls by analyzing stool samples. This research showed that the diversity of species, quantity of microbes, metabolic interactions, and relationships among the gut microbes were different from controls.

ME/CFS patients had unusually low levels of several types of bacteria, including Eubacterium rectale and Faecalibacterium prausnitzii, which generate the short-chain fatty acid butyrate. Previous research has shown that butyrate, a microbial metabolic byproduct, plays a crucial role in gut health maintenance. Butyrate provides a source of energy for cells lining the gut, aids in protecting the cells from disease, and supports the immune system in the gut.

Additional work showed that the reduction of certain bacteria levels was linked to decreases in butyrate production. With fewer butyrate-producing bacteria present, there were other species to fill the void. ME/CFS patients had higher levels of nine microbes, including two that have been linked to autoimmune disorders and inflammatory bowel disease – Enterocloster bolteae and Ruminococcus gnavus.

Symptoms of fatigue were found to increase as levels of F. prausnitzii decreased in ME/CFS patients, which suggests that disease severity may depend on gut microbe levels. People with ME/CFS also had low levels of a microbe that generates acetate.

Biochemical processes in the gut, which are influenced by relationships among gut microbes, were also notably different from controls; the bacterial network seems to be totally altered in ME/CFS patients.

The second report analyzed differences in the microbiomes of ME/CFS patients in different stages of disease. Health data, blood, and stool samples were analyzed from 149 ME/CFS patients; 74 of them had been diagnosed within the previous four years and were classified as short-term, while 75 had been diagnosed over a decade prior and were long-term. There were 74 healthy controls included in this work.

Those who were short-term had less diversity in their microbiomes and significantly lower levels of species that generate butyrate. Long-term patients had more stable microbiomes that were more similar to healthy controls, even while these individuals had more severe symptoms and worse metabolic disturbances. In all ME/CFS patients, tryptophan metabolism was decreased.

This work has shown that there could be biomarkers for ME/CFS in the microbiome, which could also help classify the disease and may lead to treatments, though a lot more research will be needed before those tests and treatments are realized.

Sources: National Institutes of Health, Cheng Guo et al Cell Host & Microbe 2023, Ruoyun Xiong et al Cell Host & Microbe 2023

Carmen Leitch

Humans carry around trillions of microbes in their gastrointestinal tracts, and research has shown that the gut microbiome …

Humans carry around trillions of microbes in their gastrointestinal tracts, and research has shown that the gut microbiome is closely linked to health. Studies have found that gut microbiomes are more healthy when they are made up of more diverse microbes, for example, and imbalances in the microbiome, or dysbiosis, is associated with disease. Scientists are now starting to look more closely at the specific types of microbes in the gut, and exactly how certain strains are influencing the development of specific disorders. A new report in Diabetes has identified two strains of gut microbes that seem to affect insulin sensitivity.

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A multitude of studies have associated the microbiome with metabolic disease. For example, research has indicated that people who have lower levels of bacteria that generate butyrate, a fatty acid, also don’t process insulin correctly.

In this new study, a bacterium called Coprococcus was found at higher levels in people who tended to have more sensitivity to insulin, while higher levels of a bacterium called Flavonifractor were found in those who tended to be less insulin sensitive. Coprococcus may be protecting people from type 2 diabetes while Flavonifractor could be promoting the development of type 2 diabetes.

But it’s also important to decipher whether microbes can cause disease, or if differences in the microbiome arise after the disease is present. Senior study author Mark Goodarzi, MD, Ph.D., the director of the Endocrine Genetics Laboratory at Cedars-Sinai, is also the principal investigator of a multicenter study called Microbiome and Insulin Longitudinal Evaluation Study (MILES), which is aiming to determine whether factors in the microbiome cause diabetes, or if diabetes changes the microbiome.

Since 2018, MILES researchers have been assessing data from Black and non-Hispanic white adults who are 40 to 80 years old. In this study, the focus was on 352 study volunteers who had not been diagnosed with diabetes. These volunteers gave stool samples, did glucose tolerance tests, and supplied other information such as data about dietary habits. In this group, 135 were found to have prediabetes and 28 people had glucose tolerance tests that met the threshold for a diabetes diagnosis.

The researchers examined 36 gut bacteria that generate butyrate in the study participants (from the stool samples), and found that Coprococcus and related bacteria are good for insulin sensitivity.

