In 2015, Nikki Schultek was in her prime: a young mother of two little boys, she had just run a half marathon. Then, a mysterious illness hit. Her asthma, previously well-managed, became increasingly severe. Over the following months, she experienced chronic pain, digestive problems and a cardiac arrhythmia. Then came the “last insult”: signs of neurodegeneration, including brain fog and lapses of memory. “It was the lowest point,” she recalls. “I began making plans for my kids, writing down notes of things that I would want to tell them if I continued to get worse.”
Schultek received various diagnoses for individual problems, but none fully matched her constellation of symptoms. Eventually, one doctor suggested that an undetected infection could lie behind her chronic pain and breathing difficulties. She tested positive for Borrelia burgdorferi and Chlamydia pneumoniae infections and was prescribed a cocktail of antibiotics. On taking them, she found that all her symptoms – including the brain fog and memory deficits – went into remission.
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Schultek has since founded a research group to explore the role of infection more generally in cognitive decline. This idea would once have been considered outlandish, but interest in the brain’s microbial community is growing rapidly. It turns out our grey matter is teeming with bacteria, viruses and fungi, and a better understanding of this unexpected microbiome has enormous potential to prevent neurodegenerative diseases. It could even reverse symptoms of decline when things go awry, as Schultek found. And, most excitingly of all, some potential treatments have a proven track record, such as antibiotics and commonly used vaccines.
The burgeoning interest in the brain’s microbiome builds on decades of research into the various microbial communities living in and on us. “The past 20 years has seen a switch from thinking that the human body is some kind of sterile entity to realising that microbes are everywhere,” says at the University of Edinburgh, UK. Initially, studies revealed the importance of the gut’s ecosystem for long-term health. Now it is becoming clear that our body’s microbial residents can influence the functioning of many other organs – and not always for the better. Some may be responsible for the that result in heart disease. Emerging .
Microbes in the brain
Until recently, however, the existence of a brain microbiome seemed far-fetched. Our central nervous system is protected by a membrane called the blood-brain barrier, which is supposed to filter out any potential pathogens before they can damage our neurons. What’s more, the brain has its own private immune system with foot soldiers called microglia to deal with any intruders. While some viruses and bacteria were known to penetrate this fortress and cause symptoms of severe illnesses such as , infiltration was thought to be a rare occurrence. It seemed inconceivable that the brain could host a whole population of diverse microbes.
A few years ago, when one of graduate students at the University of Colorado Boulder mentioned this possibility, Link was shocked. “I stopped him and I berated him,” he says. Afterwards, however, he decided to take a look at the literature, discovering that the than he had imagined – although most of the studies focused on dementia rather than the brain microbiome more generally.
As far back as the early 1990s, , then at the University of Manchester, UK, had sequenced the genes in post-mortem brain samples from people who had had Alzheimer’s disease. She and her colleagues found that the tissue was often – the microbe that causes cold sores. This appeared to be no isolated incident, with further research showing that Porphyromonas gingivalis, the bacteria behind gum disease, was similarly prevalent in the brains of people who had died with dementia.
Until recently, the existence of brain microbiome seemed far-fetched
Such findings were initially greeted with scepticism. Some suspected that the microbes were a result of contamination of the samples in the lab. Others suggested that they may have only entered the brain in the late stages of dementia, as a result of the individuals’ failing health. “Maybe it’s all after the fact,” says Link.
Such doubts began to disappear in 2010, when the late at Harvard Medical School and his colleagues took a closer look at the beta-amyloid plaques that characterise Alzheimer’s. These sticky bundles of protein are toxic to neurons and have long been considered the primary cause of the condition, yet the team’s research . “Their role is to entrap and kill pathogens,” says Lathe. “They are defending the brain.” And the discovery that suggests that invading pathogens have been a considerable threat to the brain’s health for much of evolution. What’s more, it indicates a clear mechanism through which microbes might influence the development of dementia. “It was a turning point,” says Lathe.
The mounting evidence leads him to suggest that . In our younger years, our immune system is strong enough to prevent too many of these organisms reaching our neural tissue. As we get older, however, our defences weaken – a process known as immunosenescence – allowing certain microbes to breach those defences. The beta-amyloid deposits may be a sign of the brain’s continued struggle to keep these organisms in check. Once the toxic plaques have formed, however, they may cause collateral damage to the surrounding tissue, resulting in continued cognitive decline – although this is a matter of debate. “I’m certainly interested in entertaining the idea that maybe, even before you’re sick, there’s this sort of continual challenge from microbes that enter the brain,” says Link.
We still don’t know how all these microbes end up in the brain, but Lathe notes there are several possible ways they might gain access. Organisms could use our own immune cells as a Trojan horse, for instance. “They could infect macrophages which permeate straight into the brain,” says Lathe. Others may have enzymes that allow them to squeeze through small gaps in the blood-brain barrier. Or they might travel along the nerves from the nose and mouth, some of the few direct entrances into our neural tissue. We also don’t know whether some of our brain’s inhabitants are beneficial. After all, certain microbes in the gut help with digestion, so it is possible that others in the brain aid thinking and reasoning. Link and Lathe are both open-minded about this. “It’s not obvious, but it’s not impossible,” says Link.
Do bacteria play a role in dementia?
