The original author 丨 Cassandra Willyard
Scientists set out to study how the gut microbiome affects brain health. This may lead to better, simpler treatments for brain diseases.
In 2006, shortly after neuroscientist Jane Foster set up her lab, she discovered something she thought would definitely boil the field. At the time, she and her team were studying two groups of mice: one with multiple healthy microbes in their guts, and the other with a lack of microbiota. They noticed that mice without gut bacteria didn't seem as anxious as healthy mice. When placed in a maze, some paths are open and some paths are surrounded by walls, preferring exposed paths. Bacteria in the gut seem to be influencing their brains and behaviors.
Foster, from McMaster University in Canada, wrote the study into a paper and submitted it for publication, but the result was rejected. She rewrote it and then voted, but was still rejected. "Everybody didn't believe it. They thought it was an illusion. She said. Finally, after three years and seven submissions, she finally received a letter of acceptance.
Illustration 丨Fabio Buonocore
John Cryan, a neuroscientist at The University Of Cork in Ireland, joined the field at about the same time as Foster and was fully aware of her feelings. Speaking about the connection between gut bacteria and the brain, "I feel fervently wanted to 'preach.' He said. He recalls attending an Alzheimer's disease conference in 2014. "I've never experienced a speech that was more coldly received than that."
Today, however, the gut-brain axis has become a feature of major neuroscience conferences, and Cryan says he is no longer "the lunatic from Ireland". Over the past decade, thousands of publications have shown that trillions of bacteria in the gut can have profound effects on the brain and may be linked to a range of diseases. Funding agencies such as the National Institutes of Health are investing millions of dollars to explore this link.
But with that surge of interest, there has also been hype. Maureen O'Malley, a philosopher at the University of Sydney in Australia who studies the field of microbiome research, said that while many studies have only shown correlation, some bowel researchers have claimed or implied a causal relationship, "Did you really find a cause, or did you just find an effect?" ”
Still, O'Malley said, the field has come a long way in recent years. Some research groups don't just discuss the microbiome as a whole, but instead begin to delve deeper, identifying specific microbes and mapping out complex, even surprising, pathways that connect microbes to the brain. "Doing so allows for causal attribution." She said. Mouse studies — and 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 for microbes to connect to the brain"). Therapies designed to adjust the microbiome may help prevent or treat these diseases, and some researchers and companies are already conducting human clinical trials to test this idea.
Source 丨Nik Spencer/Nature
Sarkis Mazmanian, a microbiologist at the California Institute of Technology, says it's still in its infancy, but new therapies for treating some of the most difficult brain diseases offer exciting prospects, especially given that it's much easier to manipulate the gut than the brain. Direct-to-brain therapies have been a challenge, he said, "but you can definitely change the microbiome." ”
Chaotic signal transmission
In 1817, The English surgeon James Parkinson described a number of cases of "tremor paralysis" that came to be known as Parkinson's disease. There is a person who has numbness and tingling sensations in his arms. Parkinson noticed that the man's abdomen appeared to contain "considerable build-up." He asked the man to take laxatives, and ten days later his intestines were empty and the symptoms disappeared.
Parkinson may have found the problem. Some people with this disease suffer from constipation long before the development of mobility impairments. Many researchers have accepted the idea that the disease originates in the gut, at least in some cases.
To understand this point of view, it is necessary to first understand the disease a little. The hallmark symptoms of Parkinson's disease — trembling, stiffness, and slow movement — appear as the neurons responsible for coordinating movement begin to die. The reason for the death of these neurons is still unclear, but α-synuclein appears to play a key role. In patients with Parkinson's disease, the protein is misfolded. The first misfolded protein causes more misfolding until harmful clumps called Lewy bodies begin to form in the brain.
What triggers this cascade reaction? In 2015, Robert Friedland, a neuroscientist at the University of Easyville in the United States, proposed a new theory. He read that gut bacteria can produce proteins with similar structures to misfolded α-synucleins, so he hypothesized that bacterial proteins might provide templates for misfolding[2]. He and his colleagues fed mice a special strain of E. coli that produces a clumps of protein called curli in the gut; they found that α-synuclein accumulation increased in the mice's brains [3]. Mazmanian and his team published last year in support of Friedland's theory.
It's unclear how signals in the gut reach the brain, but one possible channel is the vagus nerve. The vagus nerve, which connects the brainstem to many organs, including the colon, is the longest of the twelve cranial nerves that transmit signals between the brain and other parts of the body. "It's really a highway." Cryan said. Studies based on humans and animals have shown that the vagus nerve plays a vital role in transmitting at least some information between the gut and the brain.
