New insight of chemical constituents in Persea americana fruit against obesity via integrated pharmacology.

Persea americana fruit (PAF) is a favorable nutraceutical resource that comprises diverse unsaturated fatty acids (UFAs). UFAs are significant dietary supplementation, as they relieve metabolic disorders, including obesity (OB). In another aspect, this study was focused on the anti-OB efficacy of the non-fatty acids (NFAs) in PAF through network pharmacology (NP). Natural product activity & species source (NPASS), SwissADME, similarity ensemble approach (SEA), Swiss target prediction (STP), DisGeNET, and online Mendelian inheritance in man (OMIM) were utilized to gather significant molecules and its targets. The crucial targets were adopted to construct certain networks: protein-protein interaction (PPI), PAF-signaling pathways-targets-compounds (PSTC) networks, a bubble chart, molecular docking assay (MDA), and density function theory (DFT). Finally, the toxicities of the key compounds were validated by ADMETlab 2.0 platform. All 41 compounds in PAF conformed to Lipinski's rule, and the key 31 targets were identified between OB and PAF. On the bubble chart, PPAR signaling pathway had the highest rich factor, suggesting that the pathway might be an agonism for anti-OB. Conversely, estrogen signaling pathway had the lowest rich factor, indicating that the mechanism might be antagonism against OB. Likewise, the PSTC network represented that AKT1 had the greatest degree value. The MDA results showed that AKT1-gamma-tocopherol, PPARA-fucosterol, PPARD-stigmasterol, (PPARG)-fucosterol, (NR1H3)-campesterol, and ILK-alpha-tocopherol formed the most stable conformers. The DFT represented that the five molecules might be promising agents via multicomponent targeting. Overall, this study suggests that the NFAs in PAF might play important roles against OB.

Multistrain Probiotics Alleviate Diarrhea by Modulating Microbiome-Derived Metabolites and Serotonin Pathway.

Diarrhea, a common gastrointestinal symptom in health problems, is highly associated with gut dysbiosis. The purpose of this study is to demonstrate the effect of multistrain probiotics (Sensi-Biome) on diarrhea from the perspective of the microbiome-neuron axis. Sensi-Biome (Lactiplantibacillus plantarum, Bifidobacterium animalis subsp. lactis, Lactobacillus acidophilus, Streptococcus thermophilus, Bifidobacterium bifidum, and Lactococcus lactis) was administered in a 4% acetic acid-induced diarrhea rat model at concentrations of 1 × 108 (G1), 1 × 109 (G2), and 1 × 1010 CFU/0.5 mL (G3). Diarrhea-related parameters, inflammation-related cytokines, and stool microbiota analysis by 16S rRNA were evaluated. A targeted and untargeted metabolomics approach was used to analyze the cecum samples using liquid chromatography and orbitrap mass spectrometry. The stool moisture content (p < 0.001), intestinal movement rate (p < 0.05), and pH (p < 0.05) were significantly recovered in G3. Serotonin levels were decreased in the multistrain probiotics groups. The inflammatory cytokines, serotonin, and tryptophan hydroxylase expression were improved in the Sensi-Biome groups. At the phylum level, Sensi-Biome showed the highest relative abundance of Firmicutes. Short-chain fatty acids including butyrate, iso-butyrate, propionate, and iso-valeric acid were significantly modified in the Sensi-Biome groups. Equol and oleamide were significantly improved in the multistrain probiotics groups. In conclusion, Sensi-Biome effectively controls diarrhea by modulating metabolites and the serotonin pathway.

Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and its prevalence has increased worldwide in recent years. Additionally, there is a close relationship between MASLD and gut microbiota-derived metabolites. However, the mechanisms of MASLD and its metabolites are still unclear. We demonstrated decreased indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA) in the feces of patients with hepatic steatosis compared to healthy controls. Here, IPA and IAA administration ameliorated hepatic steatosis and inflammation in an animal model of WD-induced MASLD by suppressing the NF-κB signaling pathway through a reduction in endotoxin levels and inactivation of macrophages. Bifidobacterium bifidum metabolizes tryptophan to produce IAA, and B. bifidum effectively prevents hepatic steatosis and inflammation through the production of IAA. Our study demonstrates that IPA and IAA derived from the gut microbiota have novel preventive or therapeutic potential for MASLD treatment.

