Microbiome and metabolomics reveal the effect of gut microbiota on liver regeneration of fatty liver diseaseResearch in context
Yiqing Hu,
Xiaoyi Hu,
Li Jiang,
Jia Luo,
Jiacheng Huang,
Yaohan Sun,
Yinbiao Qiao,
Hao Wu,
Shijie Zhou,
Haoyu Li,
Jianhui Li,
Lin Zhou,
Shusen Zheng
Affiliations
Yiqing Hu
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
Xiaoyi Hu
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
Li Jiang
Laboratory of Animal Research Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
Jia Luo
The Affiliated Hospital of Kunming University of Science and Technology, The First People' Hospital of Yunnan Province, Kunming, 650500, China
Jiacheng Huang
NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
Yaohan Sun
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
Yinbiao Qiao
General Surgery, Cancer Center, Department of Colorectal Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, China
Hao Wu
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
Shijie Zhou
NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
Haoyu Li
NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
Jianhui Li
Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou, 310015, China
Lin Zhou
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China; Corresponding author. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
Shusen Zheng
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China; Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou, 310015, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan, 250117, China; Corresponding author. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
Summary: Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with impaired regenerative capacity and poor postoperative prognosis following hepatectomy. Previous research has highlighted the importance of the gut–liver axis in the physiological and pathological processes of the liver. However, the contribution of gut bacteria to the regeneration of livers with MAFLD and its metabolic regulatory mechanisms remain elusive. Methods: Partial hepatectomy (PHx) was performed on C57Bl/6J mice fed with high-fat diet (HFD) for 12 weeks. Pathological examination, immunohistochemistry, and qRT-PCR analysis were performed to assess the severity of steatosis and proliferative potential. The gut microbiome was examined by 16S rRNA gene sequencing and shotgun metagenomics, whereas liver metabolomics was analysed via untargeted and targeted metabolomics using liquid chromatography-tandem mass spectrometry (LC-MS). Findings: HFD-induced hepatic steatosis in mice led to impaired liver regeneration following PHx. The gut microbiota and liver metabolites were altered along with the liver regeneration process. Longitudinal time-series analysis revealed dynamic alterations in these data, whereas correlation analysis screened out bacterial candidates that potentially influence liver regeneration in MAFLD by modulating metabolic pathways. Among these bacteria, the dominant bacterium Akkermansia was selected for subsequent investigation. MAFLD mice gavaged with Akkermansia muciniphila (A. muciniphila) exhibited reduced liver lipid accumulation and accelerated liver regeneration, possibly through the regulation of the tricarboxylic acid (TCA) cycle. Interpretation: These data demonstrated the interplay between the gut microbiome, liver metabolomics, and liver regeneration in mice with MAFLD. A. muciniphila has the potential to serve as a clinical intervention agent to accelerate postoperative recovery in MAFLD. Funding: This work was supported by the Research Project of Jinan Microecological Biomedicine Shandong Laboratory [JNL-2022008B]; the Zhejiang Provincial Natural Science Foundation of China [LZ21H180001]; the Fundamental Research Funds for the Central Universities [No. 2022ZFJH003].