To get the bigger picture, Lathe recently attempted to in people with and without dementia. Working with colleagues at the University of Edinburgh, he examined genetic material from 79 neural samples held in brain banks in the UK and US. The analysis revealed a remarkable diversity of organisms, with as many as 100,000 species per sample. The community included viruses, bacteria and fungi. The researchers even found the remnants of a plant or alga-like organism, though they admit it could have come from pollen that somehow got into the brain. Intriguingly, this microbiome was a subset of the microbes found in the gut – representing about 20 per cent of the species found there.
This raises the question of whether some of the microbes in our brains come from the gut. A recent study in mice found that some pathogens, such as the fungus Candida albicans, can slip through the gut lining, hitch a ride with the blood and . However, these relocating fungi were mostly found in mice with impoverished gut microbiomes. “The bacteria in the gut [normally] compete with the fungus and prevent it crossing into the rest of the body,” says at the Quadram Institute in Norwich, UK, who led the study. “So, in healthy people, we don’t really get fungal translocation.” Nevertheless, Lathe’s team did find that Candida was among a variety of organisms – of unknown origin – that were more prevalent in people with dementia than in those without. “We see well-known human pathogens such as the bacteria Staphylococcus, Streptococcus, as well as the fungi Cryptococcus and Candida are all over-represented in Alzheimer’s brain,” says Lathe.
The discovery that microbes are implicated in neurodegenerative diseases already suggests potential new treatments
Other research suggests that the presence of any single pathogen may be less important in causing dementia than the . and his colleagues at Drexel University College of Medicine in Pennsylvania recently examined post-mortem brain tissue from 32 individuals, half of whom had had Alzheimer’s. Like Lathe’s team, they found a large variety of organisms. But they also learned that particular combinations of microbes were associated with different stages of the disease. A group of bacteria known as Comamonas, for instance, were considerably more prevalent in people without dementia, while Methylobacterium and Cutibacterium acnes (which causes teenage spots) dominated the distribution during the later stages of Alzheimer’s. We can only speculate about the reasons for these changes, but Lapides suggests that interactions between the different species might put additional strain on the brain. “The chemical results of their competition may be toxic,” he says.
Of course, there are other hypotheses that attempt to explain Alzheimer’s. However, the idea that the brain’s microbiome plays a role need not be at odds with these. “I suspect that there are different things that induce Alzheimer’s in different people,” says Link. He points out that even having a gene associated with the disease, such as APOE4, doesn’t dictate how it might develop: “If you’re APOE4, then you are at a higher risk of cardiovascular problems, you also have lipid transport problems and you also have alterations of your immune response.” Each one of these mechanisms may offer a different pathway for Alzheimer’s to emerge, he suggests.
But even if a dysregulated brain microbiome only underlies some cases of dementia, it may still play a role in other neurological conditions. One finding hinting at this is that the alpha-synuclein proteins associated with Parkinson’s disease also . “When you knock them out in the mice, the mice are more sensitive to brain infections,” says Link. Like beta-amyloid, alpha-synuclein may enhance survival in the short term, but – for reasons that are currently unknown – the process could spiral out of control in some people.
Although many questions remain, the discovery that microbes are implicated in neurodegenerative diseases already suggests potential new treatments. One obvious approach is to protect the body from pathogens that have been linked to Alzheimer’s. Researchers at the National Defense Medical Center in Taipei, Taiwan, for instance, followed people who had received a course of antiviral medication to treat a herpes simplex virus infection. The result appeared to be a over the following 10 years.
Other measures could against a whole range of invaders. For instance, – most commonly used as a vaccine against tuberculosis – seems to ramp up the immune system, reducing the risk of many infections besides TB for up to a year. Quite remarkably, and presumably as a result of this, some studies indicate that the injection can by as much as 45 per cent. Excitingly, several other vaccines, and the , appear to offer similar protection.
If dementia results from a problematic brain microbiome, it may even be possible to completely reverse it – a prospect that is unthinkable with our current treatments. Schultek’s recovery from her rapid decline inspired her to . Working with other members of the , the research group she set up, she identified reports of 86 people who had been diagnosed with dementia and then subsequently benefitted from antimicrobial treatments. The pathogens responsible included many that are over-represented in the brain microbiomes of people with Alzheimer’s, including Cryptococcus fungi. Tellingly, she also found a handful of cases involving B. burgdorferi – one of the bacteria implicated in her illness. “It was kind of eerie,” says Schultek. “These case reports came from clinicians around the world, but the conclusions were the same nearly every time: that infection testing should be a part of the differential diagnosis.”
Reversing cognitive decline
Schultek suspects these case studies only capture a thin slice of the people who have recovered from cognitive decline in this way. “The majority of clinicians who treat patients don’t publish the results,” she says. She also believes that rogue microbes in the brain may be the cause of neurocognitive issues in many people. Unfortunately, screening the brain’s microbiome without invasive surgery remains a challenge. But cerebrospinal fluid, taken through a lumbar puncture, provides traces of its occupants that could be used for diagnosis. “My personal hypothesis is that if we were to screen everyone, we would find evidence of ongoing, active infection in a significant portion of dementia cases,” says Schultek.
Interest in the brain’s microbiome is certainly growing. In July this year, the AlzPI held on the topic, and the Infectious Diseases Society of America now . Understandably, the link with dementia still leads research efforts, but, more broadly, there is still so much about the brain microbiome that remains to be discovered. This even includes the identity of some of our brain’s inhabitants. “We sometimes see RNA sequences that are not present in any of the genome databases,” says Link. He calls this clandestine community the “dark microbiome”. “There are probably lots of viruses and other things out there that we don’t know anything about.”