Gut-microbiota prompt activation of natural killer cell on alcoholic liver disease.

The liver is rich in innate immune cells, such as natural killer (NK) cells, natural killer T cells, and Kupffer cells associated with the gut microbiome. These immune cells are dysfunctional owing to alcohol consumption. However, there is insufficient data on the association between immune cells and gut microbiome in alcoholic liver disease (ALD). Therefore, the purpose of this study was to evaluate the effects of probiotic strains on NK cells in ALD patients. In total, 125 human blood samples [control (n = 22), alcoholic hepatitis (n = 43), and alcoholic cirrhosis (n = 60]) were collected for flow cytometric analysis. C57BL/6J mice were divided into four groups (normal, EtOH-fed, and 2 EtOH+strain groups [Phocaeicola dorei and Lactobacillus helveticus]). Lymphocytes isolated from mouse livers were analyzed using flow cytometry. The frequency of NK cells increased in patients with alcoholic hepatitis and decreased in patients with alcoholic cirrhosis. The expression of NKp46, an NK cell-activating receptor, was decreased in patients with alcoholic hepatitis and increased in patients with alcoholic cirrhosis compared to that in the control group. The number of cytotoxic CD56dimCD16+ NK cells was significantly reduced in patients with alcoholic cirrhosis. We tested the effect of oral administration P. dorei and L. helveticus in EtOH-fed mice. P. dorei and L. helveticus improved liver inflammation and intestinal barrier damage caused by EtOH supply and increased NK cell activity. Therefore, these observations suggest that the gut microbiome may ameliorate ALD by regulating immune cells.

Multi-strain probiotics alleviate loperamide-induced constipation by adjusting the microbiome, serotonin, and short-chain fatty acids in rats.

Constipation is one of the most common gastrointestinal (GI) disorders worldwide. The use of probiotics to improve constipation is well known. In this study, the effect on loperamide-induced constipation by intragastric administration of probiotics Consti-Biome mixed with SynBalance® SmilinGut (Lactobacillus plantarum PBS067, Lactobacillus rhamnosus LRH020, Bifidobacterium animalis subsp. lactis BL050; Roelmi HPC), L. plantarum UALp-05 (Chr. Hansen), Lactobacillus acidophilus DDS-1 (Chr. Hansen), and Streptococcus thermophilus CKDB027 (Chong Kun Dang Bio) to rats was evaluated. To induce constipation, 5 mg/kg loperamide was intraperitoneally administered twice a day for 7 days to all groups except the normal control group. After inducing constipation, Dulcolax-S tablets and multi-strain probiotics Consti-Biome were orally administered once a day for 14 days. The probiotics were administered 0.5 mL at concentrations of 2 × 108 CFU/mL (G1), 2 × 109 CFU/mL (G2), and 2 × 1010 CFU/mL (G3). Compared to the loperamide administration group (LOP), the multi-strain probiotics not only significantly increased the number of fecal pellets but also improved the GI transit rate. The mRNA expression levels of serotonin- and mucin-related genes in the colons that were treated with the probiotics were also significantly increased compared to levels in the LOP group. In addition, an increase in serotonin was observed in the colon. The cecum metabolites showed a different pattern between the probiotics-treated groups and the LOP group, and an increase in short-chain fatty acids was observed in the probiotic-treated groups. The abundances of the phylum Verrucomicrobia, the family Erysipelotrichaceae and the genus Akkermansia were increased in fecal samples of the probiotic-treated groups. Therefore, the multi-strain probiotics used in this experiment were thought to help alleviate LOP-induced constipation by altering the levels of short-chain fatty acids, serotonin, and mucin through improvement in the intestinal microflora.

The seamless integration of dietary plant-derived natural flavonoids and gut microbiota may ameliorate non-alcoholic fatty liver disease: a network pharmacology analysis.

