RESUMO
Camel milk (CM) is considered to protect the liver in the practice of traditional medicine in nomadic areas. The purpose of the present study was to investigate the effects of CM on the hepatic biochemical and multiple omics alterations induced by chronic alcoholic liver disease (ALD). An intragastric gavage mice Lieber DeCarli + Gao binge model (NIAAA model) was employed to investigate the inflammatory mechanism of camel milk on the liver tissue of mice. A gut microbiota of the feces of mice and transcriptomic and proteomic analyses of the liver of mice were performed. Analysis of serum and liver biochemical indexes revealed that camel milk not only prevents alcohol-induced colonic dysfunction and lipid accumulation, but also regulates oxidative stress and inflammatory cytokine production to protect against chronic ALD in mouse. The gut microbial community of mice treated with camel milk was more similar to the untreated control group than to the model group, indicating that the intake of camel milk pre- and post-alcohol gavage effectively prevents and alleviates the intestinal microbial disorder caused by chronic alcoholism in mice. Furthermore, the results of the transcriptomic and proteomic analyses of the liver tissue showed that camel milk can improve alcoholic liver injury in mice by regulating inflammatory factors and immune system disruptions. This study provides insights into the molecular mechanism by which camel milk can be developed as a potential functional food with no side effects and against liver injury.
Assuntos
Anti-Inflamatórios/administração & dosagem , Camelus , Mediadores da Inflamação/metabolismo , Intestinos/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Fígado/metabolismo , Leite , Animais , Consumo Excessivo de Bebidas Alcoólicas , Modelos Animais de Doenças , Disbiose , Alimento Funcional , Microbioma Gastrointestinal , Intestinos/imunologia , Intestinos/microbiologia , Metabolismo dos Lipídeos , Fígado/imunologia , Fígado/patologia , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Proteoma , TranscriptomaRESUMO
Uncovering the intricacies of the gut microbiome and how it interacts with the host immune system has opened up pathways in the search for the treatment of disease conditions. Alcohol-associated liver disease is a major cause of death worldwide. Research has shed light on the breakdown of the protective gut barriers, translocation of gut microbes to the liver and inflammatory immune response to microbes all contributing to alcohol-associated liver disease. This knowledge has opened up avenues for alternative therapies to alleviate alcohol-associated liver disease based on the interaction of the commensal gut microbiome as a key player in the regulation of the immune response. This review describes the relevance of the intestinal immune system, the gut microbiota, and specialized and non-specialized intestinal cells in the regulation of intestinal homeostasis. It also reflects how these components are altered during alcohol-associated liver disease and discusses new approaches for potential future therapies in alcohol-associated liver disease.
Assuntos
Microbioma Gastrointestinal , Mucosa Intestinal/imunologia , Hepatopatias Alcoólicas/imunologia , Animais , Disbiose/terapia , Homeostase , Humanos , Mucosa Intestinal/microbiologia , Fígado/imunologia , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/prevenção & controleRESUMO
Alcohol abuse and alcoholic liver diseases (ALD) have been worldwide spread. Chronic alcoholism-induced overgrowth of intestinal bacteria and fungi together with the enteric dysbiosis are important pathogenic mechanisms in ALD. We demonstrated that the water-insoluble polysaccharides (WIP) from Wolfporia cocos effectively ameliorated the hepatic inflammatory injury and fat accumulation through modulating gut microbiota in mice with alcoholic hepatic steatosis (AHS). Oral administration of WIP significantly enhanced the ratio of Firmictues to Proteobacteria, increased the abundance of Lachnospiraceae including Ruminoclostridum and unidentified_clostridials, and inhibited the ethanol-induced fungal overgrowth. Treatment with WIP activated the PPAR-γ signaling and reduced the inflammation in the colonic epithelia cell, facilitating a hypoxic state that suppresses the overgrowth of fungi and Proteobacteria in the gut. In addition, we found an overwhelming increase of the commensal fungus Meyerozyma guilliermondii in the feces of mice with AHS by culturing and ITS sequencing. Inoculation of M. guilliermondii into fungi-free mice aggravated the features of AHS. M. guilliermondii was found to generate PGE2 by biotransformation of arachidonic acid. Furthermore, the gut fungi (M. guilliermondii)-induced PGE2 production in the liver was confirmed as one of the mechanisms in the chronic AHS. The current study supports the manipulation of the gut microbiota (bacteria and fungi) as an effective and alternative strategy for alleviating ALD.
