Intestinal microbes eat our drugs – ScienceDaily

The reactions that occur after cleaning the plates are even more crucial. When a slice of yeast crosses the digestive system, the trillions of germs that live in our intestines help the body break down that bread to absorb nutrients. Since the human body can not digest certain substances – essential fibers, for example – microbes reinforce chemistry and can not perform human chemistry.

"But this type of microbial metabolism can also be detrimental," said Maini Rekdal, a graduate student of Professor Emily Balskus's lab and first author of their new study published in Science. According to Maini Rekdal, intestinal microbes can also chew drugs, often with dangerous side effects. "Maybe the drug will not reach its target in the body, maybe it will become toxic all of a sudden, maybe it will be less useful," Maini said. Rekdal.

In their study, Balskus, Maini Rekdal and their collaborators at the University of California at San Francisco describe one of the first concrete examples of how the microbiome can interfere with the path of a drug in the body. Focusing on levodopa (L-dopa), the leading treatment for Parkinson's disease, they identified the bacteria responsible for drug degradation and ways to stop this microbial interference.

Parkinson's disease attacks dopamine-producing brain nerve cells, without which the body can suffer from tremors, muscle rigidity, and balance and coordination problems. L-dopa administers dopamine to the brain to relieve symptoms. But only about 1 to 5% of the medicine actually reaches the brain.

This number and the effectiveness of the drug vary greatly from one patient to the other. Since the introduction of L-dopa at the end of the 1960s, researchers have known that the body's enzymes (tools necessary for the necessary chemistry) can break down L-dopa in the intestine, thus preventing the drug from developing. to reach the brain. Thus, the pharmaceutical industry has introduced a new drug, carbidopa, to block the undesirable metabolism of L-dopa. Taken together, the treatment seemed to work.

"Even so," said Maini Rekdal, "there is a lot of unexplained metabolism, and it varies a lot from one person to the other." This variance is a problem: not only is the drug less effective in some patients, but when L-dopa is converted to dopamine outside the brain, the compound can cause side effects, including serious gastrointestinal disorders and cardiac arrhythmias. If less medication reaches the brain, patients are often more often called upon to manage their symptoms, which can worsen these side effects.

Maini Rekdal suspects that microbes may be responsible for the disappearance of L-dopa. Previous research has shown that antibiotics improve the patient's response to L-dopa, the scientists hypothesized that bacteria could be to blame. Yet no one has identified the bacterial species that could be guilty or how and why they eat the drug.

The Balskus team has therefore launched an investigation. Unusual chemistry – L-dopa to dopamine – was their first clue.

Few bacterial enzymes can perform this conversion. But many bind to tyrosine – an amino acid similar to L-dopa. And one, derived 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 her team explored bacterial DNA to identify intestinal microbes with genes encoding a similar enzyme. Several correspond to their criteria; but only one strain, Enterococcus faecalis (E. faecalis), ate all L-dopa each time.

With this discovery, the team provided the first strong evidence linking E. faecalis and the enzyme of the bacterium (PLP-dependent tyrosine decarboxylase or TyrDC) to the metabolism of L-dopa.

And yet, a human enzyme can and must convert L-dopa to dopamine in the gut, the same reaction that carbidopa is designed to stop. In this case, why the enzyme of E. Is Faecalis immune to carbidopa?

Even though the human and bacterial enzymes perform exactly the same chemical reaction, the bacterial one is slightly different. Maini Rekdal has hypothesized that carbidopa might not be able to penetrate the microbial cells or that the slight structural variance could prevent the drug from interacting with the bacterial enzyme. If this is true, other targeted treatment with the host may be just as ineffective as carbidopa against similar microbial machinations.

But the cause may not matter. Balskus and his team have already discovered a molecule capable of inhibiting the bacterial enzyme.

"The molecule disables this unwanted bacterial metabolism without killing the bacteria, it simply targets a non-essential enzyme," said Maini Rekdal. These and similar compounds could be a starting point for the development of new drugs to improve L-dopa treatment in Parkinson's patients.

The team could have stopped there. But instead, they went further to understand a second step in microbial metabolism of L-dopa. After E. faecalis has converted the drug into dopamine, a second organism converts dopamine into another compound, meta-tyramine.

To find this second organism, Maini Rekdal left behind the microbial masses of his mother's dough to experiment with a sample of feces. He subjected his diverse microbial community to a Darwinian game, feeding the dopamine of hordes of microbes to see who was thriving.

Eggerthella lenta won. These bacteria consume dopamine and produce meta-tyramine as a by-product. This type of reaction is difficult even for chemists. "There is no way to do it on the bench," said Maini Rekdal, "and previously, there was no known enzyme that caused this exact reaction."

The byproduct of meta-tyramine may contribute to some of the harmful side effects of L-dopa; more research needs to be done. In addition to the implications for patients with Parkinson's disease, the new chemistry of E. Lenta raises other questions: why would bacteria adapt to the use of dopamine, usually associated with the brain? What can intestinal microbes do? And does this chemistry have an impact on our health?

"All of this suggests that intestinal microbes can contribute to the considerable variability observed in terms of side effects and effectiveness 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 lead to additional work to find out exactly who is in our instinct, what they can do and how they can affect our health, for better or for worse.