We comprised metabolites of gut microbiota (GM; endogenous species) and dietary plant-derived natural flavonoids (DPDNFs; exogenous species) were known as potent effectors against non-alcoholic fatty liver disease (NAFLD) via network pharmacology (NP). The crucial targets against NAFLD were identified via GM and DPDNFs. The protein interaction (PPI), bubble chart and networks of GM or natural products- metabolites-targets-key signalling (GNMTK) pathway were described via R Package. Furthermore, the molecular docking test (MDT) to verify the affinity was performed between metabolite(s) and target(s) on a key signalling pathway. On the networks of GNMTK, Enterococcus sp. 45, Escherichia sp.12, Escherichia sp.33 and Bacterium MRG-PMF-1 as key microbiota; flavonoid-rich products as key natural resources; luteolin and myricetin as key metabolites (or dietary flavonoids); AKT Serine/Threonine Kinase 1 (AKT1), CF Transmembrane conductance Regulator (CFTR) and PhosphoInositide-3-Kinase, Regulatory subunit 1 (PIK3R1) as key targets are promising components to treat NAFLD, by suppressing cyclic Adenosine MonoPhosphate (cAMP) signalling pathway. This study shows that components (microbiota, metabolites, targets and a key signalling pathway) and DPDNFs can exert combinatorial pharmacological effects against NAFLD. Overall, the integrated pharmacological approach sheds light on the relationships between GM and DPDNFs.

A metabolomics approach to the validation of predictive metabolites and phenotypic expression in non-alcoholic fatty liver disease.

AIMS: Nonalcoholic fatty liver disease (NAFLD) is becoming more common and severe. Individuals with NAFLD have an altered composition of gut- microbial metabolites. We used metabolomics profiling to identify microbial metabolites that could indicate gut-liver metabolic severity. Noninvasive biomarkers are required for NAFLD, especially for patients at high risk of disease progression. MAIN METHODS: We compared the stool metabolomes, untargeted metabolomics, and clinical data of 80 patients. Patients with nonalcoholic fatty liver (NAFL: n = 16), nonalcoholic steatohepatitis (NASH: n = 26), and cirrhosis (n = 19) and healthy control individuals (HC: n = 19) were enrolled. The identified metabolites in NAFLD were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography coupled to time-of-flight-mass spectrometry (LC-TOF-MS) were used to analyze metabolites. KEY FINDINGS: Untargeted metabolomics was used to identify and quantify 103 metabolites. Principal component analysis (PCA) was used to assess the metabolic discrimination of NAFL, NASH, and cirrhosis. Short-chain fatty acids (SCFA) levels were significantly lower in NAFLD patients, including those of acetate (p = 0.03), butyrate (p = 0.0008), and propionate. The stool cholic acid (p = 0.001) level was significantly increased in NAFLD patients. Palmitoylcarnitine and l-carnitine levels were significantly increased in NASH and cirrhosis patients. The phenotypic expression of these metabolites was linked to ß-oxidation. SIGNIFICANCE: We demonstrated a distinct metabolome profile in NAFLD patients with NAFL, NASH, and cirrhosis. We also discovered that the expression of certain metabolites and metabolic pathways was linked to NAFLD.

The convergent application of metabolites from Avena sativa and gut microbiota to ameliorate non-alcoholic fatty liver disease: a network pharmacology study.

BACKGROUND: Non-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. METHODS: We 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. RESULTS: The 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. CONCLUSION: In 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.

Characteristics of microbiome-derived metabolomics according to the progression of alcoholic liver disease.

BACKGROUND AND AIM: The prevalence and severity of alcoholic liver disease (ALD) are increasing. The incidence of alcohol-related cirrhosis has risen up to 2.5%. This study aimed to identify novel metabolite mechanisms involved in the development of ALD in patients. The use of gut microbiome-derived metabolites is increasing in targeted therapies. Identifying metabolic compounds is challenging due to the complex patterns that have long-term effects on ALD. We investigated the specific metabolite signatures in ALD patients. METHODS: This study included 247 patients (heathy control, HC: n = 62, alcoholic fatty liver, AFL; n = 25, alcoholic hepatitis, AH; n = 80, and alcoholic cirrhosis, AC, n = 80) identified, and stool samples were collected. 16S rRNA sequencing and metabolomics were performed with MiSeq sequencer and liquid chromatography coupled to time-of-flight-mass spectrometry (LC-TOF-MS), respectively. The untargeted metabolites in AFL, AH, and AC samples were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Metabolic network classifiers were used to predict the pathway expression of the AFL, AH, and AC stages. RESULTS: The relative abundance of Proteobacteria was increased and the abundance of Bacteroides was decreased in ALD samples (p = 0.001) compared with that in HC samples. Fusobacteria levels were higher in AH samples (p = 0.0001) than in HC samples. Untargeted metabolomics was applied to quantitatively screen 103 metabolites from each stool sample. Indole-3-propionic acid levels are significantly lower in AH and AC (vs. HC, p = 0.001). Indole-3-lactic acid (ILA: p = 0.04) levels were increased in AC samples. AC group showed an increase in indole-3-lactic acid (vs. HC, p = 0.040) level. Compared with that in HC samples, the levels of short-chain fatty acids (SCFAs: acetic acid, butyric acid, propionic acid, iso-butyric acid, and iso-valeric acid) and bile acids (lithocholic acids) were significantly decreased in AC. The pathways of linoleic acid metabolism, indole compounds, histidine metabolism, fatty acid degradation, and glutamate metabolism were closely associated with ALD metabolism. CONCLUSIONS: This study identified that microbial metabolic dysbiosis is associated with ALD-related metabolic dysfunction. The SCFAs, bile acids, and indole compounds were depleted during ALD progression. CLINICAL TRIAL: Clinicaltrials.gov, number NCT04339725.

