Ursolic Acid Improves Intestinal Damage and Bacterial Dysbiosis in Liver Fibrosis Mice.
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ABSTRACT:
SUBMITTER: Wan SZ
PROVIDER: S-EPMC6838135 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Project description:Liver fibrosis often appears in chronic liver disease, with extracellular matrix (ECM) deposition as the main feature. Due to the presence of the liver-gut axis, the destruction of intestinal homeostasis is often accompanied by the development of liver fibrosis. The inconsistent ecological environment of different intestinal sites may lead to differences in the microbiota. The traditional Chinese medicine ursolic acid (UA) has been proven to protect the liver from fibrosis. We investigated the changes in the microbiota of different parts of the intestine during liver fibrosis and the effect of UA on these changes based on high-throughput sequencing technology. Sequencing results suggest that the diversity and abundance of intestinal microbiota decline and the composition of the microbiota is disordered, the potentially beneficial Firmicutes bacteria are reduced, and the pathways for functional prediction are changed in the ilea and anal faeces of liver fibrosis mice compared with normal mice. However, in UA-treated liver fibrosis mice, these disorders improved. It is worth noting that the bacterial changes in the ilea and anal faeces are not consistent. In conclusion, in liver fibrosis, the microbiota of different parts of the intestines have different degrees of disorder, and UA can improve this disorder. This may be a potential mechanism for UA to achieve anti-fibrosis. This study provides theoretical guidance for the UA targeting of intestinal microbiota for the treatment of liver fibrosis.
| S-EPMC7185030 | biostudies-literature
Project description:Activation of the NOX4/NLRP3 inflammasome pathway has been associated with fibrosis in other organs. An imbalance in intestinal bacteria is an important driving factor of liver fibrosis through the liver-gut axis. This study aimed to explore whether the effect of ursolic acid (UA) on liver fibrosis was associated with the NOX4/NLRP3 inflammasome pathways and intestinal bacteria. Wild-type (WT), NLRP3-/-, and NOX4-/- mice and AP-treated mice were injected with CCI4 and treated with or without UA. The intestinal contents of the mice were collected and analyzed by 16S rRNA sequencing. UA alleviated liver fibrosis, which manifested as decreases in collagen deposition, liver injury, and the expression of fibrosis-related factors, and the expression of NOX4 and NLRP3 was significantly inhibited by UA treatment. Even after CCI4 injection, liver damage and fibrosis-related factors were significantly decreased in NLRP3-/-, NOX4-/-, and AP-treated mice. Importantly, the expression of NLRP3 was obviously inhibited in NOX4-/- and AP-treated mice. In addition, the diversity of intestinal bacteria and the abundance of probiotics in NLRP3-/- and NOX4-/- mice was significantly higher than those in WT mice, while the abundance of harmful bacteria in NLRP3-/- and NOX4-/- mice was significantly lower than that in WT mice. The NOX4/NLRP3 inflammasome pathway plays a crucial role in liver fibrosis and is closely associated with the beneficial effect of UA. The mechanism by which the NOX4/NLRP3 inflammasome pathway is involved in liver fibrosis may be associated with disordered intestinal bacteria.
| S-EPMC8451456 | biostudies-literature
Project description:Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Despite several studies on SSc treatments, effective treatments for SSc are still lacking. Since evidence suggests an association between intestinal microbiota and SSc, we focused on butyrate, which has beneficial effects in autoimmune diseases as a bacterial metabolite. Here, we investigated the therapeutic potential of sodium butyrate (SB) using a bleomycin-induced fibrosis mouse model of SSc and human dermal fibroblasts (HDFs). SB attenuated bleomycin-induced dermal and lung fibrosis in mice. SB influenced fecal microbiota composition (phyla Actinobacteria and Bacteroidetes, genera Bifidobacterium and Ruminococcus_g2). SB controlled macrophage differentiation in mesenteric lymph nodes, spleen, and bronchoalveolar lavage cells of mice with bleomycin-induced skin fibrosis. Profibrotic and proinflammatory gene expression was suppressed by SB administration in skin. Furthermore, SB inhibited transforming growth factor β1-responsive proinflammatory expression with increased acetylation of histone 3 in HDFs. Subcutaneous SB application had antifibrogenic effects on the skin. Butyrate ameliorated skin and lung fibrosis by improving anti-inflammatory activity in a mouse model of SSc. Butyrate may exhibit indirect and direct anti-fibrogenic action on fibroblasts by regulating macrophage differentiation and inhibition of histone deacetylase 3. These findings suggest butyrate as an SSc treatment.
