Scientists and health experts are exploring different ways to work out how bacteria in the gut can affect brain health and cause brain disorders. These studies will help devise better and targeted treatments for brain diseases.

Neuroscientist Jane Foster launched a laboratory in 2006 and discovered something baffling for the entire medical community. She worked with a neuroscientist team and studied two groups of mice, one with healthy gut bacteria and the other without a gut microbiome. Their study concluded that mice without a gut microbiome are less anxious than those with healthy gut bacteria. When both groups were placed in a maze with some walled-in ones while others open – the mice without gut bacteria preferred open paths. The other group seemed to be under the influence of gut bacteria.

The study was compiled and submitted for publication by Foster at McMaster University in Hamilton, Canada. However, the study was rejected, saying, “People didn’t buy it as they thought it could be an artifact.” Here study was finally accepted after 3 years d 7 submissions.

John Cryan also joined the field in 2006 and knows precisely how Foster felt. He is a neuroscientist at University College Cork in Ireland and submitted a similar study in his institution about the connection between gut bacteria and the brain. He also faced several rejections; however, his work also got an acceptance letter from the university.

Foster and Cryan are not considered “crazy neuroscientists” nowadays as the gut-brain axis is a major feature at neuroscience meetings worldwide. Thousands of studies in these past years have shown that trillions of bacteria in the gut are linked to the brain and might cause several brain disorders.

But there is a great hype along with that explosion of interest. According to some neuroscientists, there is a causal relationship between the gut microbiome and brain disorders. Some shaky ones, such as a philosopher at the University of Sydney, Maureen O’Malley, say that “most people often confuse the actual underlying cause and just another effect of the gut microbiome on the brain.”

The field has made significant strides in recent years. Rather than studying the gut microbiome as a whole, most researchers have begun studying the individual microbes and drilling down the complex pathways to identify specific bacteria or viruses linked to brain disorders. These individualized studies are what allow casual attributions to be made. Studies and clinical trials involving mice, rabbits, and preliminary work in humans suggest that gut microbes can induce or increase the risk of brain diseases such as ASD (autism spectrum disorder), Parkinson’s disease, Alzheimer’s, and others. Therapies and interventions tweaking the specific microbes could help treat and prevent these brain disorders. Most researchers and companies are already testing this idea to prevent human diseases.

According to a microbiologist, Sarkis Mazmanian, the research is still in the early days; however, the prospect of new medical therapies and intervention for some brain disorders is exciting. He further adds that getting medicine to the brain is particularly challenging due to the blood-brain barrier, but manipulating the gut microbes to prevent brain disorders is easier and more effective.

Tangle transmission

The English surgeon James Parkinson in 1817 described the classic sign “shaking palsy” that was later characterized as “Parkinson’s disease.” Patients developed prickling sensations and numbness in both upper extremities. The surgeon noticed a considerable accumulation in the man’s abdomen, suggesting he was having some abdominal problem.

Further studies have found that some people with 9mdisease develop the disease experience abdominal issues such as constipation and bloating - long before the onset of initial signs and symptoms. Many researchers have also embraced the idea that most brain disorders, including Parkinson’s disease, begin in the gut.  

To grasp the idea, basic knowledge about the disease is necessary. Resting tremors, slowness of movement, and stiffness are the hallmark signs of Parkinson’s disease. These signs develop secondary to degeneration of the neurons responsible for coordinating movement. The exact cause behind these neurons’ degeneration is not fully understood; however, a-synuclein – a neuro-protein – seems to play a vital role. Studies have linked its misfolding with the development of classic symptoms in people with Parkinson’s disease.

What causes misfolding of this protein? According to Robert Friedland -  a neurologist at the UOL (University of Louisville) in Kentucky, gut bacteria produce specific curl proteins similar in chemical structure to a-synuclein proteins. He proposed a theory that these proteins can develop misshapen a-synuclein protein in the brain and may trigger the development of Parkison’s disease.  To prove his hypothesis, he, with his colleagues, conducted a test and fed mice with E.coli bacteria that produce a curling protein called “curli.” They found more curling or degeneration of a-synuclein proteins in the mice brain.  Another study published by Mazmanian and colleagues also supports Friedland’s theory.

How this signal reaches the brain is not clear; however, most neuroscientists believe this could be likely through the vagous nerve. This nerve is the longest of the twelve cranial nerves and connects the brainstem to the gut and its organs, including the colon. Therefore, it acts as a highway for signals from the brain to the gut.