Although Flavonifractor also generates butyrate, it was associated with insulin resistance. This confirms previous research that has found higher Flavonifractor levels in diabetic people. These findings were significant after the researchers controlled for other factors that affect the development of diabetes, including sex, race, body mass index, and age.

The study authors cautioned, however that people should not yet try to change their microbiome to lower their risk of diabetes.

“As far as the idea of taking probiotics, that would really be somewhat experimental,” said Goodarzi. More research is needed to determine exactly which bacteria should be altered “… but it’s coming, probably in the next five to ten years.”

Now the researchers want to learn more about how diet changes the microbiome, and they are planning to follow up with study volunteers to learn more about changes in insulin resistance and the microbiome over time.

Sources: Cedars-Sinai Medical Center, Diabetes

Carmen Leitch

Microbes can easily share genes. Not only can different types of bacteria do this, there is also evidence …

Microbes can easily share genes. Not only can different types of bacteria do this, there is also evidence that entirely different branches of life – archaea and bacteria can also share genes. Some microbial genes can be found on small bits of DNA called mobile genetic elements, which are not a part of a microbe’s genome, but can still be expressed when they’re a microbial cell. These mobile genetic elements can move from one cell to another in a process known as horizontal gene transfer. Researchers have now found that bacteria in the maternal microbiome can share genes with bacteria in the infant microbiome, in the period just before birth until a few weeks after delivery – the perinatal period. Horizontal gene transfer enables maternal microbes to influence how bacteria in the infant microbiome are functioning, without actually moving the maternal microbes themselves. These findings have been reported in Cell.

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“This is the first study to describe the transfer of mobile genetic elements between maternal and infant microbiomes,” said senior study author Ramnik Xavier of the Broad Institute of MIT and Harvard. “Our study also, for the first time, integrated gut microbiome and metabolomic profiles from both mothers and infants and discovered links between gut metabolites, bacteria and breastmilk substrates. This investigation represents a unique perspective into the codevelopment of infant gut microbiomes and metabolomes under the influence of known maternal and dietary factors.”

The gut microbiome produces metabolites that can affect various aspects of infant development, such as immune system maturation and cognitive development during the perinatal period, a critical window. At birth, microbes move from the maternal microbiome to the infant microbiome, but we still have a lot to learn about how microbes are affecting development, and how they are developing into a microbiome themselves.

In this study, the researchers tracked the microbiomes and metabolites of 70 infant-mother pairs, from late pregnancy until the babies were one year old. This research showed that mobile genetic elements moved from microbes carried by moms and into microbes carried by infants. The mobile genetic elements that were transferred were often related to diet.

Infants were also found to have less diversity in their metabolomes compared to moms, however, there were metabolites, and links between microbes and metabolites that were identified exclusively by infants. Infants that got regular formula (that was not excessively hydrolyzed) also had metabolomes and cytokine signatures that were different from infants that were exclusively breastfed.

“The infant gut harbored thousands of unique metabolites, many of which were likely modified from breastmilk substrates by gut bacteria,” noted co-first study author Tommi Vatanen of the Broad Institute of MIT and Harvard. “Many of these metabolites likely impact immune system and cognitive development.”

This process seems to be a way for the maternal microbiome to exert an influence on the infant microbiome withouth transmitting specific species of bacteria.

Prophages, which are dormant bacteriophages, also seem to be involved in the movement of mobile genetic elements between the maternal and infant microbiomes, added Xavier.

Sources: Cell Press, Cell

Carmen Leitch

The microbes in our guts are closely connected to our brains, in a link known as the gut-brain …

The microbes in our guts are closely connected to our brains, in a link known as the gut-brain axis. Scientists have now found that a bacterium called HA-114 Lacticaseibacillus rhamnosus could help prevent amyotrophic lateral sclerosis (ALS). In a roundworm model of ALS, neurodegeneration was prevented by the microbe. The findings have been reported in Communications Biology.

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In ALS, the nerve cells that control movement, called motor neurons, gradually die off, causing a loss of movement and function. While the cause of ALS is still under investigation, this study has suggested that lipid metabolism disruptions are contributing to neurodegeneration, and HA-114 can provide protection against that deleterious influence.

Other research has also indicated that dysfunction in the gut microbiome may be involved in the development of ALS and other neurodegenerative disorders, noted lead study author Alex Parker, a Université de Montréal neuroscience professor.

