August 21, 2025 • 11 mins
Parkinson’s disease has long been defined by the death of neurons in the brain. Yet, decades before tremors appear, the first signs emerge quietly in the gut. Recent evidence reveals a puzzling disappearance: microbial pathways that once produced two well-known compounds fall silent. Their absence strips away protective metabolites, erodes the intestinal barrier, and leaves neurons exposed to toxins that ignite α-synuclein fibrils. Could the vanishing of two simple vitamins be an overlooked trigger, and a potential target, in the unfolding mystery of Parkinson’s disease?
00:00 Introduction to Parkinson's Disease
00:35 Early Signs and Gut Connection
01:19 The Braak Hypothesis and Vagus Nerve
02:08 Gut Microbiome and Vitamin Pathways
03:10 Global Meta-Analysis and Key Findings
04:37 Impact of Vitamin Deficiencies
08:57 Potential for Vitamin Supplementation
11:20 Conclusion and Future Implications
PMID: 37314861
Mark as Played
Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Speaker 1 (00:00):
Parkinson's disease is usually thought of as a brain
disorder, the slow death ofneurons that control movement.
But decades before tremorsappear, other signs emerge
Constipation, restless sleep,subtle changes that point away
from the brain and toward thegut.
Something small is missingthere, something that vanishes
quietly long before neuronsbegin to fail.
And that absence may hold oneof the most overlooked clues yet
(00:24):
in the mystery of Parkinson's.
Parkinson's disease isremembered for its outward signs
tremors, slowed movement andmuscle rigidity.
But those visible symptoms arethe only act of a much longer
(00:45):
story.
Years before the brain falters,subtle changes appear Digestion
slows, sleep fragments and mooderodes.
And beneath these warning signs, researchers have discovered an
even stranger thread In the gutentire pathways for producing
two critical compounds seem tovanish.
The disease always has beendefined by abnormal protein
(01:06):
clumps alpha-synuclein fibrilsforming in dopamine neurons of
the substantia nigra.
Yet these same fibrils appearfar beyond the brain in the
brainstem, in the autonomicnervous system, even in the
mucosa of the intestine.
Two decades ago, in 2003, theBRAC hypothesis suggested they
might start in the gut itself,climbing along the vagus nerve
(01:28):
toward the brain.
The idea seemed radical at thetime, but the evidence kept
mounting Constipation,depression and disordered sleep,
often years, even up to twodecades, before motor decline
presents.
Interestingly, patients who hadtheir vagus nerve surgically
cut a complete vagotomy showednearly half the risk of
developing Parkinson's, as ifthe disease root had been
(01:49):
severed altogether.
Yet this raised a deeperquestion what makes the gut
vulnerable in the first place?
Why does the protective mucusbarrier thin, exposing nerves to
the very toxins of modern lifepesticides, herbicides,
industrial chemicals that mightdrive the aggregation of
alpha-synuclein?
The gut microbiome has long beensuspected, but until recently
(02:12):
the evidence was murky.
Studies showed differences inbacterial communities, but not
the precise clue investigatorswere searching for.
Recently, a new line ofevidence has emerged across
patients with Parkinson's.
Researchers consistently find aloss of microbial pathways that
(02:32):
synthesize two vitaminsessential for maintaining gut
defenses.
And when those vitamins decline, the consequences ripple
outward Fewer protectivemetabolites, a compromised
barrier and a nervous systemincreasingly exposed.
Which brings us back to themystery.
Could the silent disappearanceof these vitamins, made not by
human cells but by our residentmicrobes, be the trigger that
(02:52):
sets Parkinson's in motion?
When the first reports onParkinson's and the microbiome
appeared, they were fragmentedSmall studies, different methods
and inconsistent results.
Some showed certain speciesmissing, others found entirely
different shifts.
No single signature seemed todefine the disease.
To cut through this noise,researchers in Japan turned to
(03:14):
shotgun metagenomic sequencing.
Rather than just catalogingwhich bacteria were present,
shotgun sequencing reads thegenetic instructions themselves,
the metabolic blueprints ofwhat those microbes are capable
of producing.
They didn't stop with their owndataset.
Instead, they combined it withfive other cohorts from the US,
(03:34):
germany, china and Taiwan,building a global meta-analysis
across six different countries.
The first result seemedcounterintuitive Alpha diversity
was consistently higher inParkinson's.
Alpha diversity is a measure ofhow many different species live
in the gut and how evenlybalanced they are.
Usually, higher alpha diversityis considered a good thing.
(03:56):
In this case, patients harboredmore species with abundances
more evenly distributed.
At first glance that mightsound like resilience, but the
effect was deceptive.
