Research
Gut bacteria affect brain health, new study shows
A new study suggests that the gut microbiome plays a key role in the health of our brains and points to a new approach to treating Alzheimer’s and other neurodegenerative diseases.
A growing amount of evidence indicates that the tens of trillions of microbes that normally live in our intestines — the so-called gut microbiome — have far-reaching effects on how our bodies function.
Members of this microbial community produce vitamins, help us digest food, prevent the overgrowth of harmful bacteria and regulate the immune system, among other benefits. Now, a new study suggests that the gut microbiome also plays a key role in the health of our brains, according to researchers from Washington University School of Medicine in St. Louis.
The study, in mice, found that gut bacteria — partly by producing compounds such as short chain fatty acids — affect the behaviour of immune cells throughout the body, including ones in the brain that can damage brain tissue and exacerbate neurodegeneration in conditions such as Alzheimer’s disease.
The findings, published in the journal Science, open up the possibility of reshaping the gut microbiome as a way to prevent or treat neurodegeneration.
Senior author David M. Holtzman, MD, the Barbara Burton and Reuben M Morriss III Distinguished Professor of Neurology, explained: “We gave young mice antibiotics for just a week, and we saw a permanent change in their gut microbiomes, their immune responses, and how much neurodegeneration related to a protein called tau they experienced with age.
“What’s exciting is that manipulating the gut microbiome could be a way to have an effect on the brain without putting anything directly into the brain.”
Evidence is accumulating that the gut microbiomes in people with Alzheimer’s disease can differ from those of healthy people. But it isn’t clear whether these differences are the cause or the result of the disease — or both — and what effect altering the microbiome might have on the course of the disease.
To determine whether the gut microbiome may be playing a causal role, the researchers altered the gut microbiomes of mice predisposed to develop Alzheimer’s-like brain damage and cognitive impairment.
The mice were genetically modified to express a mutant form of the human brain protein tau, which builds up and causes damage to neurons and atrophy of their brains by 9 months of age. They also carried a variant of the human APOE gene, a major genetic risk factor for Alzheimer’s. People with one copy of the APOE4 variant are three to four times more likely to develop the disease than people with the more common APOE3variant.
Along with Holtzman, the research team included gut microbiome expert and co-author Jeffrey I Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and director of the Edison Family Center for Genome Sciences & Systems Biology; first author Dong-Oh Seo, PhD, an instructor in neurology; and co-author Sangram S. Sisodia, PhD, a professor of neurobiology at the University of Chicago.
When such genetically modified mice were raised under sterile conditions from birth, they did not acquire gut microbiomes, and their brains showed much less damage at 40 weeks of age than the brains of mice harbouring normal mouse microbiomes.
When such mice were raised under normal, non-sterile conditions, they developed normal microbiomes. A course of antibiotics at two weeks of age, however, permanently changed the composition of bacteria in their microbiomes. For male mice, it also reduced the amount of brain damage evident at 40 weeks of age.
The protective effects of the microbiome shifts were more pronounced in male mice carrying the APOE3 variant than in those with the high-risk APOE4variant, possibly because the deleterious effects of APOE4canceled out some of the protection, the researchers said. Antibiotic treatment had no significant effect on neurodegeneration in female mice.
“We already know, from studies of brain tumours, normal brain development and related topics, that immune cells in male and female brains respond very differently to stimuli,” Holtzman said.
“So it’s not terribly surprising that when we manipulated the microbiome we saw a sex difference in response, although it is hard to say what exactly this means for men and women living with Alzheimer’s disease and related disorders.”
Further experiments linked three specific short-chain fatty acids — compounds produced by certain types of gut bacteria as products of their metabolism — to neurodegeneration. All three of these fatty acids were scarce in mice with gut microbiomes altered by antibiotic treatment, and undetectable in mice without gut microbiomes.
These short-chain fatty acids appeared to trigger neurodegeneration by activating immune cells in the bloodstream, which in turn somehow activated immune cells in the brain to damage brain tissue. When middle-aged mice without microbiomes were fed the three short-chain fatty acids, their brain immune cells became more reactive, and their brains showed more signs of tau-linked damage.
“This study may offer important insights into how the microbiome influences tau-mediated neurodegeneration, and suggests therapies that alter gut microbes may affect the onset or progression of neurodegenerative disorders,” said Linda McGavern, PhD, programme director at the National Institute of Neurological Disorders and Stroke (NINDS), which provided some of the funding for the study.
The findings suggest a new approach to preventing and treating neurodegenerative diseases by modifying the gut microbiome with antibiotics, probiotics, specialised diets or other means.
Holtzman asked: “What I want to know is, if you took mice genetically destined to develop neurodegenerative disease, and you manipulated the microbiome just before the animals start showing signs of damage, could you slow or prevent neurodegeneration?