Assuntos
Dinoprostona/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/tratamento farmacológico , Polissacarídeos/administração & dosagem , Wolfiporia/química , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Fungos/classificação , Fungos/genética , Fungos/crescimento & desenvolvimento , Fungos/isolamento & purificação , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Vinegar extract is rich in phenolic compounds, which can prevent free radical-induced diseases. The aim of the present study was to explore the effects of vinegar extract on gut microbiota in alcohol-treated mice and their correlation with alcohol-induced liver damage. These results showed that vinegar extract regulated the gut microbiota composition and improved intestinal homeostasis through increasing the expression levels of ZO-1, occludin, claudin-1, Reg3b, and Reg3g in alcohol-treated mice. In addition, vinegar extract inhibited the alcohol-induced production of ROS and inflammatory factors. Moreover, Bacteroidetes, Verrucomicrobia, Akkermansia, and Lactobacillus showed a significant positive correlation with Reg3b, Reg3g, ZO-1, occludin, and claudin-1 and a negative correlation with hepatic inflammation and oxidative stress parameters. However, Firmicutes, Proteobacteria, Butyricimonas, Parabacteroides, and Bilophila exhibited the opposite effect. These findings suggest that vinegar extract modulates gut microbiota and improves intestinal homeostasis, and can be used as a novel gut microbiota manipulator against alcohol-induced liver damage.
Assuntos
Ácido Acético , Alimento Funcional , Hepatopatias Alcoólicas/prevenção & controle , Extratos Vegetais/administração & dosagem , Animais , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/farmacologiaRESUMO
Alcoholic liver injury, known as the most general result of chronic alcohol intake, is induced by inflammatory responses, which is activated by intestine-derived endotoxins formed from intestinal dysbiosis. The hepatoprotective activity of rice bran phenolic extract (RBPE) on ethanol-fed mice was investigated for the first time in this study, and the underlying mechanism was explored from gut microbiota, barrier function, and hepatic inflammation. Mice were fed an alcohol-containing liquid diet alone or in mixture with RBPE for 8 weeks. RBPE treatment mitigated ethanol-induced liver damage, evidenced by the declined lipid profile levels and hepatic function markers. Moreover, ethanol intake induced intestinal microbiota dysbiosis, which was attenuated by RBPE supplementation. RBPE treatment improved the alcohol-induced decrease in the expression of ZO-1, Claudin-1, Claudin-4, and Reg3g, revealing the ameliorative effect of RBPE on intestinal barrier dysfunction. Furthermore, RBPE treatment repressed the alcohol-induced trigger of the hepatic endotoxin-TLR4-NF-κB pathway, followed by the mitigated liver inflammation. The findings indicate that RBPE supplementation ameliorates intestinal microbiota dysbiosis and barrier dysfunction, inactivates the endotoxin-TLR4-NF-κB pathway, and represses inflammatory responses in liver, and therefore, intake of RBPE or brown rice may be an effective way to mitigate alcoholic liver injury.