Gut Lactobacillus and Probiotics Lactobacillus lactis/rhamnosis Ameliorate Liver Fibrosis in Prevention and Treatment.

The progression and exacerbation of liver fibrosis are closely related to the gut microbiome. It is hypothesized that some probiotics may slow the progression of liver fibrosis. In human stool analysis [healthy group (n = 44) and cirrhosis group (n = 18)], difference in Lactobacillus genus between healthy group and cirrhosis group was observed. Based on human data, preventive and therapeutic effect of probiotics Lactobacillus lactis and L. rhamnosus was evaluated by using four mice fibrosis models. L. lactis and L. rhamnosus were supplied to 3,5-diethoxycarbonyl-1,4-dihydrocollidine or carbon tetrachloride-induced liver fibrosis C57BL/6 mouse model. Serum biochemical measurements, tissue staining, and mRNA expression in the liver were evaluated. The microbiome was analyzed in mouse cecal contents. In the mouse model, the effects of Lactobacillus in preventing and treating liver fibrosis were different for each microbe species. In case of L. lactis, all models showed preventive and therapeutic effects against liver fibrosis. In microbiome analysis in mouse models administered Lactobacillus, migration and changes in the ratio and composition of the gut microbial community were confirmed. L. lactis and L. rhamnosus showed preventive and therapeutic effects on the progression of liver fibrosis, suggesting that Lactobacillus intake may be a useful strategy for prevention and treatment.

The identification of metabolites from gut microbiota in NAFLD via network pharmacology.

The metabolites of gut microbiota show favorable therapeutic effects on nonalcoholic fatty liver disease (NAFLD), but the active metabolites and mechanisms against NAFLD have not been documented. The aim of the study was to investigate the active metabolites and mechanisms of gut microbiota against NAFLD by network pharmacology. We obtained a total of 208 metabolites from the gutMgene database and retrieved 1256 targets from similarity ensemble approach (SEA) and 947 targets from the SwissTargetPrediction (STP) database. In the SEA and STP databases, we identified 668 overlapping targets and obtained 237 targets for NAFLD. Thirty-eight targets were identified out of those 237 and 223 targets retrieved from the gutMgene database, and were considered the final NAFLD targets of metabolites from the microbiome. The results of molecular docking tests suggest that, of the 38 targets, mitogen-activated protein kinase 8-compound K and glycogen synthase kinase-3 beta-myricetin complexes might inhibit the Wnt signaling pathway. The microbiota-signaling pathways-targets-metabolites network analysis reveals that Firmicutes, Fusobacteria, the Toll-like receptor signaling pathway, mitogen-activated protein kinase 1, and phenylacetylglutamine are notable components of NAFLD and therefore to understanding its processes and possible therapeutic approaches. The key components and potential mechanisms of metabolites from gut microbiota against NAFLD were explored utilizing network pharmacology analyses. This study provides scientific evidence to support the therapeutic efficacy of metabolites for NAFLD and suggests holistic insights on which to base further research.

New insight into gut microbiota-derived metabolites to enhance liver regeneration via network pharmacology study.

