Posts Tagged ‘microbiome’

By Julie Zaugg and Jared Peng

Authorities in China have approved a drug for the treatment of Alzheimer’s disease, the first new medicine with the potential to treat the cognitive disorder in 17 years.

The seaweed-based drug, called Oligomannate, can be used for the treatment of mild to moderate Alzheimer’s, according to a statement from China’s drug safety agency. The approval is conditional however, meaning that while it can go on sale during additional clinical trials, it will be strictly monitored and could be withdrawn should any safety issues arise.

In September, the team behind the new drug, led by Geng Meiyu at the Shanghai Institute of Materia Medica under the Chinese Academy of Sciences, said they were inspired to look into seaweed due to the relatively low incidence of Alzheimer’s among people who consume it regularly.

In a paper in the journal Cell Research, Geng’s team described how a sugar contained within seaweed suppresses certain bacteria contained in the gut which can cause neural degeneration and inflammation of the brain, leading to Alzheimer’s.

This mechanism was confirmed during a clinical trial carried out by Green Valley, a Shanghai-based pharmaceutical company that will be bringing the new drug to market.

Conducted on 818 patients, the trial found that Oligomannate — which is derived from brown algae — can statistically improve cognitive function among people with Alzheimer’s in as little as four weeks, according to a statement from Green Valley.

“These results advance our understanding of the mechanisms that play a role in Alzheimer’s disease and imply that the gut microbiome is a valid target for the development of therapies,” neurologist Philip Scheltens, who advises Green Valley and heads the Alzheimer Center Amsterdam, said in the statement.

Vincent Mok, who heads the neurology division at the Chinese University of Hong Kong, said the new drug showed “encouraging results” when compared to acetylcholinesterase inhibitors — the existing treatment for mild to severe Alzheimer’s.

“It is just as effective but it has fewer side effects,” he told CNN. “It will also open up new avenues for Alzheimer’s research, focusing on the gut microbiome.”

Since very little is known about the mechanisms of the new drug, Mok said it should also be probed to see if it could have a protective effect and possibly slow down the progression of the disease in patients who have yet to develop strong symptoms of dementia.

The company said Oligomannate will be available in China “very soon,” and it is currently seeking approval to market it abroad, with plans to launch third-phase clinical trials in the US and Europe in early 2020.

Alzheimer’s disease, which starts with memory loss and escalates to severe brain damage, is believed to cause 60% to 70% of the cases of dementia reported worldwide, according to the World Health Organization. Dementia affects an estimated 50 million people worldwide, including 9.5 million people in mainland China, Hong Kong and Taiwan.

Named after Alois Alzheimer, the neuropathologist who discovered the disease in 1906, it has so far confounded researchers and pharmaceutical companies.

In October, US pharmaceutical giant Biogen said it would pursue Food and Drug Administration (FDA) approval for an experimental treatment called aducanumab, after announcing in March it was canceling a large clinical trial for the drug.

Johnson & Johnson, Merck, Pfizer and Eli Lilly have all previously abandoned projects to develop a drug for Alzheimer’s after unsatisfactory clinical data.

https://www.cnn.com/2019/11/03/health/china-alzheimers-drug-intl-hnk-scli/index.html


An infection with a drug-resistant strain of E. coli proved fatal for a man who received a fecal transplant.

The first person known to die as a result of a fecal transplant is a 73-year-old man who developed a fatal infection with antibiotic-resistant bacteria that were in the donor’s stool sample.

News of the man’s death surfaced in June; he was one of two patients in separate clinical trials who became ill after receiving fecal transplants from the same donor.

Both patients developed infections with a strain of Escherichia coli, or E. coli, that demonstrated resistance to different types of antibiotics. Details of the man’s death were described in a new study published online Oct. 30 in The New England Journal of Medicine.

The two patients, who were participants in clinical trials conducted at Massachusetts General Hospital (MGH), received fecal transplants in the form of pills that were made in November 2018.