Removal of all or part of the vagous nerve was a major therapy to treat stomach ulcers back in the 1970s. Later on, the researchers noticed a strange side effect of this procedure – that people who have undergone partial or complete resection of vagous nerve seemed to be at a lower risk of developing Parkinson’s disease and other brain disorders.

 According to a recent mice study, injecting misfolded or curled a-synuclein protein into the gut is linked to its production in the brain. However, if the same misfolded protein is added to the mice with a removed vagous nerve, no protein production is seen in the brain.  The injected a-synuclein protein seems to stay in the gut. However, according to a neuroscientists Valina Dawson at Johns Hopkins University in Baltimore, Maryland, it could be a domino effect. Mazmanian and other neuroscientists are now conducting further studies to see whether the misfolded proteins in the gut can cause Parkinson’s disease in mice with vagus nerve severed.

Studies have also shown that misfolded proteins are also a classic risk factor of several other brain conditions, including ALS (amyotrophic lateral sclerosis) and Alzheimer’s disease. Many neuroscientists find this idea plausible; however, most argue that misfolded proteins are not the only risk factor to consider.  

Hastening decline

People in favor of the gut-brain link believe that the microbiome in the gut could do more than just triggering the proteins responsible for causing some neurodegenerative disorders. Such proteins could also have a strong impact on the disease severity and prognosis. According to an Israeli immunologist, “Eran Elinav,” there is a striking similarity between the onset of most brain disorders and also in their severity. Eran Elinav wondered whether the gut microbiome helps to explain this phenomenon - so his team is working with one of the most common amyotrophic lateral sclerosis (ALS) models in mice. When they used specific mice species with microbiome deficiency from birth or used the ones with removed microbiome due to antibiotics – they found a rapid progression of ALS.

To identify the specific microbial species linked to the development of ALS, Eran and his team compared the microbiome in ALS mice with their healthy counterparts. They did the painstakingly hard work and transplanted the species one by one. They also keep the record of species linked to the development of the disease or worsening the severity and those associated with improving the signs and symptoms. They were surprised to know the influence of gut bacteria on the brain.

The underlying cause could be bacterial metabolites – byproducts of bacterial metabolism that enter the bloodstream and travel to the brain to cause the disease. At least half of these metabolites were found in the blood – either produced as a result of metabolism or modulated by microbes. The researching team separated one of the metabolites called “nicotinamide” (also called vitamin B-3) and injected it into the mice prone to ALS. Administering vitamin B-3 results in the improvement of ALS symptoms.  Eran says, “we could prove that there is a bacterium or a bacterial product that was swimming to the target (brain) and positively modified the disease process.

The team further compared the gut bacteria of people with ALS and their unaffected family members and found that diseased people have less nicotinamide in their blood. They administered vitamin B-3 to people with ALS for four and monitored their prognosis. The treatment group showed significant improvement, while all people in the placebo group showed further deterioration.

In humans, one group has been tested with 4 months of administration of nicotinamide. Interestingly, this study also shows a similar result. The treatment group showed some improvement, while other participants showed no improvement.

Elinav says, “this is just the iceberg, and we are still far away from the real outcomes. Thousands of bacteria and their metabolites can be identified that could infect individual cells in the brain.

Generational effects

The effect (bacterial microbiomes causing brain diseases) could even progress from one generation to the coming one; for instance, autism spectrum disorder (ASD). According to the epidemiological researchers, the reasons are still vaguely studied. Nevertheless, infections in women during pregnancy are more likely to increase the child’s risk of developing ASD. For instance, the expecting women in a Swedish cohort study of around 1.8 million participants in a hospital setting for any infection during pregnancy had a 79 percent greater risk of developing ASD.

Other research in mice also holds up to the link of infection with developing ASD. To imitate the infection, the researchers inject double-stranded RNA into a group of pregnant mice so that the body considers this as a viral pathogen. The babies of these mice show more repetitive behaviors and stress than those who did not receive the injection. The interaction of the new-born mice with family members was also less compared to healthy ones, which is one of the symptoms of ASD.

According to a neuroscientist “Gloria Choi,” who is working at the Massachusetts Institute for memory and learning (MIML) in Cambridge, and her collaborator Jun Huh, an immunologist at Harvard medical school in Boston, we looked into various reasons why gut infections cause ASD. The whole team tries to focus on a type of cell that fights against fungi and bacteria by producing substances like cytokines. While mimicking an infection in mice, Choi and Huh observe that the immune cells “T-helper 17 cells” start becoming hyperactive. The same type of cells is known to become hyperactive in ASD.

