A superfamily of drugs used for diseases including Type 2 diabetes, migraines, and depression may be less effective depending on the specific microbes in your gut that help metabolize the oral medications.

Drugs that act on G protein-coupled receptors (GPCRs) include more than 500 medications—more than one-third of the drugs already approved by the Food and Drug Administration—with 337 more in clinical trials.

A study published in Nature Chemistry tested 127 GPCR-targeting drugs on 30 common bacterial strains found in the human gut and measured how the drugs were metabolized. In a dozen cases, the drugs were transformed into other compounds, with five drugs becoming depleted and reducing potency, three drugs becoming depleted and increasing potency, and four showing no activity difference.

The results offer insight into why drug effectiveness varies from one person to another—potentially leading to a more thorough understanding of disease and treatment. More research is needed to understand these complex relationships, which are also influenced by factors such as genetics, age, diet, and more. Patients should consult with their doctor before stopping or starting new medication.

“Understanding how GPCR-targeted drugs interact with human gut microbiota is critical for advancing personalized medicine initiatives,” study author Qihao Wu, assistant professor at the University of Pittsburgh School of Pharmacy, said in a statement.

“This research could help open up new avenues for drug design and therapeutic optimization to ensure that treatments work better and safer for every individual.”

Study Specifics

Wu and a team at Yale, where he began the research, created a synthetic human microbial community in tubes, to which they added each of the 127 GPCR-targeting drugs individually.

They then measured whether the drugs were chemically transformed by the gut bacteria. This included identifying the compounds made in metabolization, called metabolites. Metabolites are molecules produced by the body or by microbes.

The bacterial mix metabolized 30 of the 127 tested drugs, 12 of which were heavily metabolized and lowered the concentrations of the original drug, which had been transformed into other compounds.

Why Gut Microbiota Matters

The authors noted that growing evidence shows how the gut microbiota is a key component of how orally administered drugs are metabolized, affecting how well the drugs work for us.

“Such interactions between the human gut microbiota and drugs can affect clinical outcomes and host health,” they wrote.

This point was illustrated as the researchers more closely examined one heavily metabolized drug called iloperidone, which was depleted and found to have reduced effectiveness in the study. Iloperidone is used to treat schizophrenia and bipolar I disorder.

Researchers determined that the bacterial strain Morganella morganii deactivated iloperidone while transforming it into a range of compounds in the lab and in mice.

In the case of schizophrenia, a patient taking iloperidone with reduced effect may experience a relapse in symptoms or experience symptoms to a lesser degree, such as delusions, hallucinations, disorganized or incoherent speech, and disorganized or unusual behavior.

Bugs and Drugs

Wu said the approach the team used could be broadly applied to other drugs, as well as food and supplements, to check their interaction with common gut bacteria.

Research indicates that other types of drugs also appear to be dampened by gut microbes.

A review of cardiovascular drugs and the gut microbiome published in Pharmacotherapy noted that there is a bidirectional and multifaceted relationship:

• Microbial transformation of drugs can create active, inactive, or toxic metabolites.


• Drugs can change the microbiome, alter microbial metabolism, or affect bacterial growth. This can change the microbiome’s composition and function, which can also change how a drug works.

Aspirin, statins, and digoxin are among the drugs with high evidence for microbiome–drug interactions. Statins are not GPCR-targeting drugs, although there are some cardiovascular drugs that are GPCR-targeting, such as beta-blockers and angiotensin receptor blockers.

The authors said it may be possible to use microbiome testing to predict drug response or even modulate the microbiome so that people have a better response to medication.

“We are still likely at the tip of the iceberg with our understanding of microbial interactions with drugs,” the authors wrote.

“The gut microbiome is emerging as a key to personalized medicine. Existing evidence suggests that many drugs used for the treatment of cardiovascular disease have strong interactions with the gut microbiome.”

Rising Popularity of GPCR Drugs

GPCRs are located in the plasma membrane of every cell, allowing for signals between the cells and other parts of the body. They are of high interest for drug therapy because GPCRs are responsible for regulating so many processes in the body.

Sales of obesity drugs and GPCR-targeting drugs for diabetes totaled nearly $30 billion in 2023. Clinical trials for GPCR-targeting drugs are increasing for metabolic diseases, oncology, and immunology, according to a review published in Nature Reviews Drug Discovery.

There is also much untapped potential for GPCR-targeting drugs. The authors of another Nature Reviews Drug Discovery article wrote that this superfamily of drugs hones in on diabetes, obesity, Alzheimer’s disease, and psychiatric disorders, providing “a strong driving force for continued drug discovery and development efforts in this field.”