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Interventions for non-alcoholic liver disease: a gut microbial metabolites perspective.

ABSTRACT: Over the past two decades, non-alcoholic fatty liver disease (NAFLD) has become a leading burden of hepatocellular carcinoma and liver transplantation. Although the exact pathogenesis of NAFLD has not been fully elucidated, recent hypotheses placed more emphasis on the crucial role of the gut microbiome and its derivatives. Reportedly, microbial metabolites such as short-chain fatty acids, amino acid metabolites (indole and its derivatives), bile acids (BAs), trimethylamine N-oxide (TMAO), and endogenous ethanol exhibit sophisticated bioactive properties. These molecules regulate host lipid, glucose, and BAs metabolic homeostasis via modulating nutrient absorption, energy expenditure, inflammation, and the neuroendocrine axis. Consequently, a broad range of research has studied the therapeutic effects of microbiota-derived metabolites. In this review, we explore the interaction of microbial products and NAFLD. We also discuss the regulatory role of existing NAFLD therapies on metabolite levels and investigate the potential of targeting those metabolites to relieve NAFLD.

SUBMITTER: Guo J

PROVIDER: S-EPMC9730013 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Interventions for non-alcoholic liver disease: a gut microbial metabolites perspective.

Guo Jin J Shi Chun-Xia CX Zhang Qing-Qi QQ Deng Wei W Zhang Lu-Yi LY Chen Qian Q Zhang Dan-Mei DM Gong Zuo-Jiong ZJ

Therapeutic advances in gastroenterology 20221206

Over the past two decades, non-alcoholic fatty liver disease (NAFLD) has become a leading burden of hepatocellular carcinoma and liver transplantation. Although the exact pathogenesis of NAFLD has not been fully elucidated, recent hypotheses placed more emphasis on the crucial role of the gut microbiome and its derivatives. Reportedly, microbial metabolites such as short-chain fatty acids, amino acid metabolites (indole and its derivatives), bile acids (BAs), trimethylamine N-oxide (TMAO), and e ...[more]

PMID: 36506748

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Project description:Alcoholic liver disease (ALD) is linked to a broad spectrum of diseases, including diabetes, hypertension, atherosclerosis, and even liver carcinoma. The ALD spectrum includes alcoholic fatty liver disease (AFLD), alcoholic hepatitis, and cirrhosis. Most recently, some reports demonstrated that the pathogenesis of ALD is strongly associated with metabolites of human microbiota. AFLD was the onset of disease among ALDs, the initial cause of which is alcohol consumption. Thus, we analyzed the significant metabolites of microbiota against AFLD via the network pharmacology concept. The metabolites from microbiota were retrieved by the gutMGene database; sequentially, AFLD targets were identified by public databases (DisGeNET, OMIM). The final targets were utilized for protein-protein interaction (PPI) networks and signaling pathway analyses. Then, we performed a molecular docking test (MDT) to verify the affinity between metabolite(s) and target(s) utilizing the Autodock 1.5.6 tool. From a holistic viewpoint, we integrated the relationships of microbiota-signaling pathways-targets-metabolites (MSTM) using the R Package. We identified the uppermost six key targets (TLR4, RELA, IL6, PPARG, COX-2, and CYP1A2) against AFLD. The PPI network analysis revealed that TLR4, RELA, IL6, PPARG, and COX-2 had equivalent degrees of value (4); however, CYP1A2 had no associations with the other targets. The bubble chart showed that the PI3K-Akt signaling pathway in nine signaling pathways might be the most significant mechanism with antagonistic functions in the treatment of AFLD. The MDT confirmed that Icaritin is a promising agent to bind stably to RELA (known as NF-Κb). In parallel, Bacterium MRG-PMF-1, the PI3K-Akt signaling pathway, RELA, and Icaritin were the most significant components against AFLD in MSTM networks. In conclusion, we showed that the Icaritin-RELA complex on the PI3K-Akt signaling pathway by bacterial MRG-PMF-1 might have promising therapeutic effects against AFLD, providing crucial evidence for further research.

