GPCR drugs are medications that target G protein-coupled receptors (GPCRs), a large family of cell-surface proteins. These receptors are essentially the body’s communication hubs, responsible for relaying signals from the outside of a cell to the inside. GPCR drugs work by either mimicking or blocking the natural signals. For example, opioid pain relievers target opioid receptors, mimicking the body’s natural pain-relieving signals. In contrast, beta-blockers block adrenaline and are used to treat high blood pressure and heart disease.
GPCR drugs are among the most important and successful classes of pharmaceuticals. Between 30–40% of currently available drugs target GPCRs, with many more in development or clinical trials1,2. Because GPCRs are involved in nearly every physiological process—from vision and smell to heart rate regulation and mood—they remain prime targets for new therapies3.
Drug Responses Vary Between People
The way drugs work varies widely from person to person, and the gut microbiota is understood to be a significant factor. This vast microbial community, with its trillions of organisms and immense enzymatic diversity, can chemically alter orally administered drugs before absorption4,5. Understanding the microbiota’s contribution is therefore essential for explaining why therapeutic outcomes differ so much between patients.
A Systematic Study of Microbiome–Drug Interactions
A recent study in Nature Chemistry by researchers at Yale University and the University of Pittsburgh systematically investigated how the gut microbiome metabolizes 127 orally administered GPCR-targeted drugs and how these changes impact the drugs’ pharmacological activity6.
Using SIRIUS to analyze MS/MS data, the team identified previously unknown drug metabolites produced by gut bacteria. They discovered human gut commensal bacteria to profoundly reshape the structure and activity of GPCR drugs, sometimes inactivating them, sometimes activating them. The study also uncovered novel and complex modes of drug metabolism.
Iloperidone is used to treat Schizophrenia and Bipolar I Disorder. It helps manage symptoms like hallucinations, delusions, and disorganized thinking and is used for the acute treatment of manic or mixed episodes. It works by balancing levels of key neurotransmitters in the brain, primarily dopamine and serotonin by blocking their receptors. It is associated with a lower risk of certain side effects common with older antipsychotics.
Risperidone is used to treat a variety of mental health conditions by balancing the levels of neurotransmitters, primarily dopamine and serotonin, in the brain. It helps manage symptoms such as hallucinations, delusions, and disorganized thoughts, is used for treating acute manic or mixed episodes, and can help manage irritability and aggression associated with autism in children and adolescents. It works by blocking dopamine and serotonin receptors in the brain.
Selexipag is used to treat pulmonary arterial hypertension, a rare and progressive condition that causes high blood pressure in the arteries of the lungs. It acts by mimicking prostacyclin, a naturally occurring substance that is often deficient in people with PAH. By activating the prostacyclin receptor, it causes the blood vessels in the lungs to relax and widen. This makes it easier for the heart to pump blood through the lungs, which reduces the workload on the heart and helps to improve symptoms and slow down disease progression.
Microbial ability to use sulfur to alter compounds
In the metabolism of the drug iloperidone, SIRIUS analysis supported (by isotope pattern and fragment analysis) the unexpected presence of a sulfur atom in the molecular formula of an iloperidone metabolite. This previously undescribed metabolite is formed through a novel mode of metabolism by human gut bacteria. SMART NMR revealed the sulfur-containing part of the molecule is a thiophene motif. Also risperidone, a structurally related drug, was metabolised by the gut bacteria to form corresponding thiophene products. This discovery showcases the microbiota’s sophisticated ability to use available sulfur to process and alter reactive foreign compounds.
Morganella morganii inactivates iloperidone using amino acids
While all tested bacterial strains robustly metabolised iloperidone, cultures of Morganella morganii showed a lower level of a common iloperidone metabolite. This suggested that M. morganii was utilising one or more alternative biotransformation pathways to process the drug. The study detected three new and previously undefined iloperidone metabolites. SIRIUS analysis suggested the metabolites had related molecular formulae and that they were formed through a process of conjugation with amino acid–derived structures that originate from the amino acids L-lysine and L-ornithine. When cultures of M. morganii were supplemented with L-lysine or L-ornithine, the production of the three metabolites significantly increased. Isotopically labelled “heavy” amino acids were directly incorporated into the final metabolites. When the purified metabolites were tested at the dopamine receptor, the main target of iloperidone, they completely lacked antagonist activity. This inactivation occurred because the transformation destroyed the 6-fluoro-benzisoxazole motif essential for receptor binding.
Activation and Inactivation
Overall, the study demonstrated that metabolic changes directly affect drug function. Among 12 highly metabolised drugs, five were inactivated and three were activated by the gut bacteria. For example isoxazole cleavage in iloperidone led to inactivation, while amide cleavage in selexipag led to activation. The study also mapped metabolic functions to specific bacteria. Collaborative metabolism was also observed, where different bacteria may be responsible for distinct steps in a drug’s transformation.
Implications for Drug Development and Personalized Medicine
This research underscores the significant and diverse impact of human gut commensal bacteria on the structure and efficacy of GPCR-targeted drugs. The application of computational tools like SIRIUS was critical for characterising these novel metabolic pathways, advancing our understanding of drug-microbiota interactions for potential applications in drug development and personalised medicine. The study highlights the crucial role the gut microbiome plays in influencing therapeutic outcomes.
Fun Fact: Contrary to what is stated in the article, SIRIUS is not an acronym for ‘Spectral Identification of Research Compounds by Unified Structure’. The acronym originates from the Böcker Lab’s initial work in the field of small molecule annotation, namely the identification of molecular formulas based solely on the analysis of isotope patterns7. SIRIUS is the acronym for ‘Sum formula Identification by Ranking Isotope patterns Using mass Spectrometry’. Since its publication in 2008, SIRIUS has evolved into the powerful platform it is today, going far beyond the annotation of molecular formulas.
References
- Odoemelam CS, Percival B, Wallis H, Chang MW, Ahmad Z, Scholey D, Burton E, Williams IH, Kamerlin CL, Wilson PB. G-Protein coupled receptors: structure and function in drug discovery. RSC Adv. 2020 Oct 1;10(60):36337-36348. doi: 10.1039/d0ra08003a. ↩︎
- Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov. 2017 Dec;16(12):829-842. doi: 10.1038/nrd.2017.178. ↩︎
- Liu S, Anderson PJ, Rajagopal S, Lefkowitz RJ, Rockman HA. G Protein-Coupled Receptors: A Century of Research and Discovery. Circ Res. 2024 Jun 21;135(1):174-197. doi: 10.1161/CIRCRESAHA.124.323067. ↩︎
- Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019 Jun;570(7762):462-467. doi: 10.1038/s41586-019-1291-3. ↩︎
- Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017 May 16;474(11):1823-1836. doi: 10.1042/BCJ20160510. ↩︎
- Wu Q, Song D, Zhao Y, Verdegaal AA, Turocy T, Duncan-Lowey B, Goodman AL, Palm NW, Crawford JM. Activity of GPCR-targeted drugs influenced by human gut microbiota metabolism. Nat Chem. 2025 Jun;17(6):808-821. doi: 10.1038/s41557-025-01789-w. ↩︎
- Böcker S, Letzel MC, Lipták Z, Pervukhin A. SIRIUS: decomposing isotope patterns for metabolite identification. Bioinformatics. 2009 Jan 15;25(2):218-24. doi: 10.1093/bioinformatics/btn603. ↩︎
