摘要
BACKGROUND Intestinal dysbiosis has been shown to be associated with the pathogenesis of alcoholic liver disease(ALD), which includes changes in the microbiota composition and bacterial overgrowth, but an effective microbe-based therapy is lacking. Pediococcus pentosaceus(P. pentosaceus) CGMCC 7049 is a newly isolated strain of probiotic that has been shown to be resistant to ethanol and bile salts. However, further studies are needed to determine whether P. pentosaceus exerts a protective effect on ALD and to elucidate the potential mechanism.AIM To evaluate the protective effect of the probiotic P. pentosaceus on ethanol-induced liver injury in mice.METHODS A new ethanol-resistant strain of P. pentosaceus CGMCC 7049 was isolated from healthy adults in our laboratory. The chronic plus binge model of experimental ALD was established to evaluate the protective effects. Twenty-eight C57BL/6 mice were randomly divided into three groups: The control group received a pairfed control diet and oral gavage with sterile phosphate buffered saline, the EtOH group received a ten-day Lieber-DeCarli diet containing 5% ethanol and oral gavage with phosphate buffered saline, and the P. pentosaceus group received a 5% ethanol Lieber-DeCarli diet but was treated with P. pentosaceus. One dose of isocaloric maltose dextrin or ethanol was administered by oral gavage on day 11, and the mice were sacrificed nine hours later. Blood and tissue samples(liver and gut) were harvested to evaluate gut barrier function and liver injury-related parameters. Fresh cecal contents were collected, gas chromatography–mass spectrometry was used to measure short-chain fatty acid(SCFA) concentrations, and the microbiota composition was analyzed using 16S rRNA gene sequencing.RESULTS The P. pentosaceus treatment improved ethanol-induced liver injury, with lower alanine aminotransferase, aspartate transaminase and triglyceride levels and decreased neutrophil infiltration. These changes were accompanied by decreased levels of endotoxin and inflammatory cytokines, including interleukin-5, tumor necrosis factor-α, granulocyte colony-stimulating factor, keratinocyte-derived protein chemokine, macrophage inflammatory protein-1α and monocyte chemoattractant protein-1. Ethanol feeding resulted in intestinal dysbiosis and gut barrier disruption, increased relative abundance of potentially pathogenic Escherichia and Staphylococcus, and the depletion of SCFA-producing bacteria, such as Prevotella, Faecalibacterium, and Clostridium. In contrast, P. pentosaceus administration increased the microbial diversity, restored the relative abundance of Lactobacillus, Pediococcus, Prevotella, Clostridium and Akkermansia and increased propionic acid and butyric acid production by modifying SCFA-producing bacteria. Furthermore, the levels of the tight junction protein ZO-1, mucin proteins(mucin [MUC]-1, MUC-2 and MUC-4) and the antimicrobial peptide Reg3β were increased after probiotic supplementation.CONCLUSION Based on these results, the new strain of P. pentosaceus alleviated ethanol-induced liver injury by reversing gut microbiota dysbiosis, regulating intestinal SCFA metabolism, improving intestinal barrier function, and reducing circulating levels of endotoxin and proinflammatory cytokines and chemokines. Thus, this strain is a potential probiotic treatment for ALD.
基金
Supported by National Natural Science Foundation of China,No. 81330011,No. 81790631,No. 81570512,and No. 81790633
Science Fund for Creative Research Groups of the National Natural Science Foundation of China,No. 81121002
National Key Research and Development Program of China,No. 2018YFC2000500。
作者简介
Xian-Wan Jiang,ORCID number:0000-0003-0982-7306;Ya-Ting Li,ORCID number:0000-0002-0761-4967;Jian-Zhong Ye,ORCID number:0000-0001-8174-2580;Long-Xian Lv,ORCID number:0000-0003-4114-9402;Li-Ya Yang,ORCID number:0000-0002-7832-983X;Xiao-Yuan Bian,ORCID number:0000-0002-7275-3103;Wen-Rui Wu,ORCID number:0000-0002-8457-9675;Jing-Jing Wu,ORCID number:0000-0001-9289-0538;Ding Shi,ORCID number:0000-0003-3988-9321;Qing Wang,ORCID number:0000-0003-4914-5473;Dai-Qiong Fang,ORCID number:0000-0002-0758-3988;Kai-Cen Wang,ORCID number:0000-0002-0945-0986;Qiang-Qiang Wang,ORCID number:0000-0003-1212-4492;Yan-Meng Lu,ORCID number:0000-0002-4520-028X;Jiao-Jiao Xie,ORCID number:0000-0002-0357-1410;Corresponding author:Lan-Juan Li,PhD,Academic Research,Doctor,Professor,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,National Clinical Research Center for Infectious Diseases,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,The First Affiliated Hospital,College of Medicine,Zhejiang University,No.79 Qingchun Road,Hangzhou 310003,Zhejiang Province,China.E-mail:ljli@zju.edu.cn,ORCID number:0000-0001-6945-0593.
