Peptidoglycan isolated from the fruit of Lycium barbarum alleviates liver fibrosis in mice by regulating the TGF-β/Smad7 signaling and gut microbiota

Ying-Min Nie; Wan-Qi Zhou; Ting Niu; Meng-Fei Mao; Yu-Xue Zhan; Yun Li; Kai-Ping Wang; Mei-Xia Li; Kan Ding

doi:10.1038/s41401-024-01454-x

Peptidoglycan isolated from the fruit of Lycium barbarum alleviates liver fibrosis in mice by regulating the TGF-β/Smad7 signaling and gut microbiota

Acta Pharmacol Sin. 2025 Jan 20. doi: 10.1038/s41401-024-01454-x. Online ahead of print.

Authors

Ying-Min Nie^#^{1

2}, Wan-Qi Zhou^#^{1

3

4}, Ting Niu^{1

5}, Meng-Fei Mao^{1

2}, Yu-Xue Zhan⁶, Yun Li^{1

2}, Kai-Ping Wang⁷, Mei-Xia Li^{8

9}, Kan Ding^{10

11

12

13

14}

Affiliations

¹ Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
² University of Chinese Academy of Sciences, Beijing, 100049, China.
³ School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
⁴ Lingang Laboratory, Shanghai, 201203, China.
⁵ Department of Pancreatic-biliary Surgery, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
⁶ Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, Wuhan, 430030, China.
⁷ Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, Wuhan, 430030, China. [email protected].
⁸ Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
⁹ University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
¹⁰ Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
¹¹ University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
¹² School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China. [email protected].
¹³ Lingang Laboratory, Shanghai, 201203, China. [email protected].
¹⁴ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan Tsuihang New District, Zhongshan, 528400, China. [email protected].

^# Contributed equally.

PMID: 39833303
DOI: 10.1038/s41401-024-01454-x

Abstract

The hepatoprotective effect of the fruit of Lycium barbarum has been documented in China over millennia. Lycium barbarum polysaccharides (LBPs) were the first macromolecules reported to mitigate liver fibrosis in carbon tetrachloride (CCl₄)-treated mice. Herein, a neutral peptidoglycan, named as LBPW, was extracted from the fruit of Lycium barbarum. In this study, we investigated the hepatoprotective mechanisms of LBPW. CCl₄-induced liver fibrosis mice were administered LBPW (50, 100, 200 mg ·kg^-1 ·d^-1, i.p.) or (100, 200, 300 mg· kg^-1 ·d^-1, i.g.) for 6 weeks. We showed that either i.p. or i.g. administration of LBPW dose-dependently attenuated liver damage and fibrosis in CCl₄-treated mice. Pharmacokinetic analysis showed that cyanine 5.5 amine (Cy5.5)-labeled LBPW (Cy5.5-LBPW) could be detected in the liver through i.p. and i.g. administration with i.g.-administered Cy5.5-LBPW mainly accumulating in the intestine. In TGF-β1-stimulated LX-2 cells as well as in the liver of CCl₄-treated mice, we demonstrated that LBPW significantly upregulated Smad7, a negative regulator of TGF-β/Smad signaling, to retard the activation of hepatic stellate cells (HSCs) and prevent liver fibrosis. On the other hand, LBPW significantly boosted the abundance of Akkermansia muciniphila (A. muciniphila) and fortified gut barrier function. We demonstrated that A. muciniphila might be responsible for the efficacy of LBPW since decreasing the abundance of this bacterium by antibiotics (Abs) blocked the effectiveness of LBPW. Overall, our results show that LBPW may exert the hepatoprotective effect via rebalancing TGF-β/Smad7 signaling and propagating gut commensal A. muciniphila, suggesting that LBPW could be leading components to be developed as new drug candidates or nutraceuticals against liver fibrosis.

Keywords: Akkermansia muciniphila; Lycium barbarum; LBPW; TGF-β/Smad7; liver fibrosis; peptidoglycan.