Fecal microbiota transplantation (FMT) — commonly known as a “poop transplant” or fecal transplant — is emerging as an effective experimental treatment for Clostridium difficile, or C. diff, a potentially life-threatening bacterial gut infection. In guts with depleted microbial diversity, poop transplants boost diversity with microbial infusions from a healthy person’s gut microbiome, distilled from stool samples and delivered as an enema or an oral pill.

But FMT is also being tested as a method of restoring gut microbial diversity for conditions not caused by C. diff. The two clinical trials at MGH were testing the impact of FMT on microbiome issues associated with liver disease and the effectiveness of preventive FMT prior to stem cell transplants.

Eight days after the 73-year-old patient received his last FMT dose, he developed a fever and chills, and exhibited “altered mental status,” according to the study. His condition quickly worsened. The man developed sepsis — an extreme immune response to infection causing inflammation throughout the body and organ damage — and died two days later, with evidence of an antibiotic-resistant strain of E. coli in his blood.

The other patient who became ill from the FMT, a 69-year-old man, also tested positive for the drug-resistant strain of E. coli. However, his infection responded to treatment with antibiotics. Eventually, he was pronounced “clinically stable,” the researchers wrote in the study.

Antibiotic resistance in harmful bacteria is a growing concern worldwide. With the emergence of these so-called superbugs — some of which can share their resistance with other bacteria — entire classes of antibiotics are becoming less effective at quelling infections, and health practitioners are losing key weapons in their disease-fighting arsenals.

High-risk patients

In January 2019, a regulatory review by the U.S. Food and Drug Administration (FDA) dictated that stool samples for FMT had to be screened for drug-resistant microbes. But as this E. coli strain is rare in healthy people, the pills that were produced in November were not tested retroactively, the study authors reported.

Both of the FMT-sickened patients were considered at high risk for bacterial infection because of conditions that weakened their immune systems. The man who recovered had advanced cirrhosis — severe scarring of the liver — and the man who died had recently undergone a stem cell transplant and was taking immunosuppressing drugs so that the transplant would not be rejected, the scientists reported. Samples from the same donor were administered to 22 patients in all, and although several other recipients tested positive for the resistant E. coli, the bacteria didn’t make them ill.

On Nov. 4, FDA officials will conduct a 7-hour public hearing at the agency’s Silver Spring, Maryland, campus, “to obtain public input on the state of the science regarding FMT to treat C. difficile infection not responsive to standard therapies,” according to a notice on the FDA website.

The FDA hearing will also review clinical evidence to evaluate the effectiveness and risks of using FMT to combat persistent C. difficile “and to better understand the impact of FDA’s enforcement policy on product development,” agency officials said in the statement.

https://www.livescience.com/fecal-transplant-death.html?utm_source=Selligent&utm_medium=email&utm_campaign=9583&utm_content=20191101_LS_Essentials_Newsletter+-+adhoc+&utm_term=3675605&m_i=uxOuCb14GZ_f_Gtk%2Bp9nsep0qM1OWDMFvl255HddfzLlp4atZ49G7gBQyO3IdDiaYEBisgwkAznzqIBplBPr0oSWQdXtA95quF

by DAVID NIELD

Dosing medicines can be a tricky process: How much of a medication actually ends up hitting its target can vary a lot between patients, sometimes for mysterious reasons. As it turns out, even the things living in our bodies could be gobbling up our drugs.

In a series of experiments with levodopa (L-dopa) drug treatments for Parkinson’s, a new study has found that the gut microbes Enterococcus faecalis and Eggerthella lenta can intercept L-dopa and chemically transform it before it reaches the brain.

While this research only focuses on a specific treatment for one condition, the team behind the work thinks we might be underappreciating the role that our gut microbiome plays in controlling the efficacy and potency of medicines.

“Maybe the drug is not going to reach its target in the body, maybe it’s going to be toxic all of a sudden, maybe it’s going to be less helpful,” says chemical biologist Maini Rekdal from Harvard University.

The job of L-dopa is to deliver dopamine to the brain, replacing the dopamine eaten up by Parkinson’s. However, since the introduction of L-dopa in the 1960s, scientists have known that enzymes in the gut can stop this delivery from happening, leading to some nasty side effects as dopamine “spills out” before reaching the brain.

