Do we have microbes in our brains? A theory that divides scientists

When Spain-based immunologist Irene Salinas, from the University of New Mexico in the United States, began searching for bacteria in the brains of healthy fish, it might have seemed like a futile task: every biology student knows that a strict filter keeps the brain free of microbes, and that breaking that sterility only leads to a potentially fatal infection. But Salinas found what she was looking for: her 2024 study supports the existence of a brain microbiome in fish. However, not all experts accept the validity of her results. The possibility of a brain microbiome keeps scientists engaged in a lively discussion with crucial ramifications toward a possible role for bacteria in neurodegenerative diseases such as Alzheimer’s.

Since the importance of the microbial life that inhabits our bodies in terms of health and disease has been recognized, scientists have undertaken extensive searches to detail this human microbiome. The result is projects such as the Human Microbiome Compendium, which has just published a vast analysis of 168,000 samples from people around the world to build a geographic atlas of the intestinal microbiome. Even the microbiome in our home, which is an extension of our own, can keep us healthy or make us sick. But is there a microbiome in the brain, the privileged organ that the blood-brain barrier — a wall of cells in the blood vessels — keeps safe from any threat circulating in the blood?

The idea began to gain traction nearly a decade ago, when an analysis of the brains of people with HIV found up to 173 types of genetic material from bacteria and bacteriophage viruses — which attack bacteria — in all samples, including in HIV-negative controls. Another study of the brains of Alzheimer’s patients found abundant bacteria and fungi, but also, although in smaller numbers, the authors found “a remarkable diversity of brain microbes in the controls,” they wrote.

This latest study was deposited in the preprint repository bioRxiv in February 2023, but almost two years later it has still not been published in a peer-reviewed scientific journal. This, coupled with the possibility of contamination in the samples, has kept other scientists between cautious skepticism and radical opposition to the idea of a brain microbiome, despite the publication of new research.

Salmon brains

Meanwhile, in her evolutionary immunology lab, Salinas was studying nasal immunity in vertebrates, with two intriguing facts in mind: First, the nasal cavity, a hotbed of microbes, is extremely close to the olfactory bulb, the region of the brain that receives odors; second, fish harbor a peculiar variety of bacteria in their blood and organs when they are perfectly healthy. Could some of these microbes infiltrate the olfactory bulb?

Salinas found bacteria not only in the olfactory bulb of salmon and trout, but throughout their brains. Her study, published in Science Advances, was welcomed by a section of the scientific community as the first solid evidence of a brain microbiome, albeit only in fish. “Whether this is a distinctive feature of other teleosts [the largest group of fish] or a universal symbiotic relationship found in all vertebrates remains to be investigated,” the immunologist and her collaborators wrote.

But when The Guardian published an article on the brain microbiome last December, a group of scientists responded with a letter in which they wrote: “The weight of expert opinion in medical microbiology rejects the existence of a ‘brain microbiome’ in the sense of a resident microbial community in healthy human brains.” A report in New Scientist on the human brain microbiome also received harsh criticism from some scientists on X, forcing its author, David Robson, to publish a response in Medium.

The letter to The Guardian was co-written by Mark Pallen, a researcher at the Quadram Institute in Norwich, UK, and professor of microbial genomics at the University of East Anglia. Pallen strongly dismisses the hypothesis of a brain microbiome. “I don’t believe the fish work either,” he says, adding a lengthy and detailed argument. “While the study is interesting, multiple lines of evidence and common problems in small microbiome studies suggest that the most likely explanation for these results is contamination (environmental or in reagents), or transient artefactual infiltrations, rather than stable resident bacterial communities in the fish brains,” he summarizes.

For her part, Salinas defends her conclusions. “This is a highly debated topic, so there will always be skeptics,” she says. The researcher maintains that her study includes the necessary rigorous controls and repetitions of the experiments to ensure that both the genetic sequences obtained and the culture of bacteria correspond to a real presence of microbes in the brain of healthy fish. “Regardless of how stable this community is and the philosophical differences of opinion on the definition of a microbiome, our work shows that the brain of fish coexists with bacteria, even in homeostasis [normal equilibrium] and in a healthy state,” she reiterates.

The infectious hypothesis of Alzheimer's

Beyond the “philosophical” aspects of what Salinas refers to, the implications of this scientific controversy are enormous for society. In recent years, evidence has grown in support of a previously unthinkable idea, according to which Alzheimer’s and other neurodegenerative diseases could have their origin in infections. Microorganisms have been observed in the brains of patients, including those that cause pneumonia, gastric ulcers, acne, periodontal disease, and other ailments, as well as certain fungi and viruses such as herpes. A new review of studies that has gathered data from 130 million people, with one million cases of dementia, has found a reduction in risk associated with the use of antibiotics, antivirals and vaccines, pointing to the infectious theory.

However, as Pallen cautions, the presence of microbes in diseased brains does not imply that there is a healthy brain microbiome: as we age, both the immune system and the blood-brain barrier weaken. “Although bacteria may leak into the central nervous system at older ages, the best interpretation is that this does not constitute a normal or healthy microbiome, but rather probably reflects increased susceptibility and, potentially, a pre-pathological state.”

Even then, separating cause and effect is no easy task. According to Christopher Link, a professor at the University of Colorado at Boulder who researches the cellular and molecular basis of neurodegenerative diseases, while the presence of microbes in the brains of these patients is compelling, “interpreting this is complicated because late-stage Alzheimer’s brains have significant breakdown of the blood-brain barrier, and microbial deposition could be a consequence of the disease.” Link suspects that microbes will continue to be detected in the human brain, but judges that “the current level of evidence does not support the existence of microbes in the healthy human brain.” But, he adds, there are no strong reasons to rule this out, either.

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