Assuntos
Disbiose/tratamento farmacológico , Mucosa Intestinal/microbiologia , Hepatopatias Alcoólicas/prevenção & controle , NF-kappa B/imunologia , Oryza/química , Fenóis/administração & dosagem , Extratos Vegetais/administração & dosagem , Receptor 4 Toll-Like/imunologia , Animais , Disbiose/genética , Disbiose/imunologia , Disbiose/microbiologia , Endotoxinas/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Substâncias Protetoras/administração & dosagem , Receptor 4 Toll-Like/genéticaRESUMO
This aim of this study is to assess the possible effects of dietary okra seed oil (OSO) consumption on attenuation of alcohol-induced liver damage and gut microbiota dysbiosis, and associated mechanisms in mice. Mice were orally administered alcohol alone or in combination with OSO at 400 and 800 mg per kg bw for 8 weeks. OSO caused a strong inhibition of abnormal weight loss and liver fat accumulation in alcohol-administered mice. Malonaldehyde production was also effectively antagonized, and glutathione peroxidase and superoxide dismutase activities were elevated by OSO treatment in ethanol-based mice (p < 0.05). Concentrations of hepatic TNF-α, IL-1 and IL-6 were decreased after OSO treatment when compared with alcohol-treated mice, respectively (p < 0.05). As revealed by 16S rDNA gene sequence analysis, OSO notably reduced the Proteobacteria proportion and enhanced the Bacteroidetes population of alcohol-treated mice, and a significant reduction in Clostridium XlVa and Staphylococcus was observed, revealing that OSO attenuated the alcohol-induced gut dysbiosis. OSO also attenuated lipid metabolic disorder by modulating metabolism of serum free fatty acids in ethanol-based mice, but had no significant difference in cecum total short-chain fatty acids among the tested mice. Amelioration of these parameters and liver injury via H&E staining examination demonstrated that OSO consumption could effectively protect against liver damage and maintain intestinal eubiosis in mice.
Assuntos
Abelmoschus/química , Disbiose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/tratamento farmacológico , Óleos de Plantas/administração & dosagem , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Disbiose/genética , Disbiose/metabolismo , Disbiose/microbiologia , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos , Sementes/químicaRESUMO
Alcoholic liver disease (ALD), a disorder caused by excessive alcohol intake represents a global health care burden. ALD encompasses a broad spectrum of hepatic injuries including asymptomatic steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The susceptibility of alcoholic patients to develop ALD is highly variable and its progression to more advanced stages is strongly influenced by several hits (i.e., amount and duration of alcohol abuse). Among them, the intestinal microbiota and its metabolites have been recently identified as paramount in ALD pathophysiology. Ethanol abuse triggers qualitative and quantitative modifications in intestinal flora taxonomic composition, mucosal inflammation, and intestinal barrier derangement. Intestinal hypermeability results in the translocation of viable pathogenic bacteria, Gram-negative microbial products, and pro-inflammatory luminal metabolites into the bloodstream, further corroborating the alcohol-induced liver damage. Thus, the premise of this review is to discuss the beneficial effect of gut microbiota modulation as a novel therapeutic approach in ALD management.
Assuntos
Alcoolismo/microbiologia , Microbioma Gastrointestinal/fisiologia , Hepatopatias Alcoólicas/microbiologia , Alcoolismo/genética , Alcoolismo/imunologia , Alcoolismo/fisiopatologia , Animais , Antibacterianos/efeitos adversos , Ácidos e Sais Biliares/metabolismo , Dieta , Suplementos Nutricionais/microbiologia , Disbiose/imunologia , Disbiose/metabolismo , Transplante de Microbiota Fecal , Hepatócitos/metabolismo , Humanos , Intestinos/microbiologia , Fígado/metabolismo , Fígado/fisiopatologia , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/fisiopatologiaRESUMO
This study investigated the modulatory effects of Decaisnea insignis seed oil (DISO), which was rich in palmitoleic acid (55.25%), palmitic acid (12.25%), and oleic acid (28.74%), on alcohol-induced metabolism disorder in mice. Fifty mice were orally administered with 38% alcohol (0.4 mL/day) and without or with DISO (3, 6, and 12 g/kg) for consecutive 12 weeks. DISO inhibited the alcohol-induced weight loss and liver function abnormality (p < 0.01) and shifted the profiles of cecal microbiome: elevating the abundance of Lactobacillus, Ruminoccoceae_UCG_004 (p < 0.05) and decreasing abundance of Parabacteroides (p < 0.05). This treatment also regulated metabolome response of amino acid and lipid metabolism in cecal content: upregulating 5-hydroxyindole-3-acetic acid (p < 0.05), 6-hydroxynicotinic acid, 5-methoxytryptamine, nicotinamide, and nicotinic acid (p < 0.1) and downregulating androsterone, tryptophan, and indole-3-acetamide (p < 0.05). DISO protected against alcoholic liver injury and gut microbiota dysbiosis by enriching the relative abundance of Lactobacillus, which was positively associated with the improvement of intestinal permeability and tryptophan metabolism.