Moreover, the T-helper 17 cells start churning out a certain cytokine known as IL-17. IL-17 seems to significantly affect the animals; the scientists see that the adult babies show higher neural activity causing behaviors like autism.

Dr. Huh describes that “Not every expecting woman who gets the infection during a hospital stay during pregnancy pass on the neurodevelopment disorders in their children.” Huh, and Choi’s focus was mainly on accumulating long gut microbes known as “segmented filamentous bacteria.” These pathogens have a previous history of stimulating T-helper 17 cells’ formation. The team found out that treating pregnant mice with an antibiotic to kill bacteria and eventually stimulate an immune response causes no such development of behavioral changes.

Choi and Huh is very keenly looking to determine whether the coronavirus pandemic might lead to a higher risk of ASD. The experts are obtaining samples from pregnant women who suffer from SARS-Co V-2 infection and classifying the bacteria in the guts and the levels of IL-7 in the blood of these women. According to David Amaral, studying ASD at the University of California, Davis, it is a well-known fact that the coronavirus - just like any other infection - initiates the mother’s immune system. So it is the likelihood that SARS-Co V-2 might increase the risk of developing psychiatric disorders. However, there is no solid evidence in support of this theory.

Mauro Costa-Mattioli, a neurobiologist working at Baylor College of Medicine in Houston, Texas, studies the relationship between ASD and gut bacteria. But rather than investigating the microbes causing the disorder, he explains a treatment that might treat the symptoms of ASD. He accidentally stumbles on the bacterium years ago while working on mice with babies that have autism-like signs. When those ill mice were housed with neurotypical mice, their symptoms and behaviors of ASD start disappearing. Mauro Costa-Mattioli and his colleagues, while working on the mice, conclude that the affected ones have a missing bacterium species: called Lactobacillus reuteri.

The testing of L. Reuteri on numerous other mouse models reveals that the bacterium could alter some of the ASD-like behaviors in every model. Moreover, just in the case of Parkinson’s, the scientists could cease the effect in mice if the vagus nerve suffers from damage. It is yet not clear that what type of signal L. Reuteri transfers. The team finds that some strains of L. Reuteri might alter the behaviors while others are not able to do it. The researchers are now discovering what genes take part in this process. If they find the particular gene behind the production of a key metabolite, it can be put in any bacteria to obtain a specific and targeted treatment.

One expert group is already working in Italy by trying L. Reuteri as a treatment in 80 children having ASD. The participants started taking a placebo tablet or L. Reuteri for six months, and the experts monitored the symptoms. Mauro Costa-Mattioli is expected to launch his own trial very soon. However, a neurogeneticist, Kevin Mitchell, working at Trinity College Dublin, is not so persuasive about the mice studies. Mitchell finds the discussion of therapeutic potential as foolish and a bit irresponsible given the complexity of the situation.

Meanwhile, the researchers discover more brain disorders linked to the gut microbiome, including Alzheimer’s disease and depression. Gut microbes might even affect how the brain starts recovering after injury. Corinne Benakis is a neurobiologist working at the institute for dementia and stroke research (IDSR) at the Ludwig Maximilians University of Munich in Germany. He studied mice’s treatment with antibiotics to clear some of their gut bacteria before having a stroke. Benakis and her colleagues discover that antibiotics could lower brain damage severity.

Many mechanistic questions remain unanswered in these studies. Researchers realize that they have yet to find microbe pathways to the brain. The hardest step is to validate the animal findings in humans and proceeding towards trials.

But there’s also enormous interest — and not just from academics. In February 2019, Axial Therapeutics in Waltham, Massachusetts, a company co-founded by Mazmanian to develop therapies for neurodegenerative and neuropsychiatric diseases, raised US$25 million in financing. Another company, Finch Therapeutics in Somerville, Massachusetts, which is developing an oral microbiome drug for ASD, announced in September that it had raised $90 million.

However, there is an immense interest in this field – and not just by the researchers. Many therapeutic companies, including the Axial Therapeutics of Mazmanian, are developing therapies for neuropsychiatric and neurodegenerative diseases. They have allocated $25 million for this project. Similarly, Finch Therapeutics in Somerville is another such company that has announced $90 million for developing an oral microbiome drug for treating ASD.

                     How the Gut Microbiome affects the Brain and Mind