In the 1970s, a common treatment for stomach ulcers was the removal of all or part of the nerves to suppress the production of stomach acid. But in recent decades, researchers have noticed a strange side effect: People who have undergone this procedure seem to be less susceptible to Parkinson's disease [5].
In one mouse study, after injecting the misfolded α-synuclein into the intestines of mice, it reappeared in the brain. However, if the researchers first removed the vagus nerve, no α-synuclein appeared in the brain [6]. The injected α-synuclein itself appears to remain in the gut, but Valina Dawson, a neuroscientist at Johns Hopkins University and co-author of the study, believes there may be a domino effect: Misfolded proteins transmit errors to the vagus nerve until the proteins in the brain eventually misfold. Mazmanian and colleagues are currently conducting experiments to see if curli protein in the gut still causes Parkinson's disease symptoms in mice whose vagus nerve has been removed.
Because misfolded proteins are markers 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 linked to these diseases. Dawson thinks the idea makes sense, but says bacterial amyloid isn't the only factor to consider. For example, Parkinson's disease is a complex disease that manifests itself differently in different people. Still, she said, "it could be the way to start the first step." ”
Accelerate deterioration
Proponents of gut-brain connectivity say the microbiome can do more than trigger some neurodegenerative diseases: it may also affect its severity. Eran Elinav, an immunologist at the Weizmann Institute of Science in Israel and the German Cancer Research Center in Heidelberg, was struck by the difference in the progression of ALS: some als patients progressed slowly, while others deteriorated rapidly. Elinav wondered if the microbiome could help explain these differences, so he and his team set out to use one of the most common als mouse models. When they used antibiotics to eliminate the microbiota, or mice that were born without a microbiota, they found that als progressed much faster than mice with a normal microbiota [7].
The team compared gut bacteria from ALS mice and their co-nest healthy mice and found several microbial species that appeared to be linked to the disease. Painstakingly transplanting these species one by one into another group of mice without any gut bacteria, they identified two microbial species that worsened ALS symptoms, and another that appeared to make symptoms better. "Then we asked ourselves, 'How could this strain, which lives only in the gut, magically affect a brain-focused disease?' Elinav said.
Segmented filamentous bacteria (green) in the intestines overstimulate the immune systems of infected pregnant mice, altering brain development in intra-abdominal mice. 丨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 run throughout the body. Elinav said at least half of the small molecules in the blood are "made or regulated by microbes." He and his team analyzed metabolites produced by beneficial microbes and injected mice prone to ALS with a molecule called niacinamide, also known as vitamin B3. They found that niacinamide entered the brain and improved symptoms in mice [7]. "We can prove that there is a bacterium, we can prove that there is a product of this bacterium, we can prove that it 'swims' to the right target organ and does something that is good for the course of the disease." He said.
They compared the microbiota of ALS patients and their unaffected family members and found that ALS patients had less niacinamide in their bodies [7]. The metabolite could be used as a supplement, said Elinav, who and his colleagues are planning a clinical trial for it.
At least one group has tested vitamin B3 as a treatment for ALS in a small trial, though other compounds have also been used in combination. Over the course of four months, they injected als subjects with vitamin B3. There was improvement in the treatment group, but almost all of the people in the placebo group experienced a decrease in health [8].
"This is just the beginning." Elinav said. There are many more bacteria and metabolites present, and every cell in the body is affected by them. Once you realize this, he says, "you begin to understand that the effects of the microbiome can be greatly extended beyond where they actually live." ”
Intergenerational effects
This influence may even be passed on from generation to generation. In the case of autism spectrum disorder (ASD), the cause of the disease is unknown, but according to epidemiological studies, infections of mothers during pregnancy appear to increase the risk of asD in children. For example, in a Cohort of nearly 1.8 million people in Sweden, mothers who had been hospitalized for infection during pregnancy were at a 79 percent higher risk of being diagnosed with ASD after birth [9].
Mouse studies also support this link. To mimic the infection, the researchers injected pregnant mice with double-stranded RNA, which the mice's bodies treated as viral invasions. The offspring of the former mouse exhibited more repetitive behaviors, anxiety, and less interaction with other mice than those of the uninjected mice—symptoms that mirrored symptoms in patients with ASD [10].
Gloria Choi, a neuroscientist at MIT's Pickall Institute for Learning and Memory, and her husband and collaborator, Jun Huh, an immunologist at Harvard Medical School in Boston, wanted to know why. The cells they focus on fight off bacteria and fungi by producing a molecule called a cytokine. Choi and Huh used mice to simulate infection and found that helper T cells 17 (Th17) became overactive, producing a cytokine called IL-17. The molecule enters the brains of developing mice — possibly through the placenta — and then binds to brain receptors. This appears to have had a profound effect on the mice: the researchers found that the neural activity of the adult offspring increased, causing them to develop autism-like behavior [11].
