In a
new study, researchers at the University of California San Francisco, describe
one of the first concrete examples of how the microbiome can interfere with a
drug's intended path through the body. Focusing on levodopa (L-dopa), the
primary treatment for Parkinson's disease, they identified which bacteria are
responsible for degrading the drug and how to stop this microbial interference.
Parkinson's
disease attacks nerve cells in the brain that produce dopamine, without which
the body can suffer tremors, muscle rigidity, and problems with balance and
coordination. L-dopa delivers dopamine to the brain to relieve symptoms. But
only about 1 to 5% of the drug actually reaches the brain.
This
number -- and the drug's efficacy -- varies widely from patient to patient.
Since the introduction of L-dopa in the late 1960s, researchers have known that
the body's enzymes (tools that perform necessary chemistry) can break down
L-dopa in the gut, preventing the drug from reaching the brain. So, the
pharmaceutical industry introduced a new drug, carbidopa, to block unwanted
L-dopa metabolism. Taken together, the treatment seemed to work.
"Even
so," lead researcher professor Maini Rekdal said, "there's a lot of
metabolism that's unexplained, and it's very variable between people."
That variance is a problem: Not only is the drug less effective for some
patients, but when L-dopa is transformed into dopamine outside the brain, the
compound can cause side effects, including severe gastrointestinal distress and
cardiac arrhythmias. If less of the drug reaches the brain, patients are often
given more to manage their symptoms, potentially exacerbating these side
effects.
Maini Rekdal
suspected microbes might be behind the L-dopa disappearance. Since previous
research showed that antibiotics improve a patient's response to L-dopa,
scientists speculated that bacteria might be to blame. Still, no one identified
which bacterial species might be culpable or how and why they eat the drug.
So,
the Balskus team launched an investigation. The unusual chemistry -- L-dopa to
dopamine -- was their first clue.
Few
bacterial enzymes can perform this conversion. But, a good number bind to
tyrosine -- an amino acid similar to L-dopa. And one, from a food microbe often
found in milk and pickles (Lactobacillus brevis), can accept both tyrosine and
L-dopa.
Using
the Human Microbiome Project as a reference, Maini Rekdal and his team hunted
through bacterial DNA to identify which gut microbes had genes to encode a
similar enzyme. Several fit their criteria; but only one strain, Enterococcus
faecalis (E. faecalis), ate all the L-dopa, every time.
With
this discovery, the team provided the first strong evidence connecting E.
faecalis and the bacteria's enzyme (PLP-dependent tyrosine decarboxylase or
TyrDC) to L-dopa metabolism.
And
yet, a human enzyme can and does convert L-dopa to dopamine in the gut, the
same reaction carbidopa is designed to stop. Then why, the team wondered, does
the E. faecalis enzyme escape carbidopa's reach?
Even
though the human and bacterial enzymes perform the exact same chemical
reaction, the bacterial one looks just a little different. Maini Rekdal
speculated that carbidopa may not be able to penetrate the microbial cells or
the slight structural variance could prevent the drug from interacting with the
bacterial enzyme. If true, other host-targeted treatments may be just as
ineffective as carbidopa against similar microbial machinations.
"The
molecule turns off this unwanted bacterial metabolism without killing the
bacteria; it's just targeting a non-essential enzyme," Maini Rekdal said.
This and similar compounds could provide a starting place for the development
of new drugs to improve L-dopa therapy for Parkinson's patients.
The
team might have stopped there. But instead, they pushed further to unravel a
second step in the microbial metabolism of L-dopa. After E. faecalis converts
the drug into dopamine, a second organism converts dopamine into another
compound, meta-tyramine.
To
find this second organism, Maini Rekdal left behind his mother dough's
microbial masses to experiment with a fecal sample. He subjected its diverse
microbial community to a Darwinian game, feeding dopamine to hordes of microbes
to see which prospered.
Eggerthella
lenta won. These bacteria consume dopamine, producing meta-tyramine as a
by-product. This kind of reaction is challenging, even for chemists.
"There's no way to do it on the bench top," Maini Rekdal said,
"and previously no enzymes were known that did this exact reaction."
The
meta-tyramine by-product may contribute to some of the noxious L-dopa side
effects; more research needs to be done. But, apart from the implications for
Parkinson's patients, E. lenta's novel chemistry raises more questions: Why
would bacteria adapt to use dopamine, which is typically associated with the
brain? What else can gut microbes do? And does this chemistry impact our
health?
"All
of this suggests that gut microbes may contribute to the dramatic variability
that is observed in side effects and efficacy between different patients taking
L-dopa," Balskus said.
But
this microbial interference may not be limited to L-dopa and Parkinson's
disease. Their study could shepherd additional work to discover exactly who is
in our gut, what they can do, and how they can impact our health, for better or
worse.
See:
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology
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