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  • Writer's pictureP.K. Peterson

What’s Bugging the Brain?

“Everything we do, every thought we’ve ever had, is produced by the human brain. But exactly how it operates remains one of the biggest unsolved mysteries, and it seems the more we probe its secrets, the more surprises we find.”

- Neil deGrasse Tyson, American astrophysicist, author, and science communicator

“Our results support the idea that viral infections and related inflammation in the nervous system may be common – and possibly avoidable – risk factors for these types of disorders.”

- Andrew B. Singelton, Ph.D., British neurogeneticist, Director, National Institutes of Health Center for Alzheimer’s and Related Dementias

What is the body’s most important organ system? During the early years of my infectious diseases career, I debated this question with colleagues in other disciplines. Not surprisingly, cardiologists voted unanimously for the heart, nephrologists for the kidneys, endocrinologists for the pituitary or other glands, and so on. Practicing in a subspecialty that claims no single organ as its own, I had no dog in this fight. I do think, however, that the neurologists had it right—the brain. In this week’s Germ Gems post, I summarize recent findings that expand our understanding of how viruses contribute to neurodegenerative disorders and how microbes residing outside the brain, that is in the gut microbiome, may also bug the brain.

Synopsis of neuroanatomy. Some scientists claim that the brain is the most complex thing in the universe. I believe they are right. But to a simpleminded infectious diseases doctor, the brain contains only four cell types: neurons (on average, about 86 billion of them, each connected with up to 10,000 other neurons via as many as 1,000 trillion synapses) and approximately the same number of cells called glia (astrocytes, microglia, and oligodendrocytes).

Glial cells provide essential support of for neurons. But they can also serve as targets for viruses, and when microglia are activated they produce mediators that participate in brain injury.

The blood-brain barrier. The blood-brain barrier (BBB) is comprised of endothelial cells in blood vessels and astrocytes in the brain. It is a brain structure that plays a pivotal role in defense of the nervous system against foreign invaders such as viruses. For decades, scientists interested in how microbes and cells of the immune system are excluded from or gain entry to the brain have extensively studied the BBB.

What happens when guardians of the brain fail? In a June 2022 review article in the journal Nature, “Guardians of the brain: how a special immune system protects our grey matter,” science journalist, Diana Kwon, provides an up-to-date understanding of the BBB. She wrote, “Scientists have discovered that the job of protecting the brain isn’t as straightforward as they thought. They’ve learnt that its fortifications have gateways and gaps, and that its borders are bustling with active immune cells.”

Viral illnesses linked to brain diseases. In the article “Virus exposure and neurodegenerative disease risk across national biobanks” in the January 19, 2023 issue of the journal Neuron, scientists published the results of a massive analysis of 450,000 electronic health records that provide insights into how gaps in protection of the brain may play a role in neurodegenerative diseases. The researchers found at least 22 links between viral infections and neurodegenerative diseases. They were quick to point out that their findings represented correlations not causations. Nonetheless, McMaster University viral immunologist Matthew Miller commented that the widespread associations were startling both for the number of viruses and number of neurodegenerative diseases involved. (It is worth noting that SARS-CoV-2, the cause of COVID-19, was excluded from the analysis.)

The viral illnesses incriminated in the neurodegenerative diseases included influenza, herpes, and hepatitis viruses, and the most common neurodegenerative disorders were Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. Some of the viral exposures that were associated with an increased risk of neurodegeneration occurred up to 15 years before development of the neurodegenerative disease.

How viruses impact the brain. Viral infections can result in brain inflammation (encephalitis) that is characterized by dead neurons and immune cells such as microglia, macrophages, and lymphocytes. But in the case of the viral illnesses associated with neurodegenerative diseases found in the study published in Neuron, such inflammation (encephalitis) didn’t antedate development of the neurodegenerative disorder. In fact, as is the case in the recent SARS-CoV-2-related illness long Covid, the precise mechanism of neuropathogenesis is yet to be established. (See my September 7, 2022 Germ Gems post, “Long Covid: Older Adults at Risk”).

Outside influences on the brain (the gut-brain axis). In my opinion, the most exciting developments in the field of microbiology in the 21st century are characterization of the human microbiome and studies of its impact on health and disease. Doing research in this field is a daunting task given the fact that the most studied microbiome (in the gut) contains about 40 trillion bacteria, 10 times as many viruses, and an assortment of fungi, and parasites.

Despite the complexity of research in this field, it’s become increasingly clear that bidirectional communication is going on between members of the gut microbiome and the brain (the so-called gut-brain access). Scientists in both academia and the pharmaceutical industry are starting to explore the potential involvement of microbes in the gut on neurodegenerative diseases such as Alzheimer’s disease.

On January 13, 2023, in an editorial in Science, “Gut microbes modulate neurodegeneration,” the editors discuss the implication of an article in the same journal issue. Using a mouse model of Alzheimer’s disease, the researchers demonstrated that gut bacteria play a causative role in tau-mediated neurodegeneration. Tau protein is over-expressed in brains of patients with Alzheimer’s disease. Similar research is underway in animal models of Parkinson’s disease.

By and large, gut microbes produce many of the same neurotransmitters that are found in the nervous system. Influences of the gut microbiome, perhaps involving these neurotransmitters, on moods, such as happiness, were highlighted in previous Germ Gems posts (see January 1, 2020, “Does Your Microbiome Shape Happiness?” and January 13, 2021, “What’s Your Psychobiome Telling You?”). On December 6, 2022, a pair of studies were published in the journal Nature Communications that identified a gut microbiome link to another mood, that is, depression.

Led by microbiologist Christoph Thaiss, researchers at the University of Pennsylvania recently carried out one of the most provocative studies of the influences of the gut microbiome on behavior. The study was published on December 14, 2022 in Nature, “A microbiome-dependent gut-brain pathway regulates motivation for exercise.”

Using genetically identical germ-free mice, these researchers found that the daily distance mice covered on a running wheel was markedly influenced by the nature of the microbes in the mouse gut microbiome. They found a five-fold difference in how far mice ran in the running wheels—some ran more than 30 kilometers (18.6 miles) in 48 hours, whereas others rarely moved in their wheels.

In a subsequent article published in Science, “Exercise-crazy mice have their gut microbes to thank,” Harvard microbiologist, Aleksandar Kostic, who wasn’t involved in the study, commented, that the work “establishes just how critical the microbiome is for exercise and goes incredibly deep in providing a new gut-brain [connection].”

A number of supplements are already on the market that reportedly improve exercise capacity. My guess is that I’m not the only one who would be interested in the development of a pill containing exercise-inducing microbes to help give me a boost to get off the couch and log some more miles on my daily walks.

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Main Page images courtesy of Shuxian Hu, MD. Dr. Hu is a scientist in the Neuroimmunology Research Laboratory at the University of Minnesota.

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