Assuntos
Álcoois/efeitos adversos , Disbiose/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/prevenção & controle , Magnoliopsida/química , Óleos de Plantas/administração & dosagem , Consumo de Bebidas Alcoólicas/efeitos adversos , Aminoácidos/metabolismo , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Ceco/efeitos dos fármacos , Ceco/microbiologia , Disbiose/metabolismo , Disbiose/microbiologia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Metaboloma/efeitos dos fármacos , Camundongos , Microbiota/efeitos dos fármacos , Sementes/químicaRESUMO
Liver injury is the most common consequence of alcohol abuse, which is promoted by the inflammatory response triggered by gut-derived endotoxins produced as a consequence of intestinal microbiota dysbiosis and barrier dysfunction. The aim of this study was to investigate whether modulation of intestinal microbiota and barrier function, and liver inflammation contributes to the hepatoprotective effect of lychee pulp phenolic extract (LPPE) in alcohol-fed mice. Mice were treated with an ethanol-containing liquid diet alone or in combination with LPPE for 8 weeks. LPPE supplementation alleviated ethanol-induced liver injury and downregulated key markers of inflammation. Moreover, LPPE supplementation reversed the ethanol-induced alteration of intestinal microbiota composition and increased the expression of intestinal tight junction proteins, mucus protecting proteins, and antimicrobial proteins. Furthermore, in addition to decreasing serum endotoxin level, LPPE supplementation suppressed CD14 and toll-like receptor 4 expression, and repressed the activation of nuclear factor-κB p65 in the liver. These data suggest that intestinal microbiota dysbiosis, intestinal barrier dysfunction, and liver inflammation are improved by LPPE, and therefore, the intake of LPPE or Litchi pulp may be an effective strategy to alleviate the susceptibility to alcohol-induced hepatic diseases.
Assuntos
Disbiose/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Litchi/química , Hepatopatias Alcoólicas/tratamento farmacológico , Fígado/imunologia , Fenóis/administração & dosagem , Extratos Vegetais/administração & dosagem , Substâncias Protetoras/administração & dosagem , Animais , Disbiose/etiologia , Disbiose/imunologia , Disbiose/microbiologia , Etanol/efeitos adversos , Frutas/química , Humanos , Intestinos/imunologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Fígado/efeitos dos fármacos , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologiaRESUMO
BACKGROUND: Alcoholic liver disease (ALD) represents a chronic wide-spectrum of liver injury caused by consistently excessive alcohol intake. Few satisfactory advances have been made in management of ALD. Thus, novel and more practical treatment options are urgently needed. Flaxseed oil (FO) is rich in α-linolenic acid (ALA), a plant-derived n-3 polyunsaturated fatty acids (PUFAs). However, the impact of dietary FO on chronic alcohol consumption remains unknown. METHODS: In this study, we assessed possible effects of dietary FO on attenuation of ALD and associated mechanisms in mice. Firstly, mice were randomly allocated into four groups: pair-fed (PF) with corn oil (CO) group (PF/CO); alcohol-fed (AF) with CO group (AF/CO); PF with FO group (PF/FO); AF with FO group (AF/FO). Each group was fed modified Lieber-DeCarli liquid diets containing isocaloric maltose dextrin a control or alcohol with corn oil and flaxseed oil, respectively. After 6 weeks feeding, mice were euthanized and associated indications were investigated. RESULTS: Body weight (BW) was significantly elevated in AF/FO group compared with AF/CO group. Dietary FO reduced the abnormal elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in chronic ethanol consumption. Amelioration of these parameters as well as liver injury via HE staining in dietary FO supplementation in ALD demonstrated that dietary FO can effectively benefit for the protection against ALD. To further understand the underlying mechanisms, we investigated the inflammatory cytokine levels and gut microbiota. A series of inflammatory cytokines, including TNF-α, IL-1ß, IL-6 and IL-10, were determined. As a result, TNF-α, IL-1ß and IL-6 were decreased in AF/FO group compared with control group; IL-10 showed no significant alteration between AF/CO and AF/FO groups (p > 0.05). Sequencing and analysis of gut microbiota gene indicated that a reduction of Porphyromonadaceae and Parasutterella, as well as an increase in Firmicutes and Parabacteroides, were seen in AF group compared with PF control. Furthermore, dietary FO in ethanol consumption group induced a significant reduction in Proteobacteria and Porphyromonadaceae compared with AF/CO group. CONCLUSION: Dietary FO ameliorates alcoholic liver disease via anti-inflammation and modulating gut microbiota, thus can potentially serve as an inexpensive interventions for the prevention and treatment of ALD.