Enhanced alcoholic liver disease in mice with intestine-specific farnesoid X receptor deficiency

et al. 2021

J Exp Clin Cancer Res

Background Alcohol-induced intestinal dysbiosis disrupts and inflammatory responses are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigated the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissected the pathogenic role of Fmo5 in AFLD-induced liver pathology. Methods The expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. The WGCNA approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform KEGG pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized using Cytoscape software. The Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expression. ELISA assay was used to detect the levels of serum inflammatory cytokines. Lipid droplets in the cytoplasm were observed using Oil Red O staining. Apoptosis was detected using a TUNEL assay and flow cytometry analysis. ROS levels were detected using flow cytometry analysis. Nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation was used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD. Results Fmo5 is a key DEG and is closely associated with the gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to the PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal models with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. The NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury. Conclusion Our data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition and alleviated AFLD-induced liver injury, apoptosis, and inflammatory response by inhibiting the nuclear translocation of NF-κB p65 to inhibit the NF-κB signaling pathway.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

et al. 2021

J Exp Clin Cancer Res

“…With the decrease of liver function, the intestinal balance is destroyed [19]. The accumulation of harmful substances such as alcohol leads to liver injury and promotes the secretion of bile acid into the intestinal tract by the liver, thereby regulating the activity of various metabolic reactions in the intestinal tract [2,4,5,13]. The change in the type and number of intestinal ora is an important factor leading to abnormal liver function [20].…”

Section: Discussionmentioning

confidence: 99%

“…When the body is stimulated by alcohol, the excessive input of lipids leads to the disturbance of lipoprotein synthesis and metabolism in the liver, and the insu cient oxidation of fatty acids, which leads to the deposition of fat in the liver, resulting in fatty liver. Alcoholic fatty liver disease (AFLD) is caused by long-term heavy drinking and is the most common and reversible stage of alcoholic liver disease [1,2][3] [4]. Although numerous studies have been conducted on the pathogenesis of alcoholic fatty liver at home and abroad [3], there is still no effective treatment for alcoholic fatty liver in the clinic.…”

mentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance 

et al. 2020

Preprint

BackgroundAlcohol-induced intestinal dysbiosis disrupts and inflammatory responses are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigated the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissected the pathogenic role of Fmo5 in AFLD-induced liver pathology.MethodsThe expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. The WGCNA approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform KEGG pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized using Cytoscape software. The Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expression. ELISA assay was used to detect the levels of serum inflammatory cytokines. Lipid droplets in the cytoplasm were observed using Oil Red O staining. Apoptosis was detected using a TUNEL assay and flow cytometry analysis. ROS levels were detected using flow cytometry analysis. Nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation was used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD.ResultsFmo5 is a key DEG and is closely associated with the gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to the PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal models with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. The NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury.ConclusionOur data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition and alleviated AFLD-induced liver injury, apoptosis, and inflammatory response by inhibiting the nuclear translocation of NF-κB p65 to inhibit the NF-κB signaling pathway.

“…AFLD is the most common and reversible stage of alcoholic liver disease [3]. When the body is stimulated by alcohol, the excessive input of lipids leads to the disturbance of lipoprotein synthesis and metabolism in the liver, and the insu cient oxidation of fatty acids, which leads to the deposition of fat in the liver, resulting in fatty liver [4]. Although a large number of studies have been done on the pathogenesis of alcoholic fatty liver at home and abroad [3], there is still no effective treatment for alcoholic fatty liver in clinic.…”

Section: Introductionmentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

et al. 2020

Preprint

Abstract Background Alcohol-induced intestinal dysbiosis disrupts and inflammatory response are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigate the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissect the pathogenic role of Fmo5 in AFLD-induced liver pathology. Materials and methods The expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. Weighted gene co-expression network analysis (WGCNA) approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized by Cytoscape software. Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expressions. ELISA assay was used to detect the level of serum inflammatory cytokines. Lipid droplets in cytoplasm were observed using Oil Red O staining. Cell apoptosis was detected using TUNEL assay and flow cytometry analysis. ROS level were detected using flow cytometry analysis. The nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation were used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD. Results Fmo5 was a key DEG and closely associated with gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal model with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury. Conclusions Our data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition, alleviated AFLD-induced liver injury, apoptosis and inflammatory response via inhibiting the nuclear translocation of NF-κB p65 to inhibit NF-κB signaling pathway.