But "not every pregnant woman who gets infected or hospitalized during pregnancy necessarily gives birth to a child with neurodevelopmental disorders or autism." Huh said. There must be something that causes the mother's immune system to turn into this overactive state. Choi and Huh focused on a thin, thin gut microbe, segmented filamentous bacteria, which had previously been shown to promote the formation of Th17 cells. They used antibiotics on pregnant mice to kill the bacteria and then stimulated an immune response, finding no behavioral differences in the pups [12].
Eager to understand whether the coronavirus pandemic has led to an increased risk of developing autism, Choi and Huh are collecting samples from pregnant women infected with SARS-CoV-2 and cataloging IL-17 levels in bacteria in their guts and blood. David Amaral, who studies autism at the University of California, Davis, said that given that the new coronavirus, like any other infection, activates the mother's immune system, SARS-CoV-2 may increase the risk of altered brain development and underlying psychiatric diseases. Researchers have yet to find evidence to support this theory.
Mauro Costa-Mattioli, a neurobiologist at Baylor College of Medicine in Houston, is also studying the relationship between bacteria and autism. However, instead of finding the microbes that cause the disease, he found one that might improve its symptoms.
A small trial tested the gut bacterium Lactobacillus reuteri as a treatment for symptoms of autism spectrum disorder. 丨 Stephanie Schuller/Alistair Walsham/SPL
About five years ago, Costa-Mattioli stumbled upon the bacterium. At the time, he was studying offspring mice with autism-like symptoms. When these mice and typical developmental mice were placed together (and, as all mice would do, eat the excrement of the latter), their autism-like behavior disappeared. Costa-Mattioli and his colleagues found that the affected mice lacked a special bacterium: Lactobacillus reuteri.
They tested Lactobacillus reuteri in several other model mice, a bacterium capable of reversing certain autism-like behaviors in each model mouse. And, as in the Case of Parkinson's disease studies, this effect could be blocked in mice if the researchers cut off the vagus nerve [13].
Exactly what type of signal Lactobacillus reuteri sends is unknown. The team found that some strains of Lactobacillus reuteri can reverse autism-like behavior, while others cannot, and researchers are now working to identify which genes are involved. Costa-Mattioli says that if they can find the gene that produces the key metabolite, "we can put it in any bacteria, and then we may have a potential cure." "This strategy has not been validated.
A team in Italy is already experimenting with 80 children with autism using Lactobacillus reuteri. Participants will ingest Lactobacillus reuteri or placebo tablets for 6 months and be monitored for symptoms. Costa-Mattioli hopes to start his own experiment soon.
Whether it works remains to be seen, but Kevin Mitchell, a neurogeneticist at Trinity College Dublin, thinks the mouse study isn't convincing yet. Given the complexity of such diseases, he said, he thought it would be premature and "a bit irresponsible" to discuss the potential of treatment.
Meanwhile, researchers are exploring more brain diseases, including Alzheimer's disease and depression. Gut microbes may even affect how the brain recovers after an injury. Corinne Benakis, a neurobiologist at the Institute of Stroke and Dementia at the Ludwig Maximilian University in Munich, Germany, and colleagues treated mice with antibiotics to eliminate some gut bacteria before inducing a stroke. They found that antibiotics can reduce the severity of brain injury [14].
In each of these diseases, there are still many mechanical problems. Researchers in the field acknowledge that they have not yet fully described the pathways from microbes to the brain. The trickiest step will be to validate these animal findings in humans and move on to the experimental phase. "These are extraordinary views that require special evidence." Mitchell said.
But people are very interested – not just academics. In February 2019, Axial Therapeutics, in Waltham, Massachusetts, raised $25 million in funding; the company was co-founded by Mazmanian to develop neurodegenerative diseases and neuropsychiatric therapies. Another company, Somerville, Massachusetts-based Fitch Therapeutics, is developing an oral microbial drug for autism; the company announced in September 2020 that it had raised $90 million.
After Cryan's speech on the subject went cold, he watched the data accumulate. He found the growing evidence compelling and saw great promise for microbiome-based therapies. "It's not like your genome, and there's not much to do except blame your parents and grandparents. But your microbiome has the potential to change. This gives the patient a lot of agency," he says, "and it's really exciting." ”
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The original article was published under the headline How gut microbes could drive brain disorders in a news feature section of Nature on February 3, 2021
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