A second drug, carbidopa, was introduced to keep L-dopa intact, but it doesn’t always seem to help. Even with this additional drug, the effectiveness of L-dopa can vary between patients. What this new research does is identify the specific bacteria to blame, out of trillions of potential species.

With reference to the Human Microbiome Project, the team found that not only our own gut enzymes can wreak havoc on the medication, but the bacterium E. faecalis can also convert L-dopa to dopamine before it reaches the brain. Sure enough, it ate up all the L-dopa in lab tests.

Using faecal samples and supplies of dopamine, the researchers identified that another strain of gut bacteria, E. lenta, then consumes the converted dopamine and produces the neuromodulator meta-thyramine as a byproduct.

Thus, E. faecalis and E. lenta are apparently working as a sort of microbe tag team, preventing the medication from reaching its target. Furthermore, while carbidopa is used to stop a human gut enzyme from converting L-dopa to dopamine in the digestive system, it doesn’t seem to work on the E. faecalis enzyme that’s doing the same.

The good news is that the researchers have already found a molecule, alpha-fluoromethyltyrosine (AFMT), that can stop E. faecalis from breaking down L-dopa without destroying the bacterium itself, by targeting a non-essential enzyme.

Ultimately, we might end up with a way of making L-dopa significantly more effective as a Parkinson’s treatment, without as many of the side effects – but that’s still a long way off.

“All of this suggests that gut microbes may contribute to the dramatic variability that is observed in side effects and efficacy between different patients taking L-dopa,” says chemical biologist Emily Balskus from Harvard University.

Even if we can’t fix the problem just yet, we now have a proof of concept that particular combinations of gut microbes can indeed cause havoc with our meds. Hopefully, this will give other researchers food for thought and we might see similar investigations of other medicines, too.

The research has been published in Science.

https://www.sciencealert.com/gut-microbes-could-be-eating-up-our-meds-before-they-get-chance-to-work


The research has presented strong evidence that Parkinson’s disease begins in the gastrointestinal tract and spreads via the vagus nerve to the brain. Many patients have also suffered from gastrointestinal symptoms before the Parkinson’s diagnosis is made. The image is for illustrative purposes only.

A major epidemiological registry-based study from Aarhus University and Aarhus University Hospital indicates that Parkinson’s disease begins in the gastrointestinal tract; the study is the largest in the field so far.

The chronic neurodegenerative Parkinson’s disease affects an increasing number of people. However, scientists still do not know why some people develop Parkinson’s disease. Now researchers from Aarhus University and Aarhus University Hospital have taken an important step towards a better understanding of the disease.

New research indicates that Parkinson’s disease may begin in the gastrointestinal tract and spread through the vagus nerve to the brain.

“We have conducted a registry study of almost 15,000 patients who have had the vagus nerve in their stomach severed. Between approximately 1970-1995 this procedure was a very common method of ulcer treatment. If it really is correct that Parkinson’s starts in the gut and spreads through the vagus nerve, then these vagotomy patients should naturally be protected against developing Parkinson’s disease,” explains postdoc at Aarhus University Elisabeth Svensson on the hypothesis behind the study.

A hypothesis that turned out to be correct:

“Our study shows that patients who have had the the entire vagus nerve severed were protected against Parkinson’s disease. Their risk was halved after 20 years. However, patients who had only had a small part of the vagus nerve severed were not protected. This also fits the hypothesis that the disease process is strongly dependent on a fully or partially intact vagus nerve to be able to reach and affect the brain,” she says.

The research project has just been published in the internationally recognised journal Annals of Neurology.

The first clinical examination

The research has presented strong evidence that Parkinson’s disease begins in the gastrointestinal tract and spreads via the vagus nerve to the brain. Many patients have also suffered from gastrointestinal symptoms before the Parkinson’s diagnosis is made.

“Patients with Parkinson’s disease are often constipated many years before they receive the diagnosis, which may be an early marker of the link between neurologic and gastroenterologic pathology related to the vagus nerve ,” says Elisabeth Svensson.

Previous hypotheses about the relationship between Parkinson’s and the vagus nerve have led to animal studies and cell studies in the field. However, the current study is the first and largest epidemiological study in humans.

