How do gut microbes affect the brain?

By Cassandra Willyard Scientists set out to study how the gut microbiome affects brain health
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This could lead to better, simpler treatments for brain diseases
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In 2006, shortly after starting her lab, neuroscientist Jane Foster discovered something she thought would surely set the field on fire
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At the time, she and her team were studying two groups of mice: one that had a variety of healthy microbes in their guts, and the other that lacked the microbiome
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They noticed that mice without gut bacteria didn't appear to be as anxious as healthy mice
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When placed in a maze, some paths are open and some are walled, preferring the exposed path
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The bacteria in the gut seem to be influencing their brains and behavior
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Foster from McMaster University in Canada wrote the research into a paper and submitted it for publication, but it was rejected
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She rewritten and then voted, but she was still rejected
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"Everyone didn't believe it
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They thought it was an illusion
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" she said
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Finally, after three years and seven submissions, she finally got a letter of acceptance[1]
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Illustration: Fabio Buonocore John Cryan, a neuroscientist at the University of Cork in Ireland, joined the field at about the same time as Foster and knew exactly how she was feeling
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When it comes to the link between gut bacteria and the brain, "I feel a fervent urge to 'preach,' " he says
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He recalled attending an Alzheimer's conference in 2014 .
"I've never had a more under-appreciated presentation than that .
" Now, however, that the gut-brain axis is a feature of major neuroscience conferences, and Cryan says he's no longer "that lunatic from Ireland .
" Over the past decade, thousands of publications have shown that the trillions of bacteria in the gut may have profound effects on the brain and may be associated with a range of diseases .
Funding agencies such as the National Institutes of Health are investing millions to explore this connection .
But as that interest has surged, so too has the hype .
While many studies only show correlation, some gut-brain researchers claim or suggest causation, says Maureen O'Malley, a philosopher who studies the microbiome at the University of Sydney in Australia.
Or just discovered another effect?" Still, O'Malley says, the field has come a long way in recent years .
Rather than discussing the microbiome as a whole, some research groups are beginning to dig deeper, identifying specific microbes and mapping out complex and even surprising pathways that connect them to the brain .
"That's what allows causal attribution , " she said .
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Mouse studies—as well as preliminary human-based studies—suggest that microbes can trigger or alter the course of diseases such as Parkinson's disease and autism spectrum disorder (see "Possible pathways that microbes connect to the brain")
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Therapies aimed at modifying the microbiome may help prevent or treat these diseases, and some researchers and companies are already conducting human clinical trials to test this idea
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Source: Nik Spencer/Nature Caltech microbiologist Sarkis Mazmanian says it's early days, but new treatments for some difficult-to-treat brain diseases show exciting promise, especially given the manipulation of The gut is much easier to manipulate than the brain
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Therapy directed at the brain has always been a challenge, he said, "but you can certainly change the microbiome
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" Chaos signaling In 1817, British surgeon James Parkinson described what came to be known as Parkinson's A case of "shivering palsy" in Kinson's disease
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One person experienced numbness and tingling in both arms
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Parkinson noted that the man appeared to contain a "considerable accumulation" in his abdomen
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He put the man on laxatives, and after ten days his bowels emptied and his symptoms went away
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Parkinson's may have spotted the problem
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Some people with this condition suffer from constipation long before they have mobility problems
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Many researchers have embraced the idea that the disease originated in the gut, at least in some cases
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To understand this point of view, it is necessary to first understand a little about the disease
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The hallmark symptoms of Parkinson's disease -- tremors, stiffness and slow movement -- appear as the neurons responsible for coordinating movement begin to die
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Why these neurons die is unclear, but alpha-synuclein appears to play a key role
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In Parkinson's disease patients, the protein is misfolded
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The first misfolded protein leads to more misfolding until harmful clumps called Lewy bodies begin to form in the brain
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What triggers this cascade? In 2015, neuroscientist Robert Friedland of the University of Lewisville proposed a new theory
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He read that gut bacteria can produce proteins that are structurally similar to misfolded alpha-synuclein, so he hypothesized that bacterial proteins might provide templates for misfolding [2]
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He and his colleagues fed mice a special strain of E.
