“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 and author
“Your gut has capabilities that surpass all your other organs and even rival your brain."
- Emeran Mayer, M.D., gastroenterologist, neuroscientist, professor, David Geffen School of Medicine, UCLA
When I began my infectious diseases fellowship training over four decades ago, there was almost no appreciation in the field of medicine for what has become known as the “Brain-Immune Axis”—the bidirectional communication between the nervous and immune systems. In the 1980s when two interdisciplinary research fields, Psychoneuroimmunolgy and
Neuroimmunopharmacology, blossomed, the connection between the brain and immune system became obvious as did the fact that they can profoundly impact one another. In this Germ Gems post, I discuss how microbes influence the brain, thereby affecting how we feel, think, and behave.
The immune system and brain are connected. A century ago, a bacterial infection of the brain called neurosyphilis was one of the most common reasons for confinement to a mental institution. In the late 19th century, Julius Wagner-Jauregg, an Austrian psychiatrist, noted that patients suffering from neurosyphilis showed a marked improvement after becoming febrile. He then began inducing fever in patients with syphilitic dementia by inoculating the parasite that causes malaria into the circulation of these patients. In 1927, Dr. Wagner-Jauregg received the Nobel Prize for his treatment of neurosyphilis with “fever therapy.”
Back in the 1920s, neither Dr. Wagner-Jauregg nor any of his colleagues had any idea of why “fever therapy” worked. They had no understanding of the mechanism whereby the inoculation of malaria parasites into the blood of patients with neurosyphilis induced fever and consequently reduced a patient’s symptoms. Nor did they appreciate that one reason fever is beneficial in infections is that some microbes like Treponema pallidum, the bacterium that causes syphilis, can’t stand the heat.
In the last half of the 20th century researchers began searching for how an activated immune system alters brain function (cognition, mood, and behavior). This led to the discovery that cytokines, signaling molecules produced by cells of the immune system, are key mediators of many of the symptoms associated with infection. One of the best examples of this immune system-brain connection is fever. In the 1970s researchers determined that the key was the cytokine interleukin (IL)-1, which is released from activated immune cells in the process of fighting microbes.
IL-1 targets the temperature-regulating center in the brain and sets off a cascade of symptoms, such as, the “feeling” of being cold or chilled that drives behavior—in this case, an overwhelming desire to go to bed and pile on blankets. This behavior—getting under blankets—is a way to increase body temperature (that is, fever). The sensation of feeling cold when you have a fever is a kind of psychotic state, that is, you’ve lost the ability to test reality because your body temperature is in fact already elevated.
The field of cytokine research skyrocketed in the 1980s and 1990s. At last count, there are 33 interleukins (IL-1 to IL-33), and a host of other cytokines, such as tumor necrosis factor, that trigger other symptoms and behaviors associated with infections, including anorexia (loss of appetite), sleepiness, and muscle aches. (As regular readers of Germ Gems blogs may recall the generation of a “cytokine storm” is thought to play a pivotal role in development of severe COVID-19.)
The microbiome and brain are connected. The term “microbiome” refers to the microbes that share our body surfaces—the gut, skin, oral cavity, lungs, and vagina. Essentially nothing was known about these extraordinary ecosystems until the 21st century. It is now known that the human microbiome is connected to the brain (referred to as the “Microbiome-Brain Axis”).
As I described in Germ Gems posts on January 1, 2020, “Does Your Microbiome Shape Happiness?” and January 13, 2021, “What’s Your Psychobiome Telling You?”, in the past ten years, an expanding group of researchers has shown that the approximately 40 trillion bacteria in our gastrointestinal tracts (the “Gut Microbiome”) communicate with the brain. Researchers have found that these bacteria both produce and respond to the same neurochemicals—such as GABA, serotonin, norepinephrine, dopamine, acetylcholine and melatonin—that the brain uses to regulate mood and cognition.
Many of the studies on the effects of the gut microbiome on mood and behavior, such as eating disorders, show only correlations, not causal relationships. But the science in the field of the Gut Microbiome-Brain Axis is advancing, and evidence is accumulating that supports a potential role of this axis in diseases, such as Parkinson’s disease and autism, as well as in behaviors that fuel development of obesity.
In addition to the crosstalk that goes on between the gut microbiome and the brain, a similar research interest recently surfaced in studies of what is called the “Lung-Brain Axis.” Scientists hypothesize that there is a link between microbes that colonize the lungs and neurodegenerative disorders. Just like research on the Gut Microbiome-Brain Axis, right now most Lung Microbiome-Brain Axis studies are focused on the bacteria colonizing these two organs. Some researchers are also wondering about the potential involvement of other classes of microbes, such as viruses (the virome) and fungi (the fungiome) in altering our moods and behaviors. These researchers will add further insight into the complexity of both the Lung Microbiome-Brain and Gut Microbiome-Brain Axes.
Microbes that inflict brain damage. In addition to indirect effects of microbes on brain function that are mediated by cytokines released from an activated immune system, or neurotransmitters produced by the microbiome, some microbes inflict direct brain damage, and thereby affect our mood or behavior. Several of these neurotropic agents (meaning they favor tissue of the nervous system) have been subjects of previous Germ Gems posts, e.g., rabies virus, Nipah virus, and HIV. But given the recent onslaught of SARS-CoV-2, much of the research attention in this area of neuroscience has shifted to this coronavirus and the generation of various neurological and psychological sequelae.
Of the many neurological manifestations of SARS-CoV-2 infection, the entity called “long Covid” is most baffling. Moods, such as sadness, fear, anger, anxiety, and loneliness are common in long Covid patients as well as in their family members and for that matter the general public, all of whom are worried about the profound impacts of this pandemic.
In the February 9, 2022 Germ Gems post, “Long Covid: Is the Fog Lifting?” I provided an overview of this disorder as well as my thinking about its pathogenesis. I hypothesized that long Covid is closely related to another puzzling and disabling illness called ME/CFS (myalgic encephaolomyelits/chronic fatigue syndrome). I also postulated that in both of these diseases, brain damage underlies the pathogenesis of symptoms, such as, fatigue, lack of refreshing sleep, and “brain fog” (defined as the feeling of being mentally slow, fuzzy, or spaced out, and includes memory problems and lack of mental clarity).
I am impressed by the growing number of researchers who are investigating long Covid. In particular, I am intrigued by the research of Columbia University neuroscientist and psychiatrist, Dr. Maura Boldrini that was discussed in a Natural Geographic article last December, “Can COVID-19 alter your personality? Here’s what brain research shows.” Dr. Boldrini’s studies suggest that an activated immune system (inflammation) and SARS-CoV-2 infection of a population of glial cells within the brain called astrocytes are involved. (I’ve speculated that another glial cell population called microglia play a role.) Furthermore, she believes that research on how COVID-19 affects the brain may reveal important insights into other neurological disorders. I strongly agree.
In today’s Germ Gems post, I’ve only touched upon a small sample of recent research that demonstrates connections between our immune system and our microbiome and the brain. I have little doubt that in the near future scientists will discover mechanisms whereby microbes in our microbiome influence many behaviors such as eating, sleeping, exercising, and decision-making, as well as moods, including happiness, sadness, and anger. Who knows, someday in the future when someone asks “What is bugging him?” the smart (or smart aleck) answer will be: “His microbes!”
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