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  • Writer's pictureP.K. Peterson

The Brain Microbiome: A Shout-Out to Heresy

“[C]ases of ‘reversible dementia’ are starting to inspire enormous interest in the idea our brains are teeming with microorganisms—and that an imbalance in this ‘brain microbiome’ may predispose people to neurodegenerative disease.”

David Robson, science writer, New Scientist


“The heresy of one age becomes the orthodoxy of the next.”

Helen Keller, American author and disability rights advocate


 

The brain is our most awesome organ—especially to researchers interested in how the brain defends itself against foreign invaders, such as bacteria, viruses, fungi, and parasites. In the 1940s, transplantation pioneer (1960 Nobel Prize winner) Sir Peter Medawar referred to the brain as an “immunologically privileged site.” By this he meant that the brain restricts access of cells and mediators of the immune system that could potentially cause brain damage.



With this perspective in mind, I recently read an article suggesting the brain is normally “teeming with microbes.” I was about to laugh out loud but then thought again; I know that it is heresies like this, i.e., “thinking outside the box,” that can herald scientific breakthroughs. In this week’s Germ Gems post, I introduce readers to what is now called the “brain microbiome” and discuss the implications of this new avenue of research for patients suffering with Alzheimer’s disease, a devastating neurodegenerative disorder.


What is a microbiome (a recap)? A “microbiome” (from Ancient Greek mikros for “small,” and bios for “life”) refers to a “community of microorganisms living together in any given habitat.” Microbiomes are found everywhere as are their constituents—trillions of bacteria, archaea, fungi, viruses, and parasites. Even our planet has a microbiome.


In 2007, the National Institutes of Health (NIH) launched the “Human Microbiome Project” (HMP). Thereafter, a bevy of researchers worked on five microbiomes found in the human body—gut, skin, oral cavity, respiratory tract, and vagina—to determine the role of these five microbiomes in human health and disease. But what about the brain? Presumably, the NIH scientists who established the HMP shared my view: the last thing the brain wants is a microbiome.


The brain has evolved several elegant mechanisms to prevent microbes from setting up shop in (colonizing) it. The most striking example of these gatekeeper mechanisms is the blood-brain barrier; it plays a critical role in controlling the influx and efflux of biological substances essential for the brain’s metabolic activity as well as for neuronal function. But does the fact that the brain has such gatekeeper mechanisms preclude a brain microbiome? Right now, no one knows the answer.


Is there a brain microbiome? It has still not been established whether there is a brain microbiome. More and more research is being done, however, on the provocative theory of a brain microbiome.  

 

This research has been aided enormously by the technology developed by microbiologist Carl Woese and his colleagues at the University of Illinois in the 1970s. Because of this technology, it is no longer necessary to culture microorganisms from various environmental niches; their presence can be detected by molecular techniques that uncover their ribosomal RNA. This technology has been used to study anything and everything involving microbes.



In 2021, the journal Neuroscience Insights published an example of this kind of technology being applied to a study of the human brain. In his article “Is There a Brain Microbiome,” molecular biologist Christopher Link stated that numerous studies had identified microbial sequences in pathological and non-pathological human brain samples. He determined, however, that it “has not been resolved if these observations are artifactual or truly represent population of the brain by microbes.” He argued that “the evidence for the presence of microbes in diseased brains is quite strong, but a compelling demonstration of resident microbes in the healthy human brain remains to be done.”

 

Subsequently, other researchers studied resident microbes in healthy human brains. For example, in February 2023, bioRxiv published, “The remarkable complexity of the brain microbiome in health and disease.” In this study, Richard Lathe and his colleagues at the University of Edinburgh used modifications of Woese’s ribosomal RNA technique and discovered a wide spectrum of microorganisms (bacteria, fungi, viruses, and parasites) in the brains of Alzheimer’s disease patients and in the brains of healthy controls.

 

Similar findings and conclusions were also reported in an October 2023 review article, “Brain-inhabiting bacteria and neurodegenerative diseases: the ‘brain microbiome’ theory,” in Frontiers in Aging Neuroscience. Nonetheless, as the researchers in the Frontiers in Aging Neuroscience stated: “It is important to note that the concept of the brain microbiome is still in its early stages and many aspects remain to be elucidated…Nevertheless, the emerging evidence supporting the presence of a brain microbiome represents a paradigm shift in our understanding of the brain and its intricate relationship with microorganisms.”

 

Why focus on Alzheimer’s disease. An estimated 5.5 million Americans suffer from Alzheimer’s disease, a neurodegenerative disease. In the U.S., the Alzheimer’s pandemic is growing but there is still no effective therapy.

 

At this point, Alzheimer’s is considered an idiopathic disease; this means no one knows its cause. A variety of environmental toxins and microbes, as well as genetic factors, have been postulated to be involved in Alzheimer’s disease. Now, there’s also mounting evidence of a microbial cause.

 

I discussed several of the microbes and inflammatory mediators hypothesized to play a role in the neuropathogenesis of Alzheimer’s disease in my January 2021 Germ Gems post,  “Is the Alzheimer Pandemic Caused by a Microbe? And in my January 31, 2024 Germ Gems post, “Prion Diseases Are on the Rise: What’s All the Fuss?” I discussed one unusual type of infectious (contagious) particle called a prion. About the same time that my January 2024 Germ Gems was posted, the United Kingdom reported five cases of Alzheimer’s disease in people who developed the disease years after receiving prion contaminated cadaver-derived growth hormone. (See “First Cases of Medically Acquired Alzheimer Disease Reported,” Medscape, January, 29, 2024.)

 

The association of Alzheimer’s disease with prions is intriguing not only because these misfolded proteins have now been implicated in the neuropathogenesis of Alzheimer’s disease, but also because the neuroscientist who discovered prions, Stanley Prusiner, M.D., was considered an outrageous heretic when he proposed that prions—particles that contain no nucleic acid— caused scrapie, a fatal neurodegenerative disease.

 

Sometimes it takes such heretical thinking to move science along. Subsequently, it was shown that prions also cause bovine spongiform encephalopathy in cattle (“mad cow disease”) and Creutzfeldt Jakob disease, a uniformly fatal neurodegenerative disease in humans. My guess is Dr. Prusiner enjoyed a private laugh when he was awarded the 1997 Nobel Prize in Physiology or Medicine for his discovery of prions.

 


Is the jury out? In a February 19, 2024 article in New Scientist, “Why the brain’s microbiome could hold the key to curing Alzheimer’s,” science writer David Robson suggests that the University of Edinburg report in 2023 on the brain microbiome “seems to clinch the case” that the brain harbors a complex microbiome. My personal opinion is “not so fast”; we’re not there yet.

 

I believe that the “Call for Collaboration” published in the journal Alzheimer’s & Dementia in June 2023: “Establishment of a consensus protocol to explore the brain pathobiome in patients with mild cognitive impairment and Alzheimer’s disease,” is likely to attract new researchers into the highly intriguing field of brain microbiome research. If this, or a related effort. pays off and a microbial etiology is discovered for Alzheimer’s, it would be an enormous boost for neuroscientists who are studying idiopathic neurologic conditions. And, it could also net the discoverer $1 million as winner of the “Alzheimer’s Germ Quest Challenge.”

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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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