Vitamin B6 made by gut bacteria may help nerve cells in the brain produce dopamine, according to animal research into Parkinson’s disease.
Tests in worms and mice found that bacteria producing the vitamin may help cells make dopamine, a chemical involved in motor control that is lacking in Parkinson’s.
Giving vitamin B6 to mice that did not have enough restored their motor coordination, suggesting its production in the gut could be a context-dependent therapeutic target.
Growing evidence suggests that a healthy gut may support the gut-brain axis, the two-way communication system linking the digestive system and the brain, and ease Parkinson’s symptoms.
Some vitamins obtained from food or made by gut bacteria are essential for maintaining healthy nerve cells. However, exactly how these microbes may affect the development or progression of Parkinson’s remains unclear.
The study examined vitamin B6 and its active form, pyridoxal-5′-phosphate, or PLP. PLP acts as a cofactor, a substance that helps enzymes carry out chemical reactions.
It helps convert levodopa, a widely used Parkinson’s medicine, into dopamine in tissues outside the brain. This can reduce the amount of levodopa reaching the brain and make treatment less effective.
The researchers began by comparing stool sample data from people with Parkinson’s and healthy individuals.
People with Parkinson’s had significantly more bacterial genes involved in producing PLP and tyrosine decarboxylase, a bacterial enzyme that uses PLP to break down levodopa before it leaves the digestive tract.
The team then investigated whether vitamin B6 made by gut bacteria could affect Parkinson’s itself by influencing dopamine production.
The first experiments used Caenorhabditis elegans, a type of worm commonly used to study the nervous system.
The worms were fed different strains of Escherichia coli, a bacterial species found in the gut. Some strains naturally produced less PLP than others.
Worms fed the low-PLP bacteria showed poorer dopamine-dependent movement. Giving them pyridoxal, a form of vitamin B6 that can be converted into PLP, restored normal movement.
The researchers also removed the worms’ pdxK gene, which is needed to convert pyridoxal into PLP.
These worms had lower PLP and dopamine levels and moved poorly. Adding pyridoxal increased dopamine levels and improved movement, showing that bacterial vitamin B6 can help when the host cannot make enough PLP.
PLP is needed by dopa decarboxylase, the enzyme humans use to convert levodopa into dopamine.
In worms unable to produce enough levodopa, adding either pyridoxal or levodopa increased dopamine. However, both treatments were much less effective when dopa decarboxylase activity was reduced.
This suggested that bacterial vitamin B6 supports the host’s own dopamine-producing enzyme.
The researchers next studied bacteria without pdxJ, a gene involved in the main pathway that produces vitamin B6.
These bacteria produced less PLP and lower levels of other forms of vitamin B6. Unlike PLP, these other forms can enter the brain more easily before being converted into PLP.
Worms fed bacteria without pdxJ also had lower PLP and dopamine levels. Pyridoxal restored their vitamin B6 levels and normal movement.
In a Parkinson’s worm model that produces human alpha-synuclein, the protein that forms toxic clumps in the brains of people with the disease, bacteria without pdxJ led to more toxic clumps.
Worms carrying a mutation in the human LRRK2 gene, one of the most common genetic causes of Parkinson’s, also developed movement problems when fed bacteria lacking pdxJ.
The researchers then colonised mice with bacteria lacking pdxJ.
The animals had lower vitamin B6 levels in their blood and less PLP in their brains. The greatest effect occurred in the substantia nigra, the brain region where dopamine-producing nerve cells are lost in Parkinson’s.
The mice also had lower levels of tyrosine hydroxylase, an enzyme that starts dopamine production. The changes were not caused by inflammation.
During a six-week movement test, the mice developed poorer balance and coordination. Giving them pyridoxal restored vitamin B6 levels and eased their motor problems.
The study identified a molecular pathway centred on the pdxJ gene that controls vitamin B6 production. The findings suggest bacterial vitamin B6 production may be a risk factor and a potential target for future treatments.
However, its effects may depend on the circumstances. It could support dopamine production under normal conditions while also helping gut bacteria reduce the amount of levodopa available for treatment.
“The dual nature of bacterial PLP, protective under physiological conditions yet antagonistic [with an effect that counteracts treatment with levodopa], emphasises the importance of microbial metabolism in shaping both Parkinson’s onset and treatment response.”
