Transforming berberine into its intestine-absorbable form by the gut microbiota
Open accessAbstract
The gut microbiota is important in the pathogenesis of energy-metabolism related diseases. We focused on the interaction between intestinal bacteria and orally administered chemical drugs. Oral administration of berberine (BBR) effectively treats patients with metabolic disorders. However, because BBR exhibits poor solubility, its absorption mechanism remains unknown. Here, we show that the gut microbiota converts BBR into its absorbable form of dihydroberberine (dhBBR), which has an intestinal absorption rate 5-fold that of BBR in animals. The reduction of BBR to dhBBR was performed by nitroreductases of the gut microbiota. DhBBR was unstable in solution and reverted to BBR in intestine tissues via oxidization. Heat inactivation of intestinal homogenate did not inhibit dhBBR oxidization, suggesting the process a non-enzymatic reaction. The diminution of intestinal bacteria via orally treating KK-Ay mice with antibiotics decreased the BBR-to-dhBBR conversion and blood BBR; accordingly, the lipid- and glucose-lowering efficacy of BBR was reduced. Conclusively, the gut microbiota reduces BBR into its absorbable form of dhBBR, which then oxidizes back to BBR after absorption in intestine tissues and enters the blood. Thus, interaction(s) between the gut microbiota and orally administrated drugs may modify the structure and function of chemicals and be important in drug investigation.
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An important fraction of the berberine dose is metabolized by the intestinal microbiota into better-absorbed forms, such as dihydroberberine.
“In addition, an important fraction of the dose is metabolized by the intestinal microbiota into better-absorbed forms, such as dihydroberberine, which links pharmacokinetics to the state of the microbiome [43,66].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [66]
The microbiome biotransforms berberine into better-absorbed forms.
“the microbiome in turn biotransforms it into better-absorbed forms [43,66,102].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [66]
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Cites
Trott, O., & Olson, A. J. (2010) · Journal of Computational Chemistry · doi:10.1002/jcc.21334 · Cited by 38,412 · see citing works
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597 · see citing works
Functional interactions between the gut microbiota and host metabolism
Tremaroli, V., & Bäckhed, F. (2012) · Nature · doi:10.1038/nature11552 · Cited by 4,387 · see citing works
Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., Britt, E. B., Fu, X., Wu, Y., Li, L., et al. (2013) · Nature Medicine · doi:10.1038/nm.3145 · Cited by 4,386 · see citing works
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
Tang, W. H. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., Wu, Y., & Hazen, S. L. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109400 · Cited by 3,402 · see citing works
Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers
Hubatsch, I., Ragnarsson, E., & Artursson, P. (2007) · Nature Protocols · doi:10.1038/nprot.2007.303 · Cited by 1,503 · see citing works
Kong, W., Wei, J., Abidi, P., Lin, M., Inaba, S., Li, C., Wang, Y., Wang, Z., Si, S., Pan, H., et al. (2004) · Nature Medicine · doi:10.1038/nm1135 · Cited by 1,391 · see citing works
Self-citationLee, Y. S., Kim, W. S., Kim, K. H., Yoon, M. J., Cho, H. J., Shen, Y., Ye, J.-M., Lee, C. H., Oh, W. K., Kim, C. T., et al. (2006) · Diabetes · doi:10.2337/db06-0006 · Cited by 1,054 · see citing works
Gut microbiome, obesity, and metabolic dysfunction
Tilg, H., & Kaser, A. (2011) · Journal of Clinical Investigation · doi:10.1172/jci58109 · Cited by 860 · see citing works
The gastrointestinal microbiota as a site for the biotransformation of drugs
Sousa, T., Paterson, R., Moore, V., Carlsson, A., Abrahamsson, B., & Basit, A. W. (2008) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2008.07.009 · Cited by 618 · see citing works
Zhang, X., Zhao, Y., Zhang, M., Pang, X., Xu, J., Kang, C., Li, M., Zhang, C., Zhang, Z., Zhang, Y., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042529 · Cited by 615 · see citing works