When the researchers added the HA-114 microbe to the diet of the roundworm ALS model, motor neuron degeneration was suppressed, noted Parker. “The particularity of HA-114 resides in its fatty acid content.”

Roundworms called Caenorhabditis elegans have about 60 percent of their genome in common with humans and serve as common animal models. They carry some genes that have been linked to ALS.

Thirteen bacterial strains and three combinations of strains were tested on the worms. HA-114 had a significant impact, and reduced the motor disruption that occurs in models of both ALS and Huntington’s disease.

Additional work indicated that two genes, called acdh-1 and acs-20,  are involved in the neuroprotection provided by the bacteria. These genes are involved in the metabolism of fats, or lipids, and the breakdown of fatty acids for energy, a process called beta oxidation, which occurs in mitochondria.

Parker suggested that HA-114 is supplying fatty acids that enter mitochondria through a non-traditional pathway, which restores a balance in energy metabolism that becomes disrupted in ALS, and that decreases neurodegeneration.

The researchers are working on validating these findings in a mouse model of ALS, and are now planning to start a small clinical trial with ALS patients.

Sources: University of Montreal Hospital Research Centre, Communications Biology

Carmen Leitch

The microbes in the gut can metabolize some of the foods we eat to produce new molecules, some …

The microbes in the gut can metabolize some of the foods we eat to produce new molecules, some of which can affect our health. Researchers have previously shown that gut microbes can metabolize proteins in the diet to generate phenylacetylglutamine (PAG), a chemical that increases the risk of heart disease. New research has confirmed that link using human data, and expanded on what we know with an analysis of heart cells. The findings have been reported in Circulation: Heart Failure. This research may help scientists develop strategies to mitigate PAG-associated risks.

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This study assessed data from over 3,000 Americans and over 800 Europeans. It showed that increased PAG levels are linked to heart failure. Individuals with heart failure with preserved ejection fraction, in which there is a lack of heart muscle relaxation between beats, have elevated blood PAG levels, for example.

Blood PAG levels may serve to predict who is at risk for heart failure, suggested corresponding study author Stanley Hazen, M.D., Ph.D., department chair of Cardiovascular & Metabolic Sciences at the Lerner Research Institute. “The data build a strong case that making this test available for clinicians would add to their arsenal of diagnostic tests for heart failure.”

Hazen and colleagues reported that PAG can influence adrenergic receptors on platelets, which can affect things like blood clotting risks, in a study reported in Cell in 2020. That study is outlined in the video below.

This latest rsearch also showed that PAG and the parallel molecule found in mice, phenylacetylglycine, promote changes in gene expression and conditions that are related to heart failure, such as a reduction in contractility in certain heart cells.

Heart failure and cardiac disease is still a major cause of death around the world. Changes in diet that affect PAG levels may be one way to reduce the risk of heart disease.

“This study substantially expands the breadth of possible links between our diet and how our gut microbiome serves as a filter of our diet, impacting our susceptibility to develop different diseases,” said Hazen. “In this case, gut microbes form a metabolite from the amino acid phenylalanine in dietary protein, adversely impacting the function of a beating cardiac muscle cell.”

Hazen’s team is searching for the bacterium or bacteria and the enzymes they make that are involved in PAG production, and how to reduce PAG levels. Diet modifications might be a way to reduce risk too, added Hazen.

Sources: Cleveland Clinic, Circulation: Heart Failure

Carmen Leitch

Trillions of microbes live in our gastrointestinal tracts, and they are thought to exert a powerful influence on …

Trillions of microbes live in our gastrointestinal tracts, and they are thought to exert a powerful influence on various aspects of human biology, including mood. Studies have shown that there are associations between certain aspects of the gut microbiome and depression. We still don’t know much about how depression is caused on a biochemical level; research has indicated that genetics seem to only have a limited influence on the disease, for example. While there are treatments that can help some people, there are still millions of people with depression, and the disorder continues to be a leading cause of disability and mortality.

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Previous studieson depression and the microbiome have been small, done in animals, or have come to some conflicting conclusions, noted a new report in Nature Communications. This new research has expanded what we know about the gut microbiome and depression by taking a more careful approach; although this new work did not control for diet, which can be extremely difficult in human studies, it did control for medication use and lifestyle factors like exercise, weight, smoking, or drinking.

