A new study has identified a specific substance produced by a common gut bacterium that can travel to the brain and cause the loss of dopamine-producing neurons, a hallmark of Parkinson’s disease. The research, published in the journal Nature Communications, establishes a direct chemical link from a gut microbe to neurodegeneration, suggesting a new avenue for understanding and potentially treating the condition.
The investigation was led by a collaborative team of scientists, with joint supervision by Yunjong Lee from Sungkyunkwan University School of Medicine and Ara Koh from Pohang University of Science and Technology in the Republic of Korea. They were joined by researchers from institutions in China and Sweden. The team’s work was motivated by a growing body of evidence connecting the gut microbiome, the vast community of microorganisms living in our digestive tracts, to Parkinson’s disease.
While previous studies have shown that the gut bacteria composition is different in individuals with Parkinson’s disease, the specific microbes and the mechanisms by which they might influence the brain have remained largely unknown. The researchers aimed to identify a particular bacterial product, known as a metabolite, that could cross from the gut into the brain and directly contribute to the disease’s pathology.
To begin their investigation, the researchers re-analyzed genetic data from a large group of 491 individuals with Parkinson’s disease and 234 healthy controls. This analysis confirmed that people with Parkinson’s disease had higher levels of a bacterium called Streptococcus mutans in their gut. They also found that the gene for an enzyme called urocanate reductase was more abundant in the gut microbiomes of the patient group.
This enzyme is responsible for producing a metabolite called imidazole propionate. Consistent with these genetic findings, when the team measured imidazole propionate levels in blood plasma from a separate cohort of 65 patients and 65 healthy controls, they found significantly higher concentrations in the individuals with Parkinson’s disease.
Having established a correlation in humans, the researchers turned to animal models to determine if this link was causal. They introduced Streptococcus mutans into the guts of germ-free mice, which are raised in a sterile environment and have no native gut bacteria. Another group of mice received heat-killed, or pasteurized, Streptococcus mutans to test if the bacterium’s metabolic activity was necessary for any effects.
Mice colonized with live Streptococcus mutans showed a significant loss of dopamine-producing neurons in a specific area of the midbrain. They also developed signs of brain inflammation, including the activation of brain support cells called astrocytes and microglia. These brain changes were accompanied by motor impairments, as measured by a pole-climbing test. In contrast, mice given the inactive, pasteurized bacteria showed no such symptoms.
The scientists then measured metabolite levels in the mice. They found that animals colonized with live Streptococcus mutans had elevated levels of imidazole propionate in both their blood and their brain tissue, confirming that the substance produced in the gut could cross the blood-brain barrier and enter the central nervous system. This finding suggested that imidazole propionate itself could be the agent driving the brain damage.
To isolate its effect, the team engineered a harmless strain of Escherichia coli, which does not naturally produce imidazole propionate, to carry the gene for urocanate reductase from Streptococcus mutans. When these engineered bacteria were introduced into germ-free mice, the animals began to produce imidazole propionate and subsequently developed the same Parkinson’s-like symptoms: loss of dopamine neurons, brain inflammation, and motor deficits. This experiment demonstrated that the enzyme and its chemical product were sufficient to induce the pathology.
The research team also explored the molecular mechanism inside brain cells. They discovered that imidazole propionate activates a key cellular signaling pathway known as mTORC1, which is involved in cell growth, aging, and neurodegeneration. In the brains of mice colonized with Streptococcus mutans, the mTORC1 pathway was specifically activated in dopamine-producing neurons.
To confirm that this pathway was responsible for the damage, the researchers treated mice with a drug called rapamycin, which inhibits mTORC1. When mice were given both Streptococcus mutans and rapamycin, they were protected from the loss of dopamine neurons and motor problems, even though imidazole propionate levels in their brains remained high. This showed that imidazole propionate causes its toxic effects by acting through the mTORC1 pathway.
Parkinson’s disease is also characterized by the clumping of a protein called alpha-synuclein in the brain. The scientists investigated whether imidazole propionate could affect this process. They used a mouse model where small “seeds” of alpha-synuclein are injected into the brain to start the clumping process. When these mice were also colonized with Streptococcus mutans, the formation of alpha-synuclein clumps was significantly accelerated, the loss of dopamine neurons was more severe, and their motor problems worsened. This suggests that the bacterial metabolite can exacerbate the core protein-related pathology of the disease.
Finally, to prove that imidazole propionate alone was the culprit, the researchers administered the purified chemical directly to mice, either through injections into the bloodstream or directly into the brain. In both cases, the administration of imidazole propionate by itself was enough to cause the selective loss of dopamine neurons and motor deficits, and this damage was prevented by the mTORC1 inhibitor rapamycin.
While these findings provide a compelling link, the study has some limitations. The experiments were conducted in mice, and the mechanisms may not be identical in humans. Future research is needed to understand why dopamine-producing neurons appear to be particularly vulnerable to imidazole propionate. The researchers also note that long-term studies in human populations are necessary to determine if elevated levels of imidazole propionate are a risk factor that predicts the future development of Parkinson’s disease or simply a consequence of it.
These results open the door to new therapeutic strategies. For instance, developing a drug that could inhibit the urocanate reductase enzyme in the gut might lower the production of imidazole propionate and offer a way to slow or prevent the progression of the disease.
“Our study provides a mechanistic understanding of how oral microbes in the gut can influence the brain and contribute to the development of Parkinson’s disease,” said Professor Ara Koh. “It highlights the potential of targeting the gut microbiota as a therapeutic strategy, offering a new direction for Parkinson’s treatment.”
The study, “Gut microbial production of imidazole propionate drives Parkinson’s pathologies,” was authored by Hyunji Park, Jiwon Cheon, Hyojung Kim, Jihye kim, Jihyun Kim, Jeong-Yong Shin, Hyojin Kim, Gaeun Ryu, In Young Chung, Ji Hun Kim, Doeun Kim, Zhidong Zhang, Hao Wu, Katharina R. Beck, Fredrik Bäckhed, Han-Joon Kim, Yunjong Lee, and Ara Koh.
