A letter has been published in the journal Nature that states the findings of an early study supporting a “gut-brain” connection in this disease. A letter is a short version of a report outlining original research that is of interest to investigators in other fields. The study found that bacterial infections in the intestines may trigger Parkinson’s progression by altering the immune system and damaging dopaminergic neurons.
There is a gene called the PINK1 gene which codes for an enzyme that protects mitochondria — the cell’s energy-producing powerhouse. They have strong evidence that suggests mutations of this gene during periods of cellular stress are linked to early-onset hereditary Parkinson’s. Damage to the brain occurs when these genes are mutated because it causes tangles of the PINK1 protein build inside mitochondria in brain cells.
The researchers noted:
Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles.
Some studies have supported the thought that PINK1 has something to do with the clearance of damaged mitochondria. However, the findings are not consistent enough to support the protein’s exact role in the cellular cleaning process. The thing is, mice without the PINK1 gene are generally healthy.
So, even though mutations in PINK1 in Parkinson’s patients are known to promote disease progression, mice without the gene display little, if any, Parkinson’s-related motor symptoms. Meaning, the loss of the protein’s (PINK1) function may not be what triggers the neurodegenerative disorder.
Taking into consideration previous research, scientists at the Université de Montréal hypothesized that infection with a specific type of bacteria — called Gram-negative bacteria — could activate the immune system and “order it” to produce mitochondria-specific autoreactive CD8+ T-cells. CD8+ T-cells (aka cytotoxic T-lymphocytes) are very important for immune defense against infectious agents (intracellular pathogens).
The Study
- To test the theory, the researchers first conducted experiments in a lab dish, then in animal subjects.
- In the lab, they infected mouse cells with several bacteria, including Gram-positive and Gram-negative ones. Then, they observed.
- They saw that only the Gram-negative bacteria-induced the activation of an immune response. The highest levels were obtained when the intestinal bacteria Escherichia coli (EPEC) and Novosphingobium aromaticivorans were used.
- In animal studies, they infected wild-type (normal) mice and animals engineered to lack the PINK1 protein. They did so by administering the bacteria directly into the animals’ stomach by a tube (oral gavage). They wanted to determine whether Citrobacter — a Gram-negative mouse intestinal pathogen that is used as a model of human EPEC infection — triggered an immune activation.
- They found that intestinal infection with these Gram-negative bacteria was found to activate immune mechanisms necessary for CD8+ T-cells to travel to peripheral tissues and the brain (compromising cell function) in mice lacking the PINK1 protein.
- Neurons within the animals’ striatum — a brain center crucial for motor control that’s severely damaged in Parkinson’s — were significantly degenerated.
This study further strengthens the link between Parkinson’s and the gut – how the problem may begin in the gut and then spread to the brain through the nervous system. It is already known that microorganisms in the gut communicate with the central nervous system through nervous, endocrine, and immune signaling pathways.
The researchers concluded:
These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease, which highlights the relevance of the gut–brain axis in the disease.
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