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Óleo de Semente do Linho/farmacologia , Hepatopatias Alcoólicas/dietoterapia , Animais , Citocinas/sangue , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Lipopolissacarídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/patologia , Masculino , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND & AIMS: Alcoholic liver disease (ALD) is a leading cause of liver failure and mortality. In humans, severe alcoholic hepatitis is associated with key changes to intestinal microbiota (IM), which influences individual sensitivity to develop advanced ALD. We used the different susceptibility to ALD observed in two distinct animal facilities to test the efficiency of two complementary strategies (fecal microbiota transplantation and prebiotic treatment) to reverse dysbiosis and prevent ALD. METHODS: Mice were fed alcohol in two distinct animal facilities with a Lieber DeCarli diet. Fecal microbiota transplantation was performed with fresh feces from alcohol-resistant donor mice to alcohol-sensitive receiver mice three times a week. Another group of mice received pectin during the entire alcohol consumption period. RESULTS: Ethanol induced steatosis and liver inflammation, which were associated with disruption of gut homeostasis, in alcohol-sensitive, but not alcohol resistant mice. IM analysis showed that the proportion of Bacteroides was specifically lower in alcohol-sensitive mice (p<0.05). Principal coordinate analysis showed that the IM of sensitive and resistant mice clustered differently. We targeted IM using two different strategies to prevent alcohol-induced liver lesions: (1) pectin treatment which induced major modifications of the IM, (2) fecal microbiota transplantation which resulted in an IM very close to that of resistant donor mice in the sensitive recipient mice. Both methods prevented steatosis, liver inflammation, and restored gut homeostasis. CONCLUSIONS: Manipulation of IM can prevent alcohol-induced liver injury. The IM should be considered as a new therapeutic target in ALD. LAY SUMMARY: Sensitivity to alcoholic liver disease (ALD) is driven by intestinal microbiota in alcohol fed mice. Treatment of mice with alcohol-induced liver lesions by fecal transplant from alcohol fed mice resistant to ALD or with prebiotic (pectin) prevents ALD. These findings open new possibilities for treatment of human ALD through intestinal microbiota manipulation.
Assuntos
Disbiose/microbiologia , Disbiose/prevenção & controle , Microbioma Gastrointestinal/fisiologia , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/prevenção & controle , Animais , Bacteroides/genética , Bacteroides/isolamento & purificação , Bacteroides/fisiologia , Ácidos e Sais Biliares/metabolismo , Fibras na Dieta/administração & dosagem , Modelos Animais de Doenças , Suscetibilidade a Doenças/microbiologia , Transplante de Microbiota Fecal , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pectinas/administração & dosagem , Prebióticos/administração & dosagemRESUMO
OBJECTIVE: The role of lipopolysaccharide (LPS) and toll-like receptor 4 (TLR 4) in the pathogenesis of alcoholic liver disease (ALD) has been widely established. We evaluated the biological effects of probiotics (Lactobacillus rhamnosus R0011 and acidophilus R0052), KRG (Korea red ginseng), and urushiol (Rhus verniciflua Stokes) on ALD, including their effects on normal and high-fat diet in mice. METHODS: One hundred C57BL/6 mice were classified into normal (N) and high-fat diet (H) groups. Each group was divided into 5 sub-groups: control, alcohol, alcohol+probiotics, alcohol+KRG, and alcohol+urushiol. A liver function test, histology, electron-microscopy, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, and IL-10, and TLR 4 were evaluated and compared. RESULTS: In the N group, probiotics, KRG, and urushiol significantly reduced levels of TNF-α (12.3±5.1, 