Within that broader mix ofmicrobes, important functions
had gone missing.
Look closer and a patternemerged.
The mucin-degrading genusAcromantia was consistently
expanded, while short-chainfatty acid-producing bacteria
(04:18):
like Rosburia andFecalibacterium were diminished.
The shift hinted at an erosionof the gut barrier less butyrate
to feed colonocytes, more mucinconsumption, stripping the
protective lining.
It suggested that even withmore microbial variety, the
ecosystem was moving in thewrong direction.
The real breakthrough came whenthe team analyzed not the
(04:40):
taxonomy but the metabolicpathways.
Using gene set enrichmentanalyses, they tested thousands
of enzymatic functions to seewhich were consistently reduced
in Parkinson's patients.
Out of all possible pathways,two stood out above the rest
vitamin B2 riboflavin metabolismand vitamin B7 biotin
metabolism.
(05:00):
Across data sets acrosscountries, these pathways were
repeatedly and significantlydepleted.
Even after adjusting forconfounders like age, bmi,
constipation and medications.
The signal remained strong.
In other words, parkinson'spatients carried microbial
communities with fewer genes tomake riboflavin, vitamin B2, and
(05:22):
biotin vitamin B7.
To make riboflavin vitamin B2,and biotin vitamin B7.
On its own, that finding wouldalready be remarkable.
Human cells cannot synthesizethese vitamins.
We rely on diet and microbialpartners to supply them.
But the researchers took theanalysis further.
They measured metabolitesdirectly in the fecal samples
and the correlations were clear.
The reduction in riboflavin andbiotin biosynthesis genes track
(05:45):
closely with reductions inshort-chain fatty acids and
polyamines.
Both of these classes ofmolecules are absolutely
indispensable for intestinalhealth.
Short-chain fatty acids feedcolonocytes and induce
regulatory immune cells.
Polyamines maintain epithelialintegrity and anti-inflammatory
balance.
Together they help preserve themucus layer that insulates the
(06:06):
enteric nervous system fromtoxic insults.
Remove that protection and thestage is set.
Increase intestinalpermeability, exposure of
enteric neurons to pesticides,herbicides and xenobiotics and
the abnormal aggregation ofalpha-synuclein fibrils within
the gut wall.
From there the pathology canclimb upward toward the brain.
(06:27):
For decades, scientists havesuspected a gut origin for
Parkinson's.
What this study added was astrikingly specific clue Not
just a generic shift inbacterial species, but the
silencing of entire vitaminpathways.
And the loss of those pathwaysappeared to cascade directly
into the biochemicalvulnerabilities long observed in
Parkinson's Loss of barrierintegrity, chronic inflammation
(06:50):
and the initiation of proteinmisholding.
The disappearance of thesemicrobial vitamin pathways
wasn't just a statisticalcuriosity.
It connected directly to thebiochemical machinery that keeps
the gut protected.
First, riboflavin or vitamin B2,plays a structural role in
energy metabolism.
It forms part of the electrontransfer flavoprotein complex of
(07:10):
an enzyme called butyryl-CoAdehydrogenase.
This is what's called aflavoprotein, meaning that it's
reliant on the use of riboflavinvitamin B2,.
To operate, this enzyme isrequired to generate butyrate,
one of the most importantshort-chain fatty acids for
colon health.
Without adequate riboflavin,butyrate production falters.
(07:32):
Second, riboflavin indirectlygoverns polyamine synthesis
Inside cells.
Riboflavin is converted toflavin mononucleotide, or FMN,
which acts as a cofactor forpyridoxine 5-phosphate oxidase,
the enzyme that activatesvitamin B6.
Active vitamin B6, in turn isessential for the enzyme
ornithine decarboxylase, whichcatalyzes the first step in the
(07:53):
polyamine pathway producingputrazine, spermidine that one
most of us have heard of andsperamine.
These polyamines reinforce themucus layer, regulate immune
signaling and suppressinflammation.
In this way, a lack ofriboflavin can cascade into a
deficiency of both vitamin B6activity and polyamine
production, as it's been saidthat vitamin B2 is the limiting
(08:16):
nutrient to actually maintainvitamin B6 status, of course,
besides vitamin B6 itself.
Third, biotin or vitamin B7also appears to intersect with
these protective systems, butthe exact targets remain unknown
.
The enzymes most vulnerable tobiotin deficiency have not yet
been mapped.
In Parkinson's Taken together,the logic is clear when the
(08:37):
microbial supply of riboflavinand biotin collapses, butyrate
levels fall, polyamines declineand the gut's protective barrier
thins.