“That would be the equivalent of starting treatment in a person in late middle age who is still cognitively normal but on the verge of developing impairments. If we could start a treatment in these types of genetically sensitised adult animal models before neurodegeneration first becomes apparent, and show that it worked, that could be the kind of thing we could test in people.”
NICE will review whether new Alzheimer’s drugs should be offered on the NHS after an appeal found their wider impact was not fully counted.
An appeal found that the National Institute for Health and Care Excellence had failed to properly account for the wider impact of the treatments, including the heavy burden on unpaid carers, when calculating the cost effectiveness of the medicines.
Both treatments, lecanemab and donanemab, will now return to a NICE committee for further consideration.
“Today’s ruling is an opportunity for NICE to consider the real cost of Alzheimer’s on people and their families, and we welcome the decision to look again at whether new medicines could be provided on the NHS,” said David Thomas, head of policy and public affairs at Alzheimer’s Research UK.
Lecanemab and donanemab do not cure Alzheimer’s, but they slow it by targeting and clearing clumps of amyloid proteins, sticky protein build-ups in the brain linked to the disease.
While the drugs are available privately in the UK for people who can afford them, NICE ruled last year that they were too expensive to be made available on the NHS in England and Wales.
It is estimated informal dementia care costs the economy more than £20bn a year.
Alzheimer’s Research UK wants NICE to update how it assesses the value of new dementia drugs and factor in the huge additional costs this condition places on society and the wider economy.
NICE and its expert committees assess whether new drugs are good value for money for the NHS based on a wide range of evidence.
This includes how treatments perform in clinical trials, the experiences of patients and carers, and the costs of new drugs as well as any changes to NHS services needed to provide access.
When NICE weighs up whether a new Alzheimer’s drug is cost effective for the NHS, it carries out a limited assessment of the impact dementia has on the health of carers.
But the condition takes an enormous toll on families and society because caring for someone with dementia can lead people to become more isolated and give up work.
It can have a major emotional impact and put families under financial strain.
Thomas said: “Research has delivered new treatments with the potential to provide people with valuable extra months of independence, lessening the burden on carers.
“While these treatments offer modest benefits and can cause serious side effects, they provide the foundation for a future where dementia becomes a treatable condition.
“Now we need NICE to look again at how these medicines could benefit both people with early Alzheimer’s and their carers.”
Chris, whose mother Shirley is living with Alzheimer’s disease, said: “The real cost of Alzheimer’s is far greater than many people realise.
“In order to give my mum the care she needed, I moved back home to help my dad as the care was too much for him alone. After my dad passed away from Covid in 2021, I became sole carer for my mum.
“It was a very difficult period, working a full-time job, caring for Mum and dealing with the loss of my dad. Eventually I got some in-home care support to help.
“The family has borne most of the cost of Mum’s care, both in time and fees, and the family home has been sold to finance it.”
“The emotional and financial strain Alzheimer’s has taken on our family is horrendous, and I know many families across the UK are experiencing this pressure.”
He is backing Alzheimer’s Research UK’s call for NICE to change how it evaluates new dementia treatments.
The timeframe for the next NICE meetings to discuss the drugs is still to be set, and it is not certain follow-up hearings would change NICE’s guidance on access to the medicines.
But Alzheimer’s Research UK is continuing to push to make sure dementia is now a main priority for political and NHS decision-makers.
The head of the ongoing independent review into adult social care, Baroness Louise Casey, has called on the government to act, show leadership and prioritise dementia.
She has proposed appointing a dementia tsar to drive forward the prevention, treatment and care of dementia.
Baroness Casey has also argued for more funding for dementia treatment trials.
With more than 130 Alzheimer’s drugs in clinical trials worldwide, the charity says it is vital the NHS runs trials of new treatments now to understand how to deliver them to eligible patients in future.
In addition to changing how NICE assesses new medicines, the health service needs to collect real-world evidence on new dementia drugs and prepare for diagnostic tests and innovative treatments that are coming.
“Alzheimer’s Research UK is calling on the government to give dementia the same political determination that transformed cancer care,” Thomas said.
“We urgently need investment and a clear UK-wide plan so new treatments can be assessed in the NHS and reach the people who stand to benefit.”
Health and social care secretary Wes Streeting has said dementia is “one of the greatest challenges of our time” and pledged that the UK should become a world leader in dementia clinical trials.
Osteoporosis drugs may lower dementia risk, with a study suggesting one widely used treatment could help prevent Alzheimer’s and related dementias.
The research found that nitrogen-containing bisphosphonates, drugs widely used to treat osteoporosis, may significantly reduce the risk of Alzheimer’s disease and related dementias in older adults with osteoporosis or fragility fractures.