It was published with an accompanying study that investigated the microbiomes of a more diverse population as well. Data from 1,054 participants was used to find associations, which were then validated in another 1,539 individuals.

The research has shown that the microbiome and depression are connected, and that the composition of the microbiome is linked to the rates of depression in different ethnic groups. Data from the HELIUS study, which included 3,211 people, was used.

Microbiomes that lack certain species of bacteria, have fewer bacterial species in general – they are less diverse, were linked to a higher risk of depression or more symptoms of depression. This link was as statistically significant as other depression risk factors such as obesity, smoking, or a lack of exercise. While this research has not shown that factors in the microbiome cause depression, it has suggested that it may be possible to treat depression by modifying the microbiome.

The research revealed a consistent connection between depression and twelve bacterial groups, which all play a role in the production of neurotransmitters that have been related to depression, such as butyrate, glutamate, serotonin, and GABA.

“Now that we know which disturbances in the microbiome are significant for depression, this opens up new possibilities for treatment and prevention. Which is urgently needed,” said Anja Lok, a senior author of one of the studies and researcher at Amsterdam UMC.

“The substantial ethnic differences in depression do indeed appear to be related to ethnic differences in the microbiome. We don’t know exactly why this is yet,” noted a corresponding author of one of the studies, Jos Bosch, a researcher from the University of Amsterdam. “This association was not caused by differences in lifestyle such as smoking, drinking, weight or exercise, and merits further investigation. For example, diet could play a role.”

Sources: University of Amsterdam, Bosch et al Nature Communications 2022, Radjabzadeh et al Nature Communications 2022

Carmen Leitch

The microbes in the human gastrointestinal tract, known as the gut microbiome, have a significant impact on out …

The microbes in the human gastrointestinal tract, known as the gut microbiome, have a significant impact on out health and well-being. Scientists have begun to learn more about the complex relationships between diet, gut microbes, and disease. New research has now revealed that an nutrient and additive commonly found in the diet, called ergothioneine (EGT), can promote the survival of a microbe that can promote cancer development. EGT appears to shield the microbes from a natural phenomenon called oxidative stress, which is caused by an excess of free radicals, or reactive oxygen species (ROS).

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Antioxidants like EGT can protect cells from oxidative stress, and excessive oxidative stress is a common feature of disease. Immune cells can release ROS on purpose to kill bacteria, and bacteria have ways to prevent damage caused by ROS – they can use antioxidants too. In this case, the microbes are using EGT from the diet. The findings have been reported in Cell.

The study authors determined that bacteria can take up EGT, which is naturally found in grains, beans, and mushrooms, to survive longer.

The pathogenic microbe Helicobacter pylori, which is associated with gastric cancer development, outcompeted other microbes for survival in a host, using EGT to do so. The researchers used mass spectrometry and a new tool they called “reactivity-guided metabolomics” to identify specific molecules in complex environments, to show the microbes had ingested the EGT from the diet.

“We were excited to discover an unconventional mechanism that enables bacteria to withstand oxidative stress during infection,” said senior study author Stavroula Hatzios, an assistant professor at Yale University.

Bacteria take up EGT in a different way than human cells, so it could be possible to develop a specific drug that can inhibit the uptake of this nutrient by microbes in the gut, she added.

Human cells can take up dietary EGT, which has been shown to be an anti-inflammatory molecule that can prevent disease. Reduced EGT levels have been associated with a wide variety of diseases, including autoimmune and cardiovascular disorders. Bacterial uptake of EGT could have a significant influence on human health.

Sources: Yale University, Cell

Carmen Leitch

Gut bacteria have been linked to an ever-increasing number of diseases. Research is now going beyond establishing a …

Gut bacteria have been linked to an ever-increasing number of diseases. Research is now going beyond establishing a link between a disorder and the community of gut microbes, and has begun to identify specific organisms that are responsible for certain conditions. Scientists have now shown that a strain of bacteria in the Subdoligranulum genus can lead to the production of autoantibodies, which appears to cause the development of rheumatoid arthritis. The findings have been reported in Science Translational Medicine.

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Rheumatoid arthritis is an autoimmune disease in which the joints are erroneously attacked by the immune system, and the inflammation and damage that occurs in affected joints causes pain, the loss of mobility, and other serious problems. Disruption of mucosal immunity, in the gut, has been proposed to be one cause of rheumatoid arthritis.