13.4±3.9, and 12.1±4.3 vs. 27.9±15.2 pg/mL) and IL-1ß (108.4±39.4, 75.0±51.0, and 101.1±26.8 vs. 162.4±37.5 pg/mL), which were increased by alcohol. Alcohol-induced TLR 4 expression was reduced by probiotics and urushiol (0.7±0.2, and 0.8±0.1 vs. 1.0±0.3, p<0.001). In the H group, IL-10 was significantly increased by probiotics and KRG, compared with alcohol (25.3±15.6 and 20.4±6.2 vs. 7.6±5.6 pg/mL) and TLR 4 expression was reduced by probiotics (0.8±0.2 vs. 1.0±0.3, p = 0.007). CONCLUSIONS: Alcohol-induced TLR 4 expression was down-regulated by probiotics in the normal and high-fat diet groups. Probiotics, KRG, and urushiol might be effective in the treatment of ALD by regulating the gut-liver axis.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Lacticaseibacillus rhamnosus , Lactobacillus acidophilus , Hepatopatias Alcoólicas/metabolismo , Probióticos/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Catecóis/farmacologia , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Panax/químicaRESUMO
BACKGROUND & AIMS: Alcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease. METHODS: We used the Tsukamoto-French mouse model, which involves continuous intragastric feeding of isocaloric diet or alcohol for 3 weeks. Bacterial DNA from the cecum was extracted for deep metagenomic sequencing. Targeted metabolomics assessed concentrations of saturated fatty acids in cecal contents. To maintain intestinal metabolic homeostasis, diets of ethanol-fed and control mice were supplemented with saturated long-chain fatty acids (LCFA). Bacterial genes involved in fatty acid biosynthesis, amounts of lactobacilli, and saturated LCFA were measured in fecal samples of nonalcoholic individuals and patients with active alcohol abuse. RESULTS: Analyses of intestinal contents from mice revealed alcohol-associated changes to the intestinal metagenome and metabolome, characterized by reduced synthesis of saturated LCFA. Maintaining intestinal levels of saturated fatty acids in mice resulted in eubiosis, stabilized the intestinal gut barrier, and reduced ethanol-induced liver injury. Saturated LCFA are metabolized by commensal Lactobacillus and promote their growth. Proportions of bacterial genes involved in fatty acid biosynthesis were lower in feces from patients with active alcohol abuse than controls. Total levels of LCFA correlated with those of lactobacilli in fecal samples from patients with active alcohol abuse but not in controls. CONCLUSIONS: In humans and mice, alcohol causes intestinal dysbiosis, reducing the capacity of the microbiome to synthesize saturated LCFA and the proportion of Lactobacillus species. Dietary approaches to restore levels of saturated fatty acids in the intestine might reduce ethanol-induced liver injury in patients with alcoholic liver disease.
Assuntos
Bactérias/metabolismo , Suplementos Nutricionais , Etanol , Ácidos Graxos/administração & dosagem , Intestinos/microbiologia , Hepatopatias Alcoólicas/prevenção & controle , Animais , Bactérias/classificação , Bactérias/isolamento & purificação , Translocação Bacteriana , Modelos Animais de Doenças , Disbiose , Ácidos Graxos/biossíntese , Fezes/química , Fezes/microbiologia , Interações Hospedeiro-Patógeno , Mucosa Intestinal/metabolismo , Lactobacillus/metabolismo , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Metabolômica , Metagenoma , Camundongos Endogâmicos C57BL , Permeabilidade , Fatores de TempoRESUMO
OBJECTIVE: To study the structural shifts of gut flora in rats with acute alcoholic liver injury (AALI), and the effect of jianpi huoxue decoction (JPHXD) on the gut flora. METHODS: Thirty-six Sprague-Dawley rats were randomly allocated to the control, AALI and JPHXD groups equally. The rats in the control group were given water and those in AALI and JPHXD groups were given ethanol by intragastric gavage for 5 days, while rats in the JPHXD group were administered JPHXD simultaneously. The blood and liver tissue were collected at the end of the experiment. The activities of serum alkaline aminotransferase (ALT), aspartate aminotransferase (AST), hepatic γ-glutamyltranspetidase (γ-GT) and hepatic triglyceride (TG) levels were determined. Plasma endotoxin level in the portal vein was measured. Pathological changes of liver tissues were determined by hematoxylin and eosin (HE) staining and oil red O staining. The total DNA of gut flora were extracted from fecal samples by Bead-beating