We intended to identify favourable metabolite(s) and pharmacological mechanism(s) of gut microbiota (GM) for liver regeneration (LR) through network pharmacology. We utilized the gutMGene database to obtain metabolites of GM, and targets associated with metabolites as well as LR-related targets were identified using public databases. Furthermore, we performed a molecular docking assay on the active metabolite(s) and target(s) to verify the network pharmacological concept. We mined a total of 208 metabolites in the gutMGene database and selected 668 targets from the SEA (1,256 targets) and STP (947 targets) databases. Finally, 13 targets were identified between 61 targets and the gutMGene database (243 targets). Protein-protein interaction network analysis showed that AKT1 is a hub target correlated with 12 additional targets. In this study, we describe the potential microbe from the microbiota (E. coli), chemokine signalling pathway, AKT1 and myricetin that accelerate LR, providing scientific evidence for further clinical trials.

Ion-Conducting Robust Cross-Linked Organic/Inorganic Polymer Composite as Effective Binder for Electrode of Electrochemical Capacitor.

Poly(ionic liquid)s (PILs) are used in many electrochemical energy storage/conversion devices owing to their favorable physical properties. Therefore, PIL binders have been examined as polymeric binders for electrodes in energy storage systems (ESSs) and have shown superior performance. Several innovative technologies have been developed to improve the properties of polymers, with cross-linking being the most effective and easy strategy to achieve this. In this study, we designed a breakthrough complex cross-linking and composite technique that could successfully develop the physical properties of a polymer in a simple one-step process. Additionally, the technique could improve the thermal stability and mechanical properties of the polymer. The proposed polymeric binder showed better adhesion, higher capacitance, and good energy density with improved cyclic stability compared to that shown by conventional polyvinylidene fluoride (PVDF). This study revealed that cross-linked networks in polymeric binders are long-cycle-life features for electrochemical redox capacitors.

Discovery of potent indazole-based human glutaminyl cyclase (QC) inhibitors as Anti-Alzheimer's disease agents.

The toxic pyroglutamate form of amyloid-ß (pE-Aß) is important for the pathogenesis of early Alzheimer's disease (AD); therefore, reducing pE-Aß by inhibiting glutaminyl cyclase (QC) provides a promising strategy for developing disease-modifying AD drugs. In this study, potent and selective QC inhibitors with desirable drug-like properties were discovered by replacing the 3,4-dimethoxyphenyl group in a QC inhibitor with a bioisosteric indazole surrogate. Among them, 3-methylindazole-6-yl and 3-methylindazole-5-yl derivatives with an N-cyclohexylurea were identified as highly potent inhibitors with IC50 values of 3.2 nM and 2.3 nM, respectively, both of which were approximately 10-fold more potent than varoglutamstat. In addition, the three inhibitors significantly reduced pE-Aß3-40 levels in an acute animal model after intracerebroventricular (icv) injection and were selective for hQC. Further in vitro pharmacokinetic and toxicity studies, including those investigating cytotoxicity, hERG inhibition, blood-brain barrier (BBB) permeability and metabolic stability, indicated that N-(3-methylindazole-6-yl)-N'-(cyclohexyl)urea derivative exhibited the most promising efficacy, selectivity and drug-like profile; thus, it was evaluated for its in vivo efficacy in an AD model.

Elucidation of Prebiotics, Probiotics, Postbiotics, and Target from Gut Microbiota to Alleviate Obesity via Network Pharmacology Study.