coli that produces a clump of protein called "curli" in the gut; they found that the alpha-synucleus in the mouse brain increased protein accumulation [3]
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Results published last year by Mazmanian and his team support Friedland's theory [4]
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It's unclear how signals in the gut reach the brain, but one possible pathway is the vagus nerve
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The vagus nerve connects the brainstem to many organs, including the colon, and is the longest of the twelve cranial nerves that transmit signals between the brain and the rest of the body
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"It's really a highway
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" Cryan said
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Human and animal-based studies have shown that the vagus nerve plays a crucial role in at least transmitting some messages between the gut and the brain
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In the 1970s, a common treatment for stomach ulcers was to remove all or part of the nerve to suppress the production of stomach acid
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But in recent decades, researchers have noticed a strange side effect: People who have undergone the procedure seem to be less susceptible to Parkinson's disease [5]
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In a mouse study, misfolded alpha-synuclein reappeared in the brain after it was injected into the mouse gut
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However, if the researchers removed the vagus nerve first, no alpha-synuclein was present in the brain [6]
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The injected alpha-synuclein itself appears to remain in the gut, but Johns Hopkins neuroscientist and study co-author Valina Dawson believes there may be a domino effect: Misfolded proteins pass errors to The vagus nerve, until the protein in the brain eventually misfolds
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Mazmanian and colleagues are now conducting experiments to see if the curli protein in the gut can still cause Parkinson's symptoms in mice whose vagus nerves have been removed
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Because misfolded proteins are a hallmark of several other diseases that affect the brain, including Alzheimer's disease and motor neuron disease (amyotrophic lateral sclerosis, or ALS), Friedland said bacterial proteins may also be involved in these diseases
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Dawson thinks the idea makes sense, but says bacterial amyloid isn't the only factor to consider
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For example, Parkinson's disease is a complex disease that manifests differently in different people
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Still, she said, "This could be the way to start the first step
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Proponents of accelerated deterioration of the gut-brain connection say the microbiome can do more than trigger some neurodegenerative disease: it may also affect its severity
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Eran Elinav is director of the Weizmann Institute of Science in Israel and the German Cancer Research Institute in Heidelberg.
An immunologist at the center, he was struck by the disparities in the progression of ALS: some ALS patients progress slowly, while others deteriorate rapidly
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Elinav wondered if the microbiome could help explain these differences, so he and his team started using the most A common mouse model of ALS
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When they used antibiotics to eliminate the microbiota, or mice born with a lack of microbiota, they found that ALS progressed much faster in these mice than in mice with normal microbiomes [7] ]
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The team compared the gut bacteria of ALS mice and their healthy littermates and found several microbial species that appeared to be involved in the disease
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They painstakingly transplanted these species one by one into another group without any gut In mice with gut bacteria, two microbial species were identified that made ALS symptoms worse, and another that seemed to make them better
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"Then we asked ourselves, 'How could this strain that lives only in the gut? Magically affecting a disease that focuses on the brain? '" says Elinav
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Segmented
filamentous bacteria (green) in the gut overstimulate the immune system of pregnant mice with infection, altering brain development in intra-abdominal mice
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Source: Dan Littman, Alice Liang, Doug Wei, and Eric Roth The culprit may be bacterial metabolites -- small molecules produced by bacteria that can enter the bloodstream and travel throughout the body
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At least half of the small molecules in the blood are "made or regulated by microbes," Elinav said
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He and his team analyzed metabolites produced by beneficial microbes and injected mice prone to ALS with a molecule called nicotinamide, also known as vitamin B3
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They found that nicotinamide entered the brain and improved symptoms in mice [7]
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"We can show that there is a bacterium, we can show that there is a product of that bacterium, and we can show that it 'swims' to the right target organ and does something that's good for the course of the disease, " he said
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They compared the microbiota of ALS patients and their unaffected family members and found that ALS patients had less nicotinamide [7] .
The metabolite can be used as a supplement, says Elinav, of which he and his colleagues are planning a clinical trial .
At least one group has tested vitamin B3 as a treatment for ALS in a small trial, although other compounds have also been used in combination .
They injected ALS subjects with vitamin B3 over a four-month period .
Those in the treatment group improved, but nearly everyone in the placebo group experienced a decline in health [8] .
"This is just the beginning , " Elinav said .
There are many more bacteria and metabolites out there, and every cell in the body is affected by them .
Once you realize this, he says, "you start to understand that the effects of microbiota can extend significantly beyond where they actually live .
" Intergenerational effects The effects may even be passed down from one generation to the next .
In the case of autism spectrum disorder (ASD), the cause of the disorder is unknown, but according to epidemiological studies, a mother's infection during pregnancy appears to increase the risk of ASD in her child
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For example, in a Swedish cohort of nearly 1.