Osteoporosis and dementia often coexist in older adults and share several risk factors, including advanced age, female sex and reduced physical activity.
Researchers at the University of Hong Kong’s department of pharmacology and pharmacy carried out a large study using the city’s electronic medical records, covering more than 120,000 patients aged 60 and above with osteoporosis or fragility fractures between 2005 and 2020.
The team found that NBP users had a 16 per cent lower risk of developing Alzheimer’s disease and related dementias than untreated patients, and a 24 per cent lower risk than those who received other osteoporosis medicines.
The association was especially marked in women and patients with hip fractures.
The researchers estimated that treating 48 patients with NBPs for five years could potentially prevent one case of dementia, underlining the possible public health value of NBPs in high-risk groups.
Professor Cheung Ching-lung, associate professor in the department of pharmacology and pharmacy at the University of Hong Kong, said: “Our study provides evidence that NBPs may offer dual benefits in strengthening bones and reducing fracture risk, as well as potentially preventing ADRD.
“Their potential neuroprotective role provides an empirical basis and supports future research on the actual effectiveness of this medication in preventing or delaying cognitive decline associated with ADRD.
“These findings are significant as they demonstrate a potential approach for reducing dementia risk in a vulnerable population using safe and widely available NBPs.
“In our rapidly ageing society, these findings suggest that while waiting for the novel therapies, existing medications can also provide additional protection for high-risk populations.”
The same research team has previously found that osteoporosis and fractures are independent risk factors for dementia, and that patients with dementia are at higher risk of falls and fractures.
This suggests treating osteoporosis may also help reduce the burden of dementia.
NBPs, including alendronate and zoledronate, are well established and commonly prescribed osteoporosis drugs.
Emerging biological research suggests the pathways affected by NBPs may also play a role in the development of Alzheimer’s disease and related dementias, raising the possibility that they could be repurposed for prevention.
A prebiotic fibre supplement may ease arthritis pain and improve grip strength in people with knee osteoarthritis, a study suggests.
The daily supplement, made from inulin, a dietary fibre found in chicory root, Jerusalem artichokes and other vegetables, also lowered pain sensitivity and saw fewer people drop out than a digital physiotherapy programme tested alongside it.
Dr Afroditi Kouraki, lead author of the study from the University of Nottingham, said: ‘Our findings suggest that targeting gut health with a prebiotic supplement is a safe, well-tolerated, and effective way to reduce pain in people with knee osteoarthritis.
“The very low dropout rate compared to the exercise group is also encouraging from a public health perspective, people were able to fit this supplement easily into their daily lives.’
Osteoarthritis of the knee, a wear-and-tear joint condition, affects hundreds of millions of people worldwide and is a leading cause of pain and disability, particularly in older adults.
Current treatments rely heavily on pain medication, which can cause side effects, or exercise programmes, which many patients find hard to maintain.
The INSPIRE trial, led by researchers at the University of Nottingham, involved 117 adults with knee osteoarthritis and tested four groups: inulin alone, digital physiotherapy-supported exercise alone, a combination of both, and a placebo. Both inulin and physiotherapy independently reduced knee pain.
However, inulin alone improved grip strength and reduced pain sensitivity, measures linked to how the nervous system processes pain, while physiotherapy did not.
The dropout rate for those taking the supplement was just 3.6 per cent, compared with 21 per cent for the physiotherapy group, suggesting a daily supplement may be easier for people to stick with than an exercise programme.
Inulin works as a prebiotic, meaning it feeds beneficial bacteria in the gut.
This leads to the production of compounds called short-chain fatty acids, particularly butyrate, which can affect inflammation and pain pathways throughout the body.
Participants taking inulin also showed increased levels of both butyrate and GLP-1, a gut hormone linked to pain regulation and muscle health.
Higher GLP-1 levels were associated with improved grip strength, pointing to a possible gut-muscle connection.
Senior author Professor Ana Valdes added: ‘The link we observed between GLP-1 and grip strength is particularly intriguing and points to a broader gut-muscle-pain axis that warrants further investigation. This could have implications not just for osteoarthritis, but for understanding how gut health influences ageing and physical resilience more broadly.’
Professor Lucy Donaldson, director of research at Arthritis UK, said: “The pain of arthritis can severely impact quality of life. Our recent lived experience survey showed that six in ten people are living in pain most or all of the time due to their arthritis.
“Researchers are starting to explore the role of the gut microbiome in our experience of pain.
“This exciting preliminary research highlights how diet and physiotherapy can act in different ways to have benefits for people with arthritis.
“We know a variety and balance of healthy foods, including fibre, and regular physical activity matter, and we’re glad to be supporting research that explores how they work to help people with arthritis.”
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