For years, scientists have known that the gut microbiome of people with Alzheimer’s differs from that of healthy people. What remains unclear is whether these differences are a consequence of the disease, contribute to it, or simply accompany it. It is possible that part of the puzzle lies not in the gut bacteria themselves but in the molecules they produce, which end up circulating throughout the body.
A team of scientists believes it has found one such molecule. In a study published in Nature Communications, the researchers identified imidazole propionate (ImP)—a compound produced by certain gut bacteria—as a possible link between the microbiome and Alzheimer’s disease.
From the Gut to the Brain
The hypothesis put forward by the researchers begins in the gut. Some bacteria use an amino acid called histidine, and by metabolizing it, produce ImP. Some of this molecule can enter the bloodstream and circulate throughout the body.
The problem begins at the brain’s border. Experiments in the new study indicate that ImP can weaken the blood-brain barrier, which protects the brain and controls what substances can pass into it via blood. A less effective barrier can help the metabolite enter the brain, where researchers found that it can interact directly with neurons.
This is where two key players in Alzheimer’s disease come into play: the amyloid beta and tau proteins. In a brain affected by Alzheimer’s, amyloid beta accumulates, forming plaques between neurons. Tau, for its part, undergoes abnormal changes that alter its function and promote the formation of harmful structures within cells. Both phenomena are closely linked to neuronal deterioration and constitute two of the disease’s main biological hallmarks.
In the experiments, ImP appears to have the ability to exacerbate both. The researchers found that it can promote the accumulation of amyloid beta plaques and increase tau modification through a process known as phosphorylation.
The model presented in the study functions as a chain: Certain gut bacteria produce ImP; the metabolite enters the bloodstream; it can compromise the blood-brain barrier and reach the brain; and, once there, it promotes changes related to amyloid beta and tau.
But just because a biological explanation is coherent doesn’t mean that the entire chain is actually occurring in the human body. To test the extent of this relationship, the researchers first looked for evidence of it in humans and then tested different parts of the mechanism in mice and cells.
Evidence in Humans and Mice
The scientists analyzed ImP levels in the blood of 1,196 cognitively healthy adults with a mean age of 61.2 years. Those with higher levels of the metabolite scored, on average, worse on cognitive tests. They also had higher levels of pTau-217—a modified form of the tau protein used as a biomarker for Alzheimer’s—and of NfL, a protein released in greater quantities when neurons are damaged. Both can be measured in the blood and provide clues to changes in the brain even before symptoms appear.
The researchers also had access to cognitive tests and biomarker measurements taken over time. When comparing people with the highest and lowest levels of ImP, they found that the former group showed faster cognitive decline over time.
The researchers administered ImP for months to two groups of mice genetically modified to develop characteristics of Alzheimer’s disease. The results were consistent: The metabolite worsened the signs of the disease. In some animals, amyloid beta plaques increased; in others, tau abnormalities and the reaction of astrocytes—cells involved in protecting and maintaining the brain—worsened.
There Is No “Alzheimer’s Bacterium”
Several of the bacteria capable of producing ImP can also be found in healthy people.
“ImP-producing bacteria are present in a large fraction of people, but they’re not very abundant in most people,” says Federico Rey, a coauthor of the study and professor of bacteriology at the University of Wisconsin, in a statement. “But something we have learned over the years is that a microbe doesn’t have to be abundant to have an impact on the host.”
Some bacteria possess the machinery necessary to produce ImP, but having them in the gut does not necessarily mean that a person will accumulate large amounts of the metabolite. The concentration that ultimately reaches the bloodstream appears to depend on a combination of factors. The researchers found differences related to age, sex, and genetics, while previous studies have also linked ImP production to diet and the composition of the microbiome.
For the same reason, having bacteria capable of producing ImP does not mean that a person will develop Alzheimer’s disease. Age, genetics, metabolic, and vascular factors, among others, play a role in the risk of developing the disease.
A Drug to Reduce the Risk?
While it would seem to make sense to develop a drug that would eliminate or deactivate the microorganisms that produce the molecule, the authors caution that the situation is more complex. These bacteria produce ImP by metabolizing histidine, an essential amino acid that the body needs and that is present in numerous foods, particularly those rich in protein.
For the researchers, a more promising approach would be to target ImP itself or the bacterial machinery that produces it. They compare the idea to the treatment of high cholesterol. Just as introducing statins into the body lowers “bad” cholesterol to reduce cardiovascular risk, an inhibitor capable of reducing the concentration of ImP in the blood could one day be developed.
This story originally appeared on WIRED en Español and has been translated from Spanish.
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