8 million people, mothers who had been hospitalized for an infection during pregnancy had a 79% higher risk of being diagnosed with ASD after birth [9]
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Mouse studies also support this link
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To mimic the infection, the researchers injected pregnant mice with double-stranded RNA, which the mouse's body viewed as a viral invasion
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The offspring of the former mice exhibited more repetitive behaviors and anxiety, and less interaction with other mice—symptoms that mirror those of ASD patients compared to the offspring of those uninjected mice [10] ]
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Gloria Choi, a neuroscientist at MIT's Picault Institute for Learning and Memory, and her husband and collaborator Jun Huh, an immunologist at Harvard Medical School in Boston, wondered why
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The cells they focused on defend against bacteria and fungi by producing molecules called cytokines
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Using mock infections in mice, Choi and Huh found that T helper 17 (Th17) cells became hyperactive, producing a cytokine called IL-17
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The molecule entered the brains of developing mice—probably through the placenta—and then bound to receptors in the brain
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This appears to have profound effects in mice: the researchers found that the adult offspring had increased neural activity, causing them to exhibit autism-like behaviors [11]
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However, "not every pregnant woman who is infected or hospitalized during pregnancy will necessarily have a child with a neurodevelopmental disorder or autism, " Huh said
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Something must have turned the mother's immune system into this hyperactive state
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Choi and Huh focused on a group of long, thin gut microbes, segmented filamentous bacteria, that were previously shown to promote the formation of Th17 cells
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They administered antibiotics to pregnant mice to kill these bacteria and then stimulated an immune response and found no behavioral differences in the pups [12]
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Choi and Huh, eager to learn whether the coronavirus pandemic could lead to an increased risk of autism, are collecting samples from pregnant women infected with SARS-CoV-2 and cataloging their gut bacteria and IL-17 levels in their blood
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Given that SARS-CoV-2, like any other infection, activates the mother's immune system, SARS-CoV-2 may increase altered brain development and underlying psychiatric disorders, said David Amaral, who studies autism at the University of California, Davis.
risk
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Researchers have yet to find evidence to support this theory
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Mauro Costa-Mattioli, a neurobiologist at Baylor College of Medicine in Houston, is also studying the link between bacteria and autism
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However, instead of the microbe that caused the disease, he found one that might improve its symptoms
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A small trial tested the gut bacterium Lactobacillus reuteri as a treatment for symptoms of autism spectrum disorder
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Credit: Stephanie Schuller/Alistair Walsham/SPL Costa-Mattioli stumbled across this bacterium about five years ago
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At the time, he was studying mice whose offspring had autism-like symptoms
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When these mice were housed with typically developing mice (and, as all mice do, eating the latter's excrement), their autism-like behavior disappeared
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Costa-Mattioli and his colleagues found that the affected mice lacked a specific bacterium: Lactobacillus reuteri
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They tested Lactobacillus reuteri, a bacterium that reversed some of the autism-like behaviors in each model mouse, in several other model mice
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And, as in the Parkinson's disease study, if researchers cut the vagus nerve [13], they could block this effect in mice
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Exactly what type of signal Lactobacillus reuteri sends is unknown
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The team found that some strains of Lactobacillus reuteri could reverse autism-like behaviors, while others could not, and the researchers are now working to identify which genes are involved
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If they can find the gene that produces the key metabolite, Costa-Mattioli said, "we could put it in any bacterium and we might have a potential treatment
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" This strategy has yet to be tested
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A team in Italy is already trying to treat 80 children with autism with Lactobacillus reuteri
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Participants will ingest Lactobacillus reuteri or placebo tablets for 6 months and be monitored for symptoms
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Costa-Mattioli hopes to launch his own trials soon
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Whether it works remains to be seen, but neurogeneticist Kevin Mitchell of Trinity College Dublin thinks the mouse studies are not yet convincing
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Given the complexity of this type of disease, he said, he thinks discussions of therapeutic potential are premature and "a bit irresponsible
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"
At the same time, researchers are exploring more brain diseases, including Alzheimer's disease and depression
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Gut microbes may even influence how the brain recovers after injury
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Neurobiologist Corinne Benakis of the Institute for Stroke and Dementia at Ludwig-Maximilians University in Munich, Germany, and colleagues treated mice with antibiotics to eliminate some gut bacteria before inducing a stroke
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They found that antibiotics can reduce the severity of brain damage [14]
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In each of these diseases, many mechanistic questions remain
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Researchers in the field acknowledge that they have not yet adequately characterized the pathways from the microbes to the brain
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The trickiest step will be validating these animal findings in humans and moving into trials
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"These are unusual point of view, require special evidence
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"
Mitchell said
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But people are very interested - not just in academia
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In February 2019, Axial Therapeutics, a Waltham, Massachusetts-based company co-founded by Mazmanian to develop treatments for neurodegenerative diseases and neuropsychiatry, raised $25 million in funding
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Another company, Somerville, Massachusetts-based Finch Therapeutics, is developing an oral microbial drug for autism; the company announced in September 2020 that it had raised $90 million
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After Cryan's speech on the subject went cold, he watched the data pile up
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He finds the growing body of evidence compelling and sees great promise for microbiome-based therapies
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"It's not like your genome, there's nothing you can do but blame your parents and grandparents
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But it's possible for your microbiome to change
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This gives the patient a great deal of agency," he said.
"It's really exciting.

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516–523 (2016).
The original title How gut microbes could drive brain disorders was published in the news features section of Nature on February 3, 2021 © naturedoi: 10.
1038/d41586-021-00260-3 Click to read the original text Click on the text or picture to read the related article.
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What does poop from ancient humans tell us about gut microbes? Copyright notice: This article is translated by Springer Nature Shanghai Office
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The Chinese content is for reference only, and the original English version shall prevail
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