What begins as a smallbiochemical silence ripples
outward into structural weakness, exposing the enteric nervous
system to the toxins that sparkalpha-synuclein aggregation.
It would be easy to assumethese vitamin losses are simply
(08:59):
collateral damage, a downstreameffect of a body already in
decline.
But the evidence pushes back.
In animal studies, riboflavindeprivation for three weeks,
sharply reduced short-chainfatty acids Repletion restored
them almost immediately.
In humans, 50 to 100 milligramsof riboflavin for two weeks,
(09:21):
increased fecal short-chainfatty acid biosynthesis.
The vitamins weren't justmarkers, they were levers.
Even clinical observations hintat more than coincidence.
In a small study, parkinson'spatients given high doses of
riboflavin around 30 milligramstwice daily showed recovery of
motor function.
Another pilot study gave 30milligrams of riboflavin and
(09:42):
found increased abundance ofFecalibacterium prosnitzi, a
prominent butyrate-producingspecies in the gut In Crohn's
disease.
Supplementation with 100milligrams of riboflavin per day
decreased systemic oxidativestress, reduced inflammatory
markers and lowered diseaseactivity.
These are precisely theprocesses oxidative damage,
(10:03):
mitochondrial stress, chronicinflammation that also drive
Parkinson's pathology.
Biotin tells a parallel story,though not yet studied directly
in Parkinson's, trials inprogressive multiple sclerosis
have tested high-dose biotin at100 to 300 milligrams per day,
showing functional improvementsin vision and motor capacity.
Known for its anti-inflammatoryactions, biotin could in theory
(10:25):
reinforce the same fragilepathways in Parkinson's.
The implication here isprofound.
The disappearance of riboflavinin biotin might not simply
reflect the microbial aftermathof Parkinson's.
Their absence could beweakening the very defenses that
hold the disease at bay,accelerating barrier failure,
inflammation and neuronalvulnerability, and their return,
even through targetedsupplementation, may restore
(10:46):
part of what the microbiome haslost.
The loss of riboflavin andbiotin pathways leaves the gut
barrier compromised, short-chainfatty acids and polyamines
decline, the mucous layer thinsand enteric neurons are exposed
to toxins.
In this setting,alpha-synuclein fibrils form and
inflammation drives pathologyforward.
What makes this findingstriking is that these
deficiencies may not be passive.
This setting alpha-synucleinfibrils form and inflammation
(11:08):
drives pathology forward.
What makes this findingstriking is that these
deficiencies may not be passive.
Evidence suggests restoring themissing vitamins can revive
microbial metabolism, reinforcethe barrier and reduce stressors
linked to Parkinson'sprogression.
It isn't a cure, but itreframes the disease, not only
as a neurological disorder, butas one that may be shaped by the
silent disappearance, andpossibly restoration, of two
(11:31):
simple vitamins.
Until next time, stay healthy.
Parkinson's disease is usually thought of as a brain
disorder, the slow death ofneurons that control movement.
But decades before tremorsappear, other signs emerge
Constipation, restless sleep,subtle changes that point away
from the brain and toward thegut.
Something small is missingthere, something that vanishes
quietly long before neuronsbegin to fail.
And that absence may hold oneof the most overlooked clues yet
(00:24):
in the mystery of Parkinson's.
Parkinson's disease isremembered for its outward signs
tremors, slowed movement andmuscle rigidity.
But those visible symptoms arethe only act of a much longer
(00:45):
story.
Years before the brain falters,subtle changes appear Digestion
slows, sleep fragments and mooderodes.
And beneath these warning signs, researchers have discovered an
even stranger thread In the gutentire pathways for producing
two critical compounds seem tovanish.
The disease always has beendefined by abnormal protein
(01:06):
clumps alpha-synuclein fibrilsforming in dopamine neurons of
the substantia nigra.
Yet these same fibrils appearfar beyond the brain in the
brainstem, in the autonomicnervous system, even in the
mucosa of the intestine.
Two decades ago, in 2003, theBRAC hypothesis suggested they
might start in the gut itself,climbing along the vagus nerve
(01:28):
toward the brain.
The idea seemed radical at thetime, but the evidence kept
mounting Constipation,depression and disordered sleep,
often years, even up to twodecades, before motor decline
presents.
Interestingly, patients who hadtheir vagus nerve surgically
cut a complete vagotomy showednearly half the risk of
developing Parkinson's, as ifthe disease root had been
(01:49):
severed altogether.
Yet this raised a deeperquestion what makes the gut
vulnerable in the first place?
Why does the protective mucusbarrier thin, exposing nerves to
the very toxins of modern lifepesticides, herbicides,
industrial chemicals that mightdrive the aggregation of
alpha-synuclein?