Self-citationTurner, N., Li, J.-Y., Gosby, A., To, S. W. C., Cheng, Z., Miyoshi, H., Taketo, M. M., Cooney, G. J., Kraegen, E. W., James, D. E., et al. (2008) · Diabetes · doi:10.2337/db07-1552 · Cited by 535 · see citing works
Structural modulation of gut microbiota in life-long calorie-restricted mice
Zhang, C., Li, S., Yang, L., Huang, P., Li, W., Wang, S., Zhao, G., Zhang, M. H., Pang, X., Yan, Z., et al. (2013) · Nature Communications · doi:10.1038/ncomms3163 · Cited by 496 · see citing works
Reduction of polynitroaromatic compounds: the bacterial nitroreductases
Roldán, M. D., Pérez‐Reinado, E., del Castillo, F. J., et al. (2008) · FEMS Microbiology Reviews · doi:10.1111/j.1574-6976.2008.00107.x · Cited by 457 · see citing works
Zhang, H., Wei, J., Xue, R., Wu, J.-D., Zhao, W., Wang, Z., Wang, S., Zhou, Z.-X., Song, D., Wang, Y., et al. (2009) · Metabolism · doi:10.1016/j.metabol.2009.07.029 · Cited by 442 · see citing works
Self-citationInterplay between obesity and associated metabolic disorders: New insights into the gut microbiota
Cani, P. D., & Delzenne, N. M. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.06.016 · Cited by 377 · see citing works
Chen, W., Miao, Y.-Q., Fan, D.-J., Yang, S.-S., Lin, X., Meng, L.-K., & Tang, X. (2011) · AAPS PharmSciTech · doi:10.1208/s12249-011-9632-z · Cited by 363 · see citing works
Li, H., Dong, B., Park, S. W., Lee, H.-S., Chen, W., & Liu, J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.052407 · Cited by 349 · see citing works
Yang, H., & Neff, N. H. (1974) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)29881-0 · Cited by 297 · see citing works
Tissue Distribution of Berberine and Its Metabolites after Oral Administration in Rats
Tan, X.-S., Ma, J.-Y., Feng, R., Ma, C., Chen, W.-J., Sun, Y.-P., Fu, J., Huang, M., He, C.-Y., Shou, J.-W., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077969 · Cited by 266 · see citing works
Self-citationThe involvement of P-glycoprotein in berberine absorption
Pan, G., Wang, G., Liu, X., Fawcett, J. P., & Xie, Y. (2002) · Pharmacology & Toxicology · doi:10.1034/j.1600-0773.2002.t01-1-910403.x · Cited by 225 · see citing works
Xie, W., Gu, D., Li, J., Cui, K., & Zhang, Y. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024520 · Cited by 183 · see citing works
Effects and mechanisms of berberine in diabetes treatment
Yin, J., Ye, J., & Jia, W. (2012) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2012.06.003 · Cited by 183 · see citing works
Musso, G., Gambino, R., & Cassader, M. (2010) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3283347ebb · Cited by 182 · see citing works
Derosa, G., Maffioli, P., & Cicero, A. F. (2012) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2012.704014 · Cited by 171 · see citing works
The effect of gut microbiota on drug metabolism
Kang, M. J., Kim, H. G., Kim, J. S., Oh, D. G., Um, Y. J., Seo, C. S., Han, J. W., Cho, H. J., Kim, G. H., Jeong, T. C., et al. (2013) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2013.807798 · Cited by 120 · see citing works
Learning from berberine: Treating chronic diseases through multiple targets
Yao, J., Kong, W., & Jiang, J. (2013) · Science China Life Sciences · doi:10.1007/s11427-013-4568-z · Cited by 118 · see citing works
Self-citationExcretion of Berberine and Its Metabolites in Oral Administration in Rats
Ma, J., Feng, R., Tan, X., Ma, C., Shou, J., Fu, J., Huang, M., He, C., Chen, S., Zhao, Z., et al. (2013) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23718 · Cited by 107 · see citing works
Self-citationFlavin Thermodynamics Explain the Oxygen Insensitivity of Enteric Nitroreductases
Koder, R. L., Haynes, C. A., Rodgers, M. E., et al. (2002) · Biochemistry · doi:10.1021/bi025805t · Cited by 105 · see citing works
Li, Y., Yang, P., Kong, W., Wang, Y., Hu, C.-Q., Zuo, Z.-Y., Wang, Y., Gao, H., Gao, L., Feng, Y., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm801157z · Cited by 96 · see citing works
Self-citationYang, P., Song, D., Li, Y., Kong, W., Wang, Y., Gao, L., Liu, S., Cao, R., & Jiang, J. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.07.005 · Cited by 64 · see citing works
Self-citationWang, Y., Kong, W., Li, Y., Tang, S., Li, Z., Li, Y.-B., Shan, Y., Bi, C., Jiang, J., & Song, D. (2012) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2012.09.029 · Cited by 60 · see citing works
Self-citationThe involvement of intestinal monoamine oxidase in the transport and metabolism of tyramine.
Hasan, F., McCrodden, J. M., Kennedy, N. P., et al. (1988) · PubMed · Cited by 60 · see citing works
Wang, Y., Wang, Y., Zhang, H., Kong, W., Li, Y., Liu, F., Gao, R., Liu, T., Jiang, J., & Song, D. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.09.059 · Cited by 47 · see citing works
Self-citationFu, J., Ma, J., Zhang, X., et al. (2012) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2012.07.028 · Cited by 26 · see citing works
Self-citationAoo, M. F. N. (2013) · Journal of Addiction Research & Therapy · doi:10.4172/2155-6105.1000172 · Cited by 6 · see citing works
Bau, U. (1959) · ACTA MICROBIOLOGICA SINICA · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Chemical transformation of xenobiotics by the human gut microbiota
Koppel, N., Maini Rekdal, V., & Balskus, E. P. (2017) · Science · doi:10.1126/science.aag2770 · Cited by 1,080 · see citing works
Microbiota: a key orchestrator of cancer therapy
Roy, S., & Trinchieri, G. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.13 · Cited by 883 · see citing works
Berberine in Cardiovascular and Metabolic Diseases: From Mechanisms to Therapeutics
Feng, X., Sureda, A., Jafari, S., Memariani, Z., Tewari, D., Annunziata, G., Barrea, L., Hassan, S. T. S., Šmejkal, K., Malaník, M., et al. (2019) · Theranostics · doi:10.7150/thno.30787 · Cited by 465 · see citing works
Research progress on berberine with a special focus on its oral bioavailability
Liu, C.-S., Zheng, Y.-R., Zhang, Y.-F., & Long, X.-Y. (2016) · Fitoterapia · doi:10.1016/j.fitote.2016.02.001 · Cited by 363 · see citing works
Berberine pharmacology and the gut microbiota: A hidden therapeutic link
Habtemariam, S. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104722 · Cited by 352 · see citing works
Wang, Y., Tong, Q., Ma, S.-R., Zhao, Z.-X., Pan, L.-B., Cong, L., Han, P., Peng, R., Yu, H., Lin, Y., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00456-5 · Cited by 319 · see citing works
Self-citationLi, C., Ai, G., Wang, Y., Lu, Q., Luo, C., Tan, L., Lin, G., Liu, Y., Li, Y., Zeng, H., et al. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2019.104603 · Cited by 262 · see citing works
Self-citationHu, H., Zhong, D., Li, W., Lin, X., He, J., Sun, Y., Wu, Y., Shi, M., Chen, X., Xu, F., et al. (2022) · Nano Today · doi:10.1016/j.nantod.2021.101368 · Cited by 165 · see citing works
Self-citationZhang, Z.-W., Gao, C.-S., Zhang, H., Yang, J., Wang, Y.-P., Pan, L.-B., Yu, H., He, C.-Y., Luo, H.-B., Zhao, Z.-X., et al. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.02.032 · Cited by 139 · see citing works
Self-citationGut Microbiota-Mediated Personalized Treatment of Hyperlipidemia Using Berberine
Wang, Y., Tong, Q., Shou, J.-W., Zhao, Z.-X., Li, X.-Y., Zhang, X.-F., Ma, S.-R., He, C.-Y., Lin, Y., Wen, B.-Y., et al. (2017) · Theranostics · doi:10.7150/thno.18290 · Cited by 131 · see citing works
Self-citationThe mechanism of berberine alleviating metabolic disorder based on gut microbiome
Wang, H., Zhang, H., Gao, Z., Zhang, Q., & Gu, C. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.854885 · Cited by 69 · see citing works
Ming, J., Yu, X., Xu, X., Wang, L., Ding, C., Wang, Z., Xie, X., Li, S., Yang, W., Luo, S., et al. (2021) · Genome Medicine · doi:10.1186/s13073-021-00942-7 · Cited by 52 · see citing works
A patent review of berberine and its derivatives with various pharmacological activities (2016–2020)
Kong, Y., Li, L., Zhao, L.-G., Yu, P., & Li, D.-D. (2022) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2021.1974001 · Cited by 52 · see citing works
Pharmacokinetics and Pharmacological Activities of Berberine in Diabetes Mellitus Treatment
Han, Y., Xiang, Y., Shi, Y., Tang, X., Pan, L., Gao, J., Bi, R., & Lai, X. (2021) · Evidence-Based Complementary and Alternative Medicine · doi:10.1155/2021/9987097 · Cited by 51 · see citing works
Yang, S., Li, D., Yu, Z., Li, Y., & Wu, M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.709629 · Cited by 40 · see citing works
Murakami, T., Bodor, E., & Bodor, N. (2023) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2023.2203857 · Cited by 41 · see citing works
Ma, H., He, K., Zhu, J., Li, X., & Ye, X. (2019) · Fitoterapia · doi:10.1016/j.fitote.2019.03.003 · Cited by 37 · see citing works
Self-citationDehau, T., Cherlet, M., Croubels, S., Van De Vliet, M., Goossens, E., & Van Immerseel, F. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1281090 · Cited by 33 · see citing works
Cao, R. Y., Zheng, Y., Zhang, Y., Jiang, L., Li, Q., Sun, W., Gu, W., Cao, W., Zhou, L., Zheng, H., et al. (2021) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x21500762 · Cited by 31 · see citing works
Adiwidjaja, J., Boddy, A. V., & McLachlan, A. J. (2022) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-021-03266-y · Cited by 14 · see citing works
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
“In addition, an important fraction of the dose is metabolized by the intestinal microbiota into better-absorbed forms, such as dihydroberberine, which links pharmacokinetics to the state of the micro-biome [43,66].”
- Authors
- Feng, R., Shou, J.-W., Zhao, Z.-X., He, C.-Y., Ma, C., Huang, M., Fu, J., Tan, X.-S., Li, X.-Y., Wen, B.-Y., Chen, X., Yang, X.-Y., Ren, G., Lin, Y., Chen, Y., You, X.-F., Wang, Y., & Jiang, J.-D.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Shimadzu (China) (CN)
- Chinese University of Hong Kong (HK)
- Corresponding author
- Wang, Yan
- Jiang, Jian-Dong
- ORCID
- Venue
- Scientific Reports
- Published
- 2015-07-15
- Volume
- 5
- Issue
- 1
- Pages
- 12155-12155
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4502414
- OpenAlex
- W994818366
- Cited by
- 307
- References
- 37
- Citations by year
- 2026: 31 · 2025: 37 · 2024: 32 · 2023: 33 · 2022: 41 · 2021: 38 · 2020: 29 · 2019: 29 · 2018: 16 · 2017: 14 · 2016: 4 · 2015: 2
- FWCI
- 8.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81072611, 81321004, 2012ZX09301002-006, 863 Program, 2012ZX09301002-001, Z141102004414062)
- Chinese University of Hong Kong
- National High-tech Research and Development Program
- Topics
- Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- berberine, dihydroberberine, gut microbiota, intestinal drug absorption, nitroreductase, drug-microbe interactions, non-enzymatic oxidation, antibiotic-induced dysbiosis, hypolipidemic effect, glucose-lowering effect, oral bioavailability
- MeSH terms
- Gastrointestinal Microbiome, Administration, Oral, Animals, Bacteria, Bacterial Proteins, Berberine, Binding Sites, Chromatography, High Pressure Liquid, Hypoglycemic Agents, Intestinal Absorption, Intestines, Male, Nitroreductases, Oxidation-Reduction, Solubility, Rats, Sprague-Dawley, Mice, Tandem Mass Spectrometry, Molecular Docking Simulation
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