The metabolites produced by the gut microbiota have been reported as crucial agents against obesity; however, their key targets have not been revealed completely in complex microbiome systems. Hence, the aim of this study was to decipher promising prebiotics, probiotics, postbiotics, and more importantly, key target(s) via a network pharmacology approach. First, we retrieved the metabolites related to gut microbes from the gutMGene database. Then, we performed a meta-analysis to identify metabolite-related targets via the similarity ensemble approach (SEA) and SwissTargetPrediction (STP), and obesity-related targets were identified by DisGeNET and OMIM databases. After selecting the overlapping targets, we adopted topological analysis to identify core targets against obesity. Furthermore, we employed the integrated networks to microbiota-substrate-metabolite-target (MSMT) via R Package. Finally, we performed a molecular docking test (MDT) to verify the binding affinity between metabolite(s) and target(s) with the Autodock 1.5.6 tool. Based on holistic viewpoints, we performed a filtering step to discover the core targets through topological analysis. Then, we implemented protein-protein interaction (PPI) networks with 342 overlapping target, another subnetwork was constructed with the top 30% degree centrality (DC), and the final core networks were obtained after screening the top 30% betweenness centrality (BC). The final core targets were IL6, AKT1, and ALB. We showed that the three core targets interacted with three other components via the MSMT network in alleviating obesity, i.e., four microbiota, two substrates, and six metabolites. The MDT confirmed that equol (postbiotics) converted from isoflavone (prebiotics) via Lactobacillus paracasei JS1 (probiotics) can bind the most stably on IL6 (target) compared with the other four metabolites (3-indolepropionic acid, trimethylamine oxide, butyrate, and acetate). In this study, we demonstrated that the promising substate (prebiotics), microbe (probiotics), metabolite (postbiotics), and target are suitable for obsesity treatment, providing a microbiome basis for further research.

Food and Gut Microbiota-Derived Metabolites in Nonalcoholic Fatty Liver Disease.

Diet and lifestyle are crucial factors that influence the susceptibility of humans to nonalcoholic fatty liver disease (NAFLD). Personalized diet patterns chronically affect the composition and activity of microbiota in the human gut; consequently, nutrition-related dysbiosis exacerbates NAFLD via the gut-liver axis. Recent advances in diagnostic technology for gut microbes and microbiota-derived metabolites have led to advances in the diagnosis, treatment, and prognosis of NAFLD. Microbiota-derived metabolites, including tryptophan, short-chain fatty acid, fat, fructose, or bile acid, regulate the pathophysiology of NAFLD. The microbiota metabolize nutrients, and metabolites are closely related to the development of NAFLD. In this review, we discuss the influence of nutrients, gut microbes, their corresponding metabolites, and metabolism in the pathogenesis of NAFLD.

Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease.

Alcohol consumption is a global healthcare problem. Chronic alcohol consumption generates a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, fibrosis, and cirrhosis. Alcoholic liver diseases (ALD) refer to liver damage and metabolomic changes caused by excessive alcohol intake. ALD present several clinical stages of severity found in liver metabolisms. With increased alcohol consumption, the gut microbiome promotes a leaky gut, metabolic dysfunction, oxidative stress, liver inflammation, and hepatocellular injury. Much attention has focused on ALD, such as alcoholic fatty liver (AFL), alcoholic steatohepatitis (ASH), alcoholic cirrhosis (AC), hepatocellular carcinoma (HCC), a partnership that reflects the metabolomic significance. Here, we report on the global function of inflammation, inhibition, oxidative stress, and reactive oxygen species (ROS) mechanisms in the liver biology framework. In this tutorial review, we hypothetically revisit therapeutic gut microbiota-derived alcoholic oxidative stress, liver inflammation, inflammatory cytokines, and metabolic regulation. We summarize the perspective of microbial therapy of genes, gut microbes, and metabolic role in ALD. The end stage is liver transplantation or death. This review may inspire a summary of the gut microbial genes, critical inflammatory molecules, oxidative stress, and metabolic routes, which will offer future promising therapeutic compounds in ALD.

The Link between Gut Microbiota and Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the host plays a key role in the pathogenesis of HE. The link between the gut microbiome and disease can be positively utilized not only in the diagnosis area of HE but also in the treatment area. Probiotics and prebiotics aim to resolve gut dysbiosis and increase beneficial microbial taxa, while fecal microbiota transplantation aims to address gut dysbiosis through transplantation (FMT) of the gut microbiome from healthy donors. Antibiotics, such as rifaximin, aim to improve cognitive function and hyperammonemia by targeting harmful taxa. Current treatment regimens for HE have achieved some success in treatment by targeting the gut microbiota, however, are still accompanied by limitations and problems. A focused approach should be placed on the establishment of personalized trial designs and therapies for the improvement of future care. This narrative review identifies factors negatively influencing the gut-hepatic-brain axis leading to HE in cirrhosis and explores their relationship with the gut microbiome. We also focused on the evaluation of reported clinical studies on the management and improvement of HE patients with a particular focus on microbiome-targeted therapy.

Identification of Gut Microbiome Metabolites via Network Pharmacology Analysis in Treating Alcoholic Liver Disease.

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.