method and determined by ERIC-PCR fingerprint method. The similarity cluster analysis and principal component analysis were performed to analyze the ERIC-PCR fingerprint respectively. RESULTS: In the AALI group, the ratio of liver/body weight, activities of ALT, AST and hepatic γ-GT, amount of hepatic TG were elevated significantly compared with those in the control group (all P<0.01). JPHXD decreased the ratio, activities of ALT, AST, γ-GT and TG significantly compared with those in the AALI group (P<0.05 or P<0.01). HE and oil red O staining showed that fat deposited markedly in liver tissue, while JPHXD alleviated pathological changes markedly. Plasma LPS level in rat portal vein in the AALI group increased significantly (P<0.01), but it was decreased significantly in the JPHXD group (P<0.01). The cluster analysis and principal component analysis of ERIC-PCR fingerprint showed that gut flora in the AALI group changed markedly, and JPHXD could recover gut flora to some extent. CONCLUSIONS: The structure of gut flora shifted markedly during acute alcoholic liver injury, JPHXD had prevention effect through the modification of gut flora.
Assuntos
Bactérias/genética , Impressões Digitais de DNA/métodos , Medicamentos de Ervas Chinesas/uso terapêutico , Trato Gastrointestinal/microbiologia , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/microbiologia , Reação em Cadeia da Polimerase/métodos , Animais , Compostos Azo/metabolismo , Peso Corporal , Análise por Conglomerados , Sequência Consenso/genética , DNA Intergênico/genética , Congelamento , Trato Gastrointestinal/patologia , Fígado/microbiologia , Fígado/patologia , Hepatopatias Alcoólicas/patologia , Tamanho do Órgão , Filogenia , Análise de Componente Principal , Ratos , Ratos Sprague-Dawley , Sequências Repetitivas de Ácido Nucleico/genética , Coloração e RotulagemRESUMO
The effects of chronic alcohol consumption on the bowel flora and the potential therapeutic role of probiotics in alcohol-induced liver injury have not previously been evaluated. In this study, 66 adult Russian males admitted to a psychiatric hospital with a diagnosis of alcoholic psychosis were enrolled in a prospective, randomized, clinical trial to study the effects of alcohol and probiotics on the bowel flora and alcohol-induced liver injury. Patients were randomized to receive 5 days of Bifidobacterium bifidum and Lactobacillus plantarum 8PA3 versus standard therapy alone (abstinence plus vitamins). Stool cultures and liver enzymes were performed at baseline and again after therapy. Results were compared between groups and with 24 healthy, matched controls who did not consume alcohol. Compared to healthy controls, alcoholic patients had significantly reduced numbers of bifidobacteria (6.3 vs. 7.5 log colony-forming unit [CFU]/g), lactobacilli (3.15 vs. 4.59 log CFU/g), and enterococci (4.43 vs. 5.5 log CFU/g). The mean baseline alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) activities were significantly elevated in the alcoholic group compared to the healthy control group (AST: 104.1 vs. 29.15 U/L; ALT: 50.49 vs. 22.96 U/L; GGT 161.5 vs. 51.88 U/L), indicating that these patients did have mild alcohol-induced liver injury. After 5 days of probiotic therapy, alcoholic patients had significantly increased numbers of both bifidobacteria (7.9 vs. 6.81 log CFU/g) and lactobacilli (4.2 vs. 3.2 log CFU/g) compared to the standard therapy arm. Despite similar values at study initiation, patients treated with probiotics had significantly lower AST and ALT activity at the end of treatment than those treated with standard therapy alone (AST: 54.67 vs. 76.43 U/L; ALT 36.69 vs. 51.26 U/L). In a subgroup of 26 subjects with well-characterized mild alcoholic hepatitis (defined as AST and ALT greater than 30 U/L with AST-to-ALT ratio greater than one), probiotic therapy was associated with a significant end of treatment reduction in ALT, AST, GGT, lactate dehydrogenase, and total bilirubin. In this subgroup, there was a significant end of treatment mean ALT reduction in the probiotic arm versus the standard therapy arm. In conclusion, patients with alcohol-induced liver injury have altered bowel flora compared to healthy controls. Short-term oral supplementation with B. bifidum and L. plantarum 8PA3 was associated with restoration of the bowel flora and greater improvement in alcohol-induced liver injury than standard therapy alone.
