title: Transforming berberine into its intestine-absorbable form by the gut microbiota.
abstract: 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.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Ru
authors.initials: R
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Jia-Wen
authors.initials: JW
authors.lastname: Shou
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Zhen-Xiong
authors.initials: ZX
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: He
authors.affiliation: Beijing Analytical Application Center, Shimadzu (China) Co., Ltd., Beijing 100020, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Xiang-Shan
authors.initials: XS
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Xiao-Yang
authors.initials: XY
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Bao-Ying
authors.initials: BY
authors.lastname: Wen
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Xin-Yi
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Yangchao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Xue-Fu
authors.initials: XF
authors.lastname: You
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China [2] Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences / Peking Union Medical College, Beijing 100050, China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001419:Bacteria / Q000201:enzymology / Q000302:isolation & purification; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001599:Berberine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism*; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D000069196:Gastrointestinal Microbiome; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism*; D007408:Intestinal Absorption; D007422:Intestines / Q000382:microbiology*; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D009601:Nitroreductases / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D017207:Rats, Sprague-Dawley; D012995:Solubility; D053719:Tandem Mass Spectrometry
chemical_list: D001426:Bacterial Proteins; D007004:Hypoglycemic Agents; D001599:Berberine; C039639:dihydroberberine; D009601:Nitroreductases