Gut Microbiota May Hold Key to Efficacy of Diabetes Drugs

Harvard scientists report an integral role of gut bacteria acting as a gateway to bioavailability of levodopa in patients with Parkinson's disease; their work echoes similar research finding the microbiome also affects efficacy of diabetes drugs.

With Emily Balskus, PhD, and Hariom Yadav, PhD

Managing the increasing prevalence of type 2 diabetes is a daily challenge, a task that is consuming the time and attention of most clinicians in endocrinology and primary care. One of the many unresolved issues in achieving favorable outcomes in this patient population is the problem of person-to-person variability in drug efficacy. Why does a medication work for well for one patient and have seemly no effect on another?

The conundrum of individual drug benefit has had scientists looking at the gut microbiome where they have found tantalizing new clues. The research, still in the early stages, does suggest the potential for gut microbiome modulators. It is possible that one day there will be a gut microbiome modulator, a substance that boosts the effectiveness of other drugs, including the treatments for diabetes, heart disease, and many other medications.1

Gut bacteria can change potency of diabetes drugs for better or worse.

The clues are coming from researchers in a variety of fields.1-5 Emily Balskus, PhD, professor of chemistry and chemical biology at Harvard University, for example, is leading a team that examined the bacterial composition of the gut microbiome and how it may influence the absorption and metabolism of levodopa (L-dopa), commonly prescribed for Parkinson's disease; their findings were published in Science.

Gut Bacteria Influence Drug Bioavailability—Insights with Levodopa

"This work is about the discovery that gut bacteria metabolize a drug in a way we think could very likely affect drug bioavailability, efficacy and side effects," Dr. Balskus tells EndocrineWeb. Her team identified specific bacteria that appeared to weaken the power of L-dopa to work as intended.

First, a bit of background on the treatment efficacy of L-dopa for Parkinson's disease. Researchers have found that L-dopa is hugely variable between individuals, and highly dependent on the composition of their microbiota. L-Dopa is decarboxylated into active dopamine, but if the gut microbiota metabolizes L-dopa before it crosses the blood-brain barrier, the medication is rendered ineffective.

Rekdal et al,1 found that different species of bacterium are involved in L-dopa metabolism. Tyrosine decarboxylase from Enterococcus faecalis and dopamine dehydroxylase (Dadh) from Eggerthella lentaA2 sequentially metabolized L-dopa into m-tyramine. The microbial L-dopa decarboxylase can be inactivated by (S)-α-fluoromethyltyrosine (AFMT), which indicates possibilities for developing combinations of Parkinson's drugs to circumvent microbial inactivation.

Investigations of L-dopa have uncovered that it is decarboxylated into active dopamine but may be metabolized by the gut microbiota before it is able to cross the blood-brain barrier, lessening its intended function. Dr. Balskus and her team have identified the enzymes and organisms in the gut responsible for the breakdown of this drug.1

In particular, they have identified several specific species of bacteria that appear responsible for metabolizing the levodopa too soon. They also found a way to preserve the levodopa, so it is able to move cross the brain barrier to deliver better potency to do its best work. They tested thesmall molecule, alpha-fluoromethyltyrosine, in mice, which was successful in blocking the pathway that is used by the enzymes to metabolize the levodopa.1

Dr. Balskus says: "This is one of a growing number of examples of this phenomenon."  The impact of a person's  bacterial mileau, experts say, does not just apply to only one drug or just one disorder. What she and her research team have found has also been echoed by diabetes drug researchers and others.5,6  "We may be a long way from therapeutically targeting this pathway," Dr. Balskus tells EndocrineWeb, ''though this study suggests the right bacteria could be very beneficial."

Adjusting a Person's Bacterial Composition May Improve Drug Efficacy

The interaction of Parkinson's disease drugs with the gut microbiome with has been known for many years, she says; this latest research sheds light on the precise bacterial organisms and specific digestive enzymes are responsible for degrading the efficacy of L-dopa.

“While the research aimed at developing ways to prevent gut microbes from metabolizing drugs is still in early stages,” Dr. Balskus says, “that they have been able to isolate certain microbiota and gain a clearer understanding of the mechanisms behind the disruption process opens the door to strategies to stop the harmful activity."

The potential solutions, she says, include giving patients a ''co-therapy"—a drug that helps prevent the breakdown of the primary drug, to free the medication to work better—or, perhaps to use fecal transplants to change the gut microbiome. The gut microbiome, she says, may hold the key to addressing the person-to-person variability in medication response, moving us toward active precision medicine in which drug choices and doses are tailored to the individual patient.

In the future, all the variability currently precluding full drug efficacy will be evaluated even before taking the step to prescribe a drug regimen for a patient, she says.

Microbiome Interactivity May Inform Medication Potency

The study results from the Harvard investigators echo findings of diabetes drugs reported by Hariom Yadav, PhD, assistant professor of molecular medicine at the Wake Forest School of Medicine, part of Wake Forest Baptist Medical Center, in Winston-Salem, North Carolina.

In reviewing the Parkinson's paper for EndocrineWeb, Dr. Yadav says: "This study shows how the gut microbiome can convert an active drug to an inactive substance and inactive agents to more active [potency]."

Individual variability is a reality, he says. "If we take 100 people [prescribed] with the same drug, that drug is not going to work the same way in all these people. One reason might be the microbiome, and another reason could be individual genetics."

Eventually, he says, making adjustments to the gut microflora appears likely to improve the efficacy of antidiabetes medications in people with diabetes and associated chronic conditions. "That's the hope but it is a long way to confirm that," Dr. Yadav says. Currently, we know that there is an association between the gut bacteria and the bioavailability of drugs, but we don’t yet have the ability to elucidate if  ''it is causative or just a link?"

Dual Interactions of Gut Microbiota Inform Future Approach to Treatment

In his own research,6 Dr. Yadav has focused on what he calls the ''bidirectional drug-microbiome interactions of anti-diabetic drugs."  In a recent report, he says that "On one hand, drugs can manipulate gut microbiome composition and metabolic capacity. Conversely, the metabolic activities of the microbiome and its metabolites can also influence drug metabolism and effects."2

Dr. Yadav and his colleagues looked at the interactions between common anti-diabetic drugs and the microbiome. They found that the microbiome influenced the drugs 'metabolism and could make the drugs active, inactive or even toxic.2 The environmental differences detected in the gut microflora, he says, helps to explain the wide variability in the way drugs work among different patients.

By gaining a better understanding of these interactions [between gut bacteria and drugs], he says, we are ''paving the way to develop next-generation strategies to ameliorate diabetes." To this end, Dr. Yadav, too, talks about the potential of  ''microbiome modulators" to manipulate these interactions to boost the efficacy of diabetes drugs and other medications. This area of research is relatively new, he says, having only been under investigation for about a decade.

Eventually, Dr. Yadav says, we will be able to examine and evaluate a patient's microbiome in order to anticipate whether a specific drug will or won't work, and to be able to make adjustments to the gut environment so as to boost treatment efficacy while saving expense, time and frustration in treating diabetes as well as many other common chronic diseases.

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