The gut microbiome has long beensuspected, but until recently
(02:12):
the evidence was murky.
Studies showed differences inbacterial communities, but not
the precise clue investigatorswere searching for.
Recently, a new line ofevidence has emerged across
patients with Parkinson's.
Researchers consistently find aloss of microbial pathways that
(02:32):
synthesize two vitaminsessential for maintaining gut
defenses.
And when those vitamins decline, the consequences ripple
outward Fewer protectivemetabolites, a compromised
barrier and a nervous systemincreasingly exposed.
Which brings us back to themystery.
Could the silent disappearanceof these vitamins, made not by
human cells but by our residentmicrobes, be the trigger that
(02:52):
sets Parkinson's in motion?
When the first reports onParkinson's and the microbiome
appeared, they were fragmentedSmall studies, different methods
and inconsistent results.
Some showed certain speciesmissing, others found entirely
different shifts.
No single signature seemed todefine the disease.
To cut through this noise,researchers in Japan turned to
(03:14):
shotgun metagenomic sequencing.
Rather than just catalogingwhich bacteria were present,
shotgun sequencing reads thegenetic instructions themselves,
the metabolic blueprints ofwhat those microbes are capable
of producing.
They didn't stop with their owndataset.
Instead, they combined it withfive other cohorts from the US,
(03:34):
germany, china and Taiwan,building a global meta-analysis
across six different countries.
The first result seemedcounterintuitive Alpha diversity
was consistently higher inParkinson's.
Alpha diversity is a measure ofhow many different species live
in the gut and how evenlybalanced they are.
Usually, higher alpha diversityis considered a good thing.
(03:56):
In this case, patients harboredmore species with abundances
more evenly distributed.
At first glance that mightsound like resilience, but the
effect was deceptive.
Within that broader mix ofmicrobes, important functions
had gone missing.
Look closer and a patternemerged.
The mucin-degrading genusAcromantia was consistently
expanded, while short-chainfatty acid-producing bacteria
(04:18):
like Rosburia andFecalibacterium were diminished.
The shift hinted at an erosionof the gut barrier less butyrate
to feed colonocytes, more mucinconsumption, stripping the
protective lining.
It suggested that even withmore microbial variety, the
ecosystem was moving in thewrong direction.
The real breakthrough came whenthe team analyzed not the
(04:40):
taxonomy but the metabolicpathways.
Using gene set enrichmentanalyses, they tested thousands
of enzymatic functions to seewhich were consistently reduced
in Parkinson's patients.
Out of all possible pathways,two stood out above the rest
vitamin B2 riboflavin metabolismand vitamin B7 biotin
metabolism.
(05:00):
Across data sets acrosscountries, these pathways were
repeatedly and significantlydepleted.
Even after adjusting forconfounders like age, bmi,
constipation and medications.
The signal remained strong.
In other words, parkinson'spatients carried microbial
communities with fewer genes tomake riboflavin, vitamin B2, and
(05:22):
biotin vitamin B7.
To make riboflavin vitamin B2,and biotin vitamin B7.
On its own, that finding wouldalready be remarkable.
Human cells cannot synthesizethese vitamins.
We rely on diet and microbialpartners to supply them.
But the researchers took theanalysis further.
They measured metabolitesdirectly in the fecal samples
and the correlations were clear.
The reduction in riboflavin andbiotin biosynthesis genes track
(05:45):
closely with reductions inshort-chain fatty acids and
polyamines.
Both of these classes ofmolecules are absolutely
indispensable for intestinalhealth.
Short-chain fatty acids feedcolonocytes and induce
regulatory immune cells.
Polyamines maintain epithelialintegrity and anti-inflammatory
balance.
Together they help preserve themucus layer that insulates the
(06:06):
enteric nervous system fromtoxic insults.
Remove that protection and thestage is set.
Increase intestinalpermeability, exposure of
enteric neurons to pesticides,herbicides and xenobiotics and
the abnormal aggregation ofalpha-synuclein fibrils within
the gut wall.
From there the pathology canclimb upward toward the brain.
(06:27):
For decades, scientists havesuspected a gut origin for
Parkinson's.
What this study added was astrikingly specific clue Not
just a generic shift inbacterial species, but the
silencing of entire vitaminpathways.
And the loss of those pathwaysappeared to cascade directly
into the biochemicalvulnerabilities long observed in
Parkinson's Loss of barrierintegrity, chronic inflammation
(06:50):
and the initiation of proteinmisholding.
The disappearance of thesemicrobial vitamin pathways
wasn't just a statisticalcuriosity.