| S-EPMC7967124 | biostudies-literature
Project description:Background & aimsBile-acid metabolism and the intestinal microbiota are impaired in alcohol-related liver disease. Activation of the bile-acid receptor TGR5 (or GPBAR1) controls both biliary homeostasis and inflammatory processes. We examined the role of TGR5 in alcohol-induced liver injury in mice.MethodsWe used TGR5-deficient (TGR5-KO) and wild-type (WT) female mice, fed alcohol or not, to study the involvement of liver macrophages, the intestinal microbiota (16S sequencing), and bile-acid profiles (high-performance liquid chromatography coupled to tandem mass spectrometry). Hepatic triglyceride accumulation and inflammatory processes were assessed in parallel.ResultsTGR5 deficiency worsened liver injury, as shown by greater steatosis and inflammation than in WT mice. Isolation of liver macrophages from WT and TGR5-KO alcohol-fed mice showed that TGR5 deficiency did not increase the pro-inflammatory phenotype of liver macrophages but increased their recruitment to the liver. TGR5 deficiency induced dysbiosis, independently of alcohol intake, and transplantation of the TGR5-KO intestinal microbiota to WT mice was sufficient to worsen alcohol-induced liver inflammation. Secondary bile-acid levels were markedly lower in alcohol-fed TGR5-KO than normally fed WT and TGR5-KO mice. Consistent with these results, predictive analysis showed the abundance of bacterial genes involved in bile-acid transformation to be lower in alcohol-fed TGR5-KO than WT mice. This altered bile-acid profile may explain, in particular, why bile-acid synthesis was not repressed and inflammatory processes were exacerbated.ConclusionsA lack of TGR5 was associated with worsening of alcohol-induced liver injury, a phenotype mainly related to intestinal microbiota dysbiosis and an altered bile-acid profile, following the consumption of alcohol.Lay summaryExcessive chronic alcohol intake can induce liver disease. Bile acids are molecules produced by the liver and can modulate disease severity. We addressed the specific role of TGR5, a bile-acid receptor. We found that TGR5 deficiency worsened alcohol-induced liver injury and induced both intestinal microbiota dysbiosis and bile-acid pool remodelling. Our data suggest that both the intestinal microbiota and TGR5 may be targeted in the context of human alcohol-induced liver injury.
| S-EPMC7903352 | biostudies-literature
Project description:Ursolic acid (UA), a natural pentacyclic triterpenoid, has been widely reported to exert anti-oxidant and anti-inflammatory properties. However, the effects of UA on the intestinal homeostasis and gut microbiota were rarely explored. The aim of the present study was to investigate the effects of UA on intestinal health and gut microflora antibiotic-resistance in antibiotic-exposed mice. Kunming mice (n = 80) were randomly allocated into three groups and fed with one of the following diets, respectively: Cont group (n = 20), the basal diet; UA group (n = 20), the basal diet supplemented with 150 mg/kg UA; Tet group (n = 40), the basal diet supplemented with 659 mg/kg chlortetracycline. After 14 days, 10 mice in each group were euthanatized and the remaining 30 mice in the Tet group were randomly allocated into three sub-groups (n = 10 per group) as follows: the Tet group which were kept feeding a Tet diet for 14 days; the Natural Restoration (NatR) group which received a basal diet for 14 days; and the UA therapy (UaT) group which fed a basal diet supplemented with 150 mg/kg UA for 