The research project is an important piece of the puzzle in terms of the causes of the disease. In the future the researchers expect to be able to use the new knowledge to identify risk factors for Parkinson’s disease and thus prevent the disease.

“Now that we have found an association between the vagus nerve and the development of Parkinson’s disease, it is important to carry out research into the factors that may trigger this neurological degeneration, so that we can prevent the development of the disease. To be able to do this will naturally be a major breakthrough,” says Elisabeth Svensson.

https://neurosciencenews.com/parkinsons-gastrointestinal-tract-neurology-2150/

by MIKE MCRAE

Transforming the microbial environment in the guts of children diagnosed with autism could significantly ease the severity of their condition’s signature traits, according to newly published research.

A study on the effects of a form of faecal transplant therapy in children on the autism spectrum found participants not only experienced fewer gut problems, but continued to show ongoing improvements in autism symptoms two years after the procedure.

Arizona State University researchers had already discovered a dose of healthy gut microflora caused characteristics associated with autism spectrum disorder (ASD) to ease or vanish for at least a couple of months after treatment ended.

But to be taken seriously as a potential therapy, there needed to be long term improvements. So a return to the original group of volunteers for another check-up was in order.

It turned out those new microbes were settling in nicely.

“In our original paper in 2017, we reported an increase in gut diversity together with beneficial bacteria after microbiota transfer therapy (MTT), and after two years, we observed diversity was even higher and the presence of beneficial microbes remained,” says biotechnologist Dae-Wook Kang.

The gut might seem like an odd place to start in developing therapies that assist individuals with a neurological condition such as autism.

But in addition to its defining characteristics of impaired social and communication skills, sensory challenges, and reduced core strength and motor control, for up to half of those with ASD the condition can come with a bunch of gut problems.

“Many kids with autism have gastrointestinal problems, and some studies, including ours, have found that those children also have worse autism-related symptoms,” says environmental engineer Rosa Krajmalnik-Brown.

Previous studies have repeatedly pointed to the potential benefits of swapping out a ‘bad’ microbial communities for a better one, either through using probiotics or courses of antibiotics.

Most showed promising short-term effects, suggesting there was more to be explored when it comes to gut-based therapies.

“In many cases, when you are able to treat those gastrointestinal problems, their behaviour improves,” says Krajmalnik-Brown.

In an attempt to elicit a more long-term result, the researchers pulled out the big guns. Forget dropping in a few microbial tourists or killing off a handful of trouble-makers – they went for a whole mass migration.

Using a customised process of gut microflora transplantation called microbiota transfer therapy, the researchers gave 18 kids aged between 7 and 16 a belly full of new microorganisms.

All of the volunteers had both an autism diagnosis and moderate to severe gastrointestinal problems. This group was compared with 20 equivalent control subjects who had neither gut problems nor an ASD diagnosis.

Both were treated for 10 weeks and then had follow-up test sessions for a further 8 weeks.

Admittedly, the experiment wasn’t blinded, so we do need to be cautious in how we read into the results. Placebo effects can’t be ruled out in cases like this.

But saying they were ‘promising’ isn’t too strong a claim to make. The children not only experienced an 80 percent reduction in gastrointestinal symptoms, they showed significant improvements when tested with common ASD diagnostic tools.

Two years later, those same tests indicate the conditions have only improved.

“The team’s new publication reports that the study demonstrated that two years after treatment stopped the participants still had an average of a 58 percent reduction in GI symptoms compared to baseline,” says Krajmalnik-Brown.

“In addition, the parents of most participants reported a slow but steady improvement in core ASD symptoms.”

An external evaluation using a standard ASD diagnostic tool concluded 83 percent of the initial test group could be considered as severe on the autistic spectrum. Two years later, this dropped to just 17 percent.

Amazingly, 44 percent no longer made the cut-off for being on the mild end of the spectrum at all.

Overall, the evaluator determined the severity of ASD traits was reduced by 47 percent compared with their baseline.

For a therapy that has barely any side-effects, and such remarkable improvements in challenges many with ASD struggle with, it’s surely a treatment that will continue to attract attention for further research.