Assuntos
Intestinos/microbiologia , Hepatopatias Alcoólicas/tratamento farmacológico , Fígado/enzimologia , Probióticos/uso terapêutico , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Humanos , L-Lactato Desidrogenase/sangue , Hepatopatias Alcoólicas/enzimologia , Hepatopatias Alcoólicas/microbiologia , Masculino , Projetos Piloto , Estudos ProspectivosRESUMO
OBJECTIVE: To study the effects and mechanisms of Jianpi Liqi Huoxue Decoction (JLHD) in anti-alcoholic liver injury (ALI) through the pathological relation of ALI with changes of intestinal permeability and endotoxin leakage. METHODS: The liver injury model induced by Lieber-DeCarli alcoholic forage was established. Altogether 42 male SD rats were randomly divided into 4 groups, the normal group (n=6), the control group fed with non-alcohol diet (n=12), the model group fed with alcoholic diet (n=12) and the treated group fed with alcoholic diet and treated with JLHD (n=12). The medicine or distilled water was administered by gavage from the 3rd week to the end of the 6th week. Then after fasting for 5 h all the rats except those in the normal group were given lipopolysaccharide (LPS) 10 mg/kg by gavage, and the blood plasma from portal vein, serum from inferior cava vein as well as tissues of liver and intestine were prepared for detection of plasma LPS level in the portal vein to observe the change of intestinal permeability through LPS content in portal vein blood plasma, the pathological and ultrastructural changes of the small intestine by HE staining, the pathological change of liver and triglyceride (TG) content and gamma glutamyl transpeptidase (GGT) activity in liver, the changes of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, and plasma tumor necrosis factor-alpha (TNF-alpha) level. RESULTS: In rats after modeling, there were obvious fatty degeneration, significant increase of hepatic TG content and GGT activity, serum ALT and AST activity, as well as plasma TNF-alpha level, with high plasma LPS level indicating increased intestinal permeability, and seriously injured mucosa microvilla of small intestine. However, all the above abnormal changes were milder in the treated group than those in the model group. Meanwhile, the TNF-alpha content, endotoxin level and ALT activity were found to be positively correlated. CONCLUSION: JLHD could alleviate liver injury through inhibiting the alcohol induced increased intestinal permeability and lessening endotoxin leakage.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Endotoxinas/metabolismo , Intestino Delgado/microbiologia , Hepatopatias Alcoólicas/tratamento farmacológico , Animais , Mucosa Intestinal/metabolismo , Intestino Delgado/patologia , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/patologia , Masculino , Permeabilidade , Fitoterapia , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
The association of Streptococcus bovis bacteremia and endocarditis with colonic pathology, mainly neoplastic, is well known. Its relationship with liver disease without evidence of gastrointestinal disease has been rarely described. To analyze the association between S. bovis infection and liver disease, positive blood cultures for this microorganism in hospitalized patients in the Internal Medicine and Gastroenterology Departments from December 1993 until October 1995, have been reviewed. Three cases of S. bovis infection (one bacteremia, two endocarditis) were found. Alcoholic liver disease was diagnosed in all three patients, with associated hepatitis C virus in one of them. Colonic pathology was excluded by colonoscopy and/or barium enema. Other gastrointestinal disorders were excluded by means of gastroscopy, barium gastrointestinal study and abdominal ultrasonography. Antibiotic therapy was based in betalactamics, with associated aminoglycoside in two cases. One patient needed aortic and mitral valve replacement and another one needed orthotopic liver transplantation. No new gastrointestinal pathology emerged in the follow-up (5-23 months). Cases of S. bovis bacteremia and endocarditis should be screened not also for colonic pathology, but also for liver disease, particularly in alcoholics.