In this work, the researchers obtained blood samples from people who are at risk of developing RA, and the autoantibodies were isolated from those samples.

The scientists found that the autoantibodies were causing a response in certain bacteria in the Lachnospiraceae/Ruminococcaceae families. Further work revealed that bacteria of the genus Subdoligranulum, a member of those families that was isolated from the feces of people ate risk for RA, could bind to the autoantibodies and cause the activation of CD4+ T cells. This was occurring in individuals with RA, but not in healthy people.

The Subdoligranulum bacteria was put in an animal model, and the animals began to develop the same RA risk markers found in the blood of people who are at risk for RA. Some of the animals also developed RA.

“Through studies in humans and animal models, we were able to identify these bacteria as being associated with the risk for developing RA. They trigger an RA-like disease in the animal models, and in humans, we can show that this bacterium seems to be triggering immune responses specific to RA,” said study leader Kristine Kuhn, MD, Ph.D., an associate professor at CU School of Medicine.

This microbe could be a good therapeutic target for RA treatment, noted Kuhn. Now, the scientists want to assess large populations of people who are at risk for RA to see if the Subdoligranulum microbes are also linked to other factors like genetics, mucosal immunity, and environmental conditions that can lead to RA. It may help scientists find prevention strategies or other ways to stop the microbes from causing disease, added Kuhn.

Sources: CU Anschutz Medical Campus, Science Translational Medicine

Carmen Leitch

Scientists have developed a gel that can block the receptor for a molecule called succinate, which is a …

Scientists have developed a gel that can block the receptor for a molecule called succinate, which is a normal byproduct of metabolism. By blocking its receptor, the gel can lower inflammation levels in the mouth, and alter the community of oral bacteria living there. The work, which used a mouse model and human cells in culture, is the first step on the path to a simple, at-home treatment for gum disease. The work has been published in Cell Reports.

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Periodontitis, also known as periodontal or gum disease, is one of the most common inflammatory disorders, and is thought to affect almost half of all people older than 30. There are three hallmarks of gum disease: inflammation, an imbalance or dysbiosis in the oral microbiome, and degradation of the support structures and bones underlying teeth. When gum disease is left untreated, it can cause gums to become painful and bleed. Gum disease patients might have trouble chewing, and may eventually start to lose teeth. Serious gum problems can also interfere with other aspects of health.

Right now, there is not a gum disease treatment that can reduce inflammation, while simultaneously limiting disruption to the oral microbiome and preventing the loss of bone, noted co-first study author Yuqi Guo, an associate research scientist at NYU Dentistry. “There is an urgent public health need for more targeted and effective treatments for this common disease.”

Previous research has indicated that a molecule that is generated during cellular metabolism, called succinate, is associated with gum disease. Higher succinate levels also correspond to higher levels of inflammation. Abnormally high succinate levels were found in human dental plaque. This team has also shown that excess succinate activates its receptor and triggers bone loss. Thus, succinate seemed like a good target to aim for when developing treatments for excessive inflammation, and potentially, gum disease or bone loss.

The researchers engineered mice that lacked the succinate receptor. When gum disease was modeled in these succinate receptor-depleted mice, there was less dysbiosis in their oral microbiomes, and lower levels of inflammation compared to normal mice with gum disease. When mice were exposed directly to succinate, gum disease got worse in normal mice, while the mice without succinate receptors did not experience inflammation, dysbiosis, or bone loss.

Now that the researchers had evidence that high succinate levels can lead to gum disease, and blocking the receptor can relieve it, they formulated a gel containing a succinate receptor-blocking compound.

In a cell culture model, the compound lowered inflammation and other biochemical mechanisms leading to bone loss. When a mouse model of gum disease was treated with the gel, the animals had less inflammation and bone loss compared to mice that did not get the treatment, and within only a few days. There was also a shift in the oral microbiome of the mice. Bacteria called Bacteroidetes, which are dominant during gum disease, were reduced after gel treatment.

However, the investigators determined that the gel was not acting as an antibiotic and was not influencing bacterial growth directly. “This suggests that the gel changes the community of bacteria through regulating inflammation,” suggested co-senior study author Deepak Saxena, a professor at NYU Dentistry.

The researchers want to eventually create gels or oral strips that can be used at home by gum disease patients or those at risk, and a formulation that releases more slowly that can be applied to patches of gum disease.

Sources: New York University, Cell Reports


Carmen Leitch