Pharmacomicrobiomics of Non-Antibiotic Drugs: Mechanisms and Clinical Consequences of Gut Microbiota Alterations
Open accessAbstract
Background: The gut microbiota constitutes a metabolically active “second genome” that profoundly modulates drug pharmacokinetics, pharmacodynamics, and adverse reaction profiles. Beyond antibiotics, widely prescribed non-antibiotic pharmacotherapies exert clinically relevant pharmacomicrobiomic effects with implications for therapeutic optimisation and pharmacovigilance. Methods: This narrative review, conducted following PRISMA 2020 reporting principles (without PROSPERO pre-registration), searched PubMed/MEDLINE, Scopus, Web of Science, and Cochrane Library (January 2015–December 2024) for evidence on proton pump inhibitors (PPIs), metformin, NSAIDs, statins, SGLT2 inhibitors, and oral iron. Evidence tables included clinical human studies with molecular microbiota characterisation (16S rRNA or shotgun metagenomics), ≥20 participants, and a control arm; preclinical data informed mechanistic synthesis. Results: Of 68 eligible studies, 20 met criteria for the evidence tables. PPIs significantly remodelled gut microbiota composition with enrichment of oral-origin taxa (“oralisation of the gut”), associating with Clostridioides difficile infection and SIBO. Metformin enriched Akkermansia muciniphila and butyrate producers, contributing causally to glycaemic efficacy. NSAIDs compromised barrier integrity, with synergistic dysbiosis under PPI co-prescription. Statins correlated with reduced prevalence of the dysbiotic Bact2 enterotype. SGLT2 inhibitor data remained discordant. Oral iron consistently enriched Enterobacteriaceae at the expense of beneficial commensals.
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Through its intrinsic antimicrobial activity and high luminal concentrations, berberine is a prototypical example of a non-antibiotic compound that perturbs the intestinal microbial ecosystem.
“Through its intrinsic antimicrobial activity and its high luminal concentrations, berberine is a prototypical example of a non-antibiotic compound that perturbs the intestinal microbial ecosystem [43,106].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [106]
The Introduction and Discussion describe how some non-antibiotic drugs affect gut microbes, but neither identifies berberine. A search of our untruncated copy for “berberine” found no passage addressing its antimicrobial activity, luminal concentration, or effect on the intestinal microbial ecosystem. (LLM, conf=0.75)
Experimental — accuracy not yet measuredThe oral compartment, where berberine reaches its highest concentrations of all, is unexamined and belongs in the same research program.
“The oral compartment, where berberine reaches its highest concentrations of all, is unexamined and belongs in the same program [103,104,105,106,107,108].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [106]
Section 3.2 discusses gaps in sampling the small bowel and mucosa, while Section 3.3 reports an oral-microbiota study involving a proton pump inhibitor. Searches for berberine and its concentration in the oral compartment found no passage addressing the claim or proposing that compartment for berberine research. No page numbers were available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredNo study has yet measured the disposition of a co-administered drug before and after berberine while characterizing the microbiota in the same subjects, which is what would move Axis 4 from candidate to demonstrated.
“No study has yet measured the disposition of a co-administered drug before and after berberine while characterizing the microbiota in the same subjects, which is what would move Axis 4 from candidate to demonstrated.”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [106]
The Results sections on methodological quality (3.2) and polypharmacy (3.9; page numbers unavailable) discuss paired designs and co-administered drugs, but do not address berberine or the proposed before-and-after disposition study. Searches for “berberine,” “Axis 4,” and paired microbiota and drug-disposition measurements found no passage establishing that no such study exists. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Gut microbiota composition is associated with polypharmacy in elderly hospitalized patients
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The Lactobacillus Anomaly: Total Iron Abstinence
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“This example illustrates both the dominant direction of the interaction, a drug that reshapes the microbiota with downstream clinical consequences, and the role of the oral–gut axis as an anatomical–microbiological interface through which this remodelling is manifested [9].”
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Dumitru, C. N., Marcu, T., Dumitru, A. O., Tudor, S. S., Ferțu, I. D., Elisei, A.-M., & Goroftei, L. (2026) · Pharmaceuticals · doi:10.3390/ph19081313 · Cited by 2 · see citing works
“What would settle the question is a study measuring the pharmacokinetics of a microbiota-dependent victim drug before and after berberine, with the microbiota characterized in the same subjects; we set this out in Section 2.5 [104–106].”
InfluentialSelf-citationDumitru, C. N., Dumitru, A. O., Marcu, T., Earar, K., Matei, N. M., & Buzia, O. D. (2026) · Pharmaceutics · doi:10.3390/pharmaceutics18081011 · Cited by 1 · see citing works
Self-citationGut Microbiota in Metabolic Syndrome: Differences in Microbial Signatures and Clinical Profiles
Scarlata, G. G. M., Belančić, A., Scarpellini, E., Fajkić, A., Meštrović, T., Vicinanza, R., Štimac, D., & Abenavoli, L. (2026) · Medicina · doi:10.3390/medicina62081435
Dumitru, C. N., Marcu, T., Dumitru, A. O., & Matei, M. N. (2026) · Pharmaceuticals · doi:10.3390/ph19101661
Self-citation
- Authors
- Dumitru, C. N., Dumitru, A. O., Goroftei, L., Niculet, E., Ignat, M. D., Baroiu, L., Nechita, A., & Balan, G.
- Affiliations
- "Dunarea de Jos" University of Galati (RO)
- Research Centre in the Medical-Pharmaceutical Field, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University of Galați, 35 Al. I. Cuza Street, 800010 Galați, Romania
- Corresponding author
- Dumitru, Alina Oana
- Ignat, Mariana Daniela
- ORCID
- Venue
- Pharmaceutics
- Publisher
- MDPI AG
- Published
- 2026-05-26
- Volume
- 18
- Issue
- 6
- Pages
- 651
- ISSN
- 1999-4923 (ISSN-L)
- PMC
- PMC13304943
- OpenAlex
- W7162447172
- Cited by
- 4
- References
- 115
- Citations by year
- 2026: 4
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pharmaceutics (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- “Dunarea de Jos” University of Galati
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Infectious Diseases › Clostridium difficile and Clostridium perfringens research
- Keywords
- gut microbiota, non-antibiotic drugs, pharmacomicrobiomics, proton pump inhibitors, metformin, nonsteroidal anti-inflammatory drugs, statins, SGLT2 inhibitors, oral iron, dysbiosis, Clostridium difficile infection, small intestinal bacterial overgrowth, Akkermansia muciniphila, butyrate, Enterobacteriaceae, drug-microbiota interactions, pharmacovigilance
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