Project description:BackgroundNon-alcoholic fatty liver disease (NAFLD) is a serious public health issue globally, currently, the treatment of NAFLD lies still in the labyrinth. In the inchoate stage, the combinatorial application of food regimen and favorable gut microbiota (GM) are considered as an alternative therapeutic. Accordingly, we integrated secondary metabolites (SMs) from GM and Avena sativa (AS) known as potent dietary grain to identify the combinatorial efficacy through network pharmacology.MethodsWe browsed the SMs of AS via Natural Product Activity & Species Source (NPASS) database and SMs of GM were retrieved by gutMGene database. Then, specific intersecting targets were identified from targets related to SMs of AS and GM. The final targets were selected on NAFLD-related targets, which was considered as crucial targets. The protein-protein interaction (PPI) networks and bubble chart analysis to identify a hub target and a key signaling pathway were conducted, respectively. In parallel, we analyzed the relationship of GM or AS─a key signaling pathway─targets─SMs (GASTM) by merging the five components via RPackage. We identified key SMs on a key signaling pathway via molecular docking assay (MDA). Finally, the identified key SMs were verified the physicochemical properties and toxicity in silico platform.ResultsThe final 16 targets were regarded as critical proteins against NAFLD, and Vascular Endothelial Growth Factor A (VEGFA) was a key target in PPI network analysis. The PI3K-Akt signaling pathway was the uppermost mechanism associated with VEGFA as an antagonistic mode. GASTM networks represented 122 nodes (60 GM, AS, PI3K-Akt signaling pathway, 4 targets, and 56 SMs) and 154 edges. The VEGFA-myricetin, or quercetin, GSK3B-myricetin, IL2-diosgenin complexes formed the most stable conformation, the three ligands were derived from GM. Conversely, NR4A1-vestitol formed stable conformation with the highest affinity, and the vestitol was obtained from AS. The given four SMs were no hurdles to develop into drugs devoid of its toxicity.ConclusionIn conclusion, we show that combinatorial application of AS and GM might be exerted to the potent synergistic effects against NAFLD, dampening PI3K-Akt signaling pathway. This work provides the importance of dietary strategy and beneficial GM on NAFLD, a data mining basis for further explicating the SMs and pharmacological mechanisms of combinatorial application (AS and GM) against NAFLD.

Project description:Background Non-alcoholic fatty liver disease (NAFLD), the most common liver disease, is closely associated with metabolic conditions such as obesity and diabetes mellitus, which significantly impact human health outcomes. The impaired lipid profiles observed in NAFLD individuals can further contribute to cardiovascular events. Despite the high prevalence of NAFLD, there is currently no confirmed intervention approved for its treatment. This study aimed to summarize the results of meta-analysis studies of randomized control trials assessing the impact of gut microbial therapy (probiotics, synbiotics, and prebiotics) on the lipid profile of individuals with NAFLD. Methods A systematic search was conducted on PubMed, Scopus, Web of Science, and Cochrane Library up to November 1, 2022. Meta-analyses surveying the impact of microbial therapy on lipid profile parameters (triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol (TC)) in the NAFLD population were included in our umbrella review. The final effect size (ES) was estimated, and sensitivity and subgroup analyses were performed to explore heterogeneity. Results Fifteen studies were included in this umbrella review. Microbial therapy significantly reduced TG (ES − 0.31, 95% CI − 0.51, − 0.11, P < 0.01), TC (ES − 1.04, 95% CI − 1.46, − 0.61, P < 0.01), and LDL (ES − 0.77, 95% CI − 1.15, − 0.39, P < 0.01) in individuals with NAFLD. However, the effect on HDL was not statistically significant (ES − 0.06; 95% CI − 0.19, 0.07, P = 0.39). Conclusion Considering the absence of approved treatments for NAFLD and the promising role of microbial therapies in improving the three lipid profiles components in individuals with NAFLD, the use of these agents as alternative treatment options could be recommended. The findings underscore the potential of gut microbial therapy, including probiotics, synbiotics, and prebiotics, in managing NAFLD and its associated metabolic complications. Trial registration PROSPERO (CRD42022346998). Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s13643-023-02299-x.

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Interventions for non-alcoholic liver disease: a gut microbial metabolites perspective.

Publications

Interventions for non-alcoholic liver disease: a gut microbial metabolites perspective.

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