It connected directly to thebiochemical machinery that keeps
the gut protected.
First, riboflavin or vitamin B2,plays a structural role in
energy metabolism.
It forms part of the electrontransfer flavoprotein complex of
(07:10):
an enzyme called butyryl-CoAdehydrogenase.
This is what's called aflavoprotein, meaning that it's
reliant on the use of riboflavinvitamin B2,.
To operate, this enzyme isrequired to generate butyrate,
one of the most importantshort-chain fatty acids for
colon health.
Without adequate riboflavin,butyrate production falters.
(07:32):
Second, riboflavin indirectlygoverns polyamine synthesis
Inside cells.
Riboflavin is converted toflavin mononucleotide, or FMN,
which acts as a cofactor forpyridoxine 5-phosphate oxidase,
the enzyme that activatesvitamin B6.
Active vitamin B6, in turn isessential for the enzyme
ornithine decarboxylase, whichcatalyzes the first step in the
(07:53):
polyamine pathway producingputrazine, spermidine that one
most of us have heard of andsperamine.
These polyamines reinforce themucus layer, regulate immune
signaling and suppressinflammation.
In this way, a lack ofriboflavin can cascade into a
deficiency of both vitamin B6activity and polyamine
production, as it's been saidthat vitamin B2 is the limiting
(08:16):
nutrient to actually maintainvitamin B6 status, of course,
besides vitamin B6 itself.
Third, biotin or vitamin B7also appears to intersect with
these protective systems, butthe exact targets remain unknown
.
The enzymes most vulnerable tobiotin deficiency have not yet
been mapped.
In Parkinson's Taken together,the logic is clear when the
(08:37):
microbial supply of riboflavinand biotin collapses, butyrate
levels fall, polyamines declineand the gut's protective barrier
thins.
What begins as a smallbiochemical silence ripples
outward into structural weakness, exposing the enteric nervous
system to the toxins that sparkalpha-synuclein aggregation.
It would be easy to assumethese vitamin losses are simply
(08:59):
collateral damage, a downstreameffect of a body already in
decline.
But the evidence pushes back.
In animal studies, riboflavindeprivation for three weeks,
sharply reduced short-chainfatty acids Repletion restored
them almost immediately.
In humans, 50 to 100 milligramsof riboflavin for two weeks,
(09:21):
increased fecal short-chainfatty acid biosynthesis.
The vitamins weren't justmarkers, they were levers.
Even clinical observations hintat more than coincidence.
In a small study, parkinson'spatients given high doses of
riboflavin around 30 milligramstwice daily showed recovery of
motor function.
Another pilot study gave 30milligrams of riboflavin and
(09:42):
found increased abundance ofFecalibacterium prosnitzi, a
prominent butyrate-producingspecies in the gut In Crohn's
disease.
Supplementation with 100milligrams of riboflavin per day
decreased systemic oxidativestress, reduced inflammatory
markers and lowered diseaseactivity.
These are precisely theprocesses oxidative damage,
(10:03):
mitochondrial stress, chronicinflammation that also drive
Parkinson's pathology.
Biotin tells a parallel story,though not yet studied directly
in Parkinson's, trials inprogressive multiple sclerosis
have tested high-dose biotin at100 to 300 milligrams per day,
showing functional improvementsin vision and motor capacity.
Known for its anti-inflammatoryactions, biotin could in theory
(10:25):
reinforce the same fragilepathways in Parkinson's.
The implication here isprofound.
The disappearance of riboflavinin biotin might not simply
reflect the microbial aftermathof Parkinson's.
Their absence could beweakening the very defenses that
hold the disease at bay,accelerating barrier failure,
inflammation and neuronalvulnerability, and their return,
even through targetedsupplementation, may restore
(10:46):
part of what the microbiome haslost.
The loss of riboflavin andbiotin pathways leaves the gut
barrier compromised, short-chainfatty acids and polyamines
decline, the mucous layer thinsand enteric neurons are exposed
to toxins.
In this setting,alpha-synuclein fibrils form and
inflammation drives pathologyforward.
What makes this findingstriking is that these
deficiencies may not be passive.
This setting alpha-synucleinfibrils form and inflammation
(11:08):
drives pathology forward.
What makes this findingstriking is that these
deficiencies may not be passive.
Evidence suggests restoring themissing vitamins can revive
microbial metabolism, reinforcethe barrier and reduce stressors
linked to Parkinson'sprogression.
It isn't a cure, but itreframes the disease, not only
as a neurological disorder, butas one that may be shaped by the
silent disappearance, andpossibly restoration, of two
(11:31):
simple vitamins.
Until next time, stay healthy.
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