Faecal transplants might sound a little gross, but you might as well get used to them. We’re bound to be seeing them used for a variety of things in the future, from treating superbugs to winning sports.

Now that we’re learning our neurological health is intimately connected with our digestive system, transplanting microbial communities from a healthy gut is seen as the next big thing in treating brain disorders.

This isn’t to say microflora cause autism. It’s a complex condition that has its roots in a diverse range of genes and environmental influences that nudge the brain’s development early in life.

But if we can swap out even a few of those influences, we just might be able to make life a little easier for those who need it.

This research was published in Scientific Reports.

https://www.sciencealert.com/autism-severity-cut-in-half-in-kids-who-underwent-radical-faecal-transplant-therapy

By Carl Zimmer

In 2014 John Cryan, a professor at University College Cork in Ireland, attended a meeting in California about Alzheimer’s disease. He wasn’t an expert on dementia. Instead, he studied the microbiome, the trillions of microbes inside the healthy human body.

Dr. Cryan and other scientists were beginning to find hints that these microbes could influence the brain and behavior. Perhaps, he told the scientific gathering, the microbiome has a role in the development of Alzheimer’s disease.

The idea was not well received. “I’ve never given a talk to so many people who didn’t believe what I was saying,” Dr. Cryan recalled.

A lot has changed since then: Research continues to turn up remarkable links between the microbiome and the brain. Scientists are finding evidence that microbiome may play a role not just in Alzheimer’s disease, but Parkinson’s disease, depression, schizophrenia, autism and other conditions.

For some neuroscientists, new studies have changed the way they think about the brain.

One of the skeptics at that Alzheimer’s meeting was Sangram Sisodia, a neurobiologist at the University of Chicago. He wasn’t swayed by Dr. Cryan’s talk, but later he decided to put the idea to a simple test.

“It was just on a lark,” said Dr. Sisodia. “We had no idea how it would turn out.”

He and his colleagues gave antibiotics to mice prone to develop a version of Alzheimer’s disease, in order to kill off much of the gut bacteria in the mice. Later, when the scientists inspected the animals’ brains, they found far fewer of the protein clumps linked to dementia.

Just a little disruption of the microbiome was enough to produce this effect. Young mice given antibiotics for a week had fewer clumps in their brains when they grew old, too.

“I never imagined it would be such a striking result,” Dr. Sisodia said. “For someone with a background in molecular biology and neuroscience, this is like going into outer space.”

Following a string of similar experiments, he now suspects that just a few species in the gut — perhaps even one — influence the course of Alzheimer’s disease, perhaps by releasing chemical that alters how immune cells work in the brain.

He hasn’t found those microbes, let alone that chemical. But “there’s something’s in there,” he said. “And we have to figure out what it is.”

‘It was considered crazy’

Scientists have long known that microbes live inside us. In 1683, the Dutch scientist Antonie van Leeuwenhoek put plaque from his teeth under a microscope and discovered tiny creatures swimming about.

But the microbiome has stubbornly resisted scientific discovery. For generations, microbiologists only studied the species that they could grow in the lab. Most of our interior occupants can’t survive in petri dishes.

In the early 2000s, however, the science of the microbiome took a sudden leap forward when researchers figured out how to sequence DNA from these microbes. Researchers initially used this new technology to examine how the microbiome influences parts of our bodies rife with bacteria, such as the gut and the skin.

Few of them gave much thought to the brain — there didn’t seem to be much point. The brain is shielded from microbial invasion by the so-called blood-brain barrier. Normally, only small molecules pass through.

“As recently as 2011, it was considered crazy to look for associations between the microbiome and behavior,” said Rob Knight, a microbiologist at the University of California, San Diego.

He and his colleagues discovered some of the earliest hints of these links. Investigators took stool from mice with a genetic mutation that caused them to eat a lot and put on weight. They transferred the stool to mice that had been raised germ-free — that is, entirely without gut microbiomes — since birth.

After receiving this so-called fecal transplant, the germ-free mice got hungry, too, and put on weight.

Altering appetite isn’t the only thing that the microbiome can do to the brain, it turns out. Dr. Cryan and his colleagues, for example, have found that mice without microbiomes become loners, preferring to stay away from fellow rodents.

The scientists eventually discovered changes in the brains of these antisocial mice. One region, called the amygdala, is important for processing social emotions. In germ-free mice, the neurons in the amygdala make unusual sets of proteins, changing the connections they make with other cells.

Studies of humans revealed some surprising patterns, too. Children with autism have unusual patterns of microbial species in their stool. Differences in the gut bacteria of people with a host of other brain-based conditions also have been reported.

But none of these associations proves cause and effect. Finding an unusual microbiome in people with Alzheimer’s doesn’t mean that the bacteria drive the disease. It could be the reverse: People with Alzheimer’s disease often change their eating habits, for example, and that switch might favor different species of gut microbes.

Fecal transplants can help pin down these links. In his research on Alzheimer’s, Dr. Sisodia and his colleagues transferred stool from ordinary mice into the mice they had treated with antibiotics. Once their microbiomes were restored, the antibiotic-treated mice started developing protein clumps again.

“We’re extremely confident that it’s the bacteria that’s driving this,” he said. Other researchers have taken these experiments a step further by using human fecal transplants.

If you hold a mouse by its tail, it normally wriggles in an effort to escape. If you give it a fecal transplant from humans with major depression, you get a completely different result: The mice give up sooner, simply hanging motionless.

As intriguing as this sort of research can be, it has a major limitation. Because researchers are transferring hundreds of bacterial species at once, the experiments can’t reveal which in particular are responsible for changing the brain.

Now researchers are pinpointing individual strains that seem to have an effect.

To study autism, Dr. Mauro Costa-Mattioli and his colleagues at the Baylor College of Medicine in Houston investigated different kinds of mice, each of which display some symptoms of autism. A mutation in a gene called SHANK3 can cause mice to groom themselves repetitively and avoid contact with other mice, for example.

In another mouse strain, Dr. Costa-Mattioli found that feeding mothers a high-fat diet makes it more likely their pups will behave this way.

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by IRIS KULBATSKI

Consuming a mixture of sugar syrup and glyphosate, the active ingredient in Monsanto’s Roundup herbicide, alters honey bees’ microbiomes, and these changes increased mortality among insects exposed to pathogenic bacteria, according to a study published yesterday (September 24) in PNAS.

Glyphosate is the most commonly used herbicide worldwide. It acts by blocking a key plant enzyme used in the production of amino acids. Researchers are divided on whether the chemical is safe to animals at the levels it is usually used as a herbicide. However, some bacteria are known to produce this enzyme, and the new study demonstrates what some researchers have suspected: glyphosate may harm animals indirectly by killing their resident microbes.

Nancy Moran of the University of Texas at Austin and colleagues found that glyphosate consumption can lower the levels of the common bee symbiont Snodgrassella alvi by up to five times in the guts of honey bees, and high levels of the herbicide thwarted growth of S. alvi in vitro. Moreover, bees were more susceptible to infection by Serratia marcescens, a bacterium commonly present at low levels in beehives, after drinking the glyphosate–sugar water cocktail: only 12 percent of the insects survived, compared with 47 percent of infected bees that had not been fed glyphosate.

Given these findings, more research is warranted to determine whether the proposed mechanism of honey bee morbidity contributes significantly to issues of colony collapse and overall rates of honey bee decline worldwide, University of Illinois bee geneticist Gene Robinson tells Science.

Moreover, the current study raises the possibility that glyphosate may alter the gut microbiome of other animals, including humans, Moran tells Science.

https://www.the-scientist.com/news-opinion/herbicide-may-harm-microbiome-of-bees-64860?utm_campaign=TS_DAILY%20NEWSLETTER_2018&utm_source=hs_email&utm_medium=email&utm_content=66214269&_hsenc=p2ANqtz–RVJMklVdDEAWS-ddB7O5kVzSQTWCLWqUOnn8jMfmpot3jBytURnj14l3Nx2fPlFTeNO-ZlmSqqln8Wjtd9SqOUpzqTQ&_hsmi=66214269