Gut Microbiota, a Potential Mediated Target for Reducing Geniposide Hepatotoxicity by Interacting with Isoflavones
Wen Yang,
Wen Zhang,
Xinhui Huang,
Shuwen Geng,
Yujia Zhai,
Yuetong Jiang,
Tian Tian,
Yuye Gao,
Jing He,
Taohong Huang,
Yunxia Li,
Wenjing Zhang,
Jun Wen,
Jian-lin Wu,
Guangji Wang,
Tingting Zhou
Affiliations
Wen Yang
Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University, Shanghai 200433, China
Wen Zhang
Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University, Shanghai 200433, China
Xinhui Huang
Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University, Shanghai 200433, China
Shuwen Geng
Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University, Shanghai 200433, China
Yujia Zhai
Naval Medical Center, Naval Medical University, Shanghai 200433, China
Yuetong Jiang
Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University, Shanghai 200433, China
Tian Tian
Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University, Shanghai 200433, China
Yuye Gao
Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University, Shanghai 200433, China
Jing He
Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University, Shanghai 200433, China
Taohong Huang
Shimadzu China Co. Ltd., Shanghai 200233, China
Yunxia Li
Department of Neurology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200092, China
Wenjing Zhang
Department of Psychiatry, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
Jun Wen
Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University, Shanghai 200433, China
Jian-lin Wu
State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Macao 999078, China
Guangji Wang
State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; Corresponding authors.
Tingting Zhou
Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University, Shanghai 200433, China; Corresponding authors.
Geniposide, the principal active iridoid glucoside ingredient in Fructus gardeniae used in numerous traditional Chinese clinical prescriptions, has been shown to cause herbal hepatotoxicity because of its glycone metabolite genipin. This study explored the role of gut microbiota in alleviating geniposide hepatotoxicity with isoflavones in soy products. Metabolic profiling using ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF-MS) revealed two metabolic pathways and six main forms of geniposides in vivo. Enzyme inhibitor experiments have shown that isoflavones alter geniposide metabolism by mediating specific enzymes, including β-glucosidase (β-GC) and sulfotransferase (SULT), in an established pseudo-sterile rat model. Isoflavones pretreatment by gavage for three weeks optimized the structure of the gut microbiota was linked to the regulation of key metabolic enzymes. Furthermore, experiments involving fecal microbiota transplantation (FMT) established the direct contribution of the gut microbiota to the regulation of enzyme activities and geniposide metabolism. This study demonstrated that isoflavones in soy products regulated the metabolic enzymes of geniposode dependent on gut microbiota, especially Lactobacillus spp., which was further verified in our clinical trials analyzed using 16S ribosomal RNA (rRNA) and metagenomic sequencing, thus regulating geniposide metabolism. Furthermore, as dominant beneficial bacterium, Lactobacillus spp. were discovered to be promising microbial targets for the better management of geniposide hepatotoxicity. These findings provide valuable insights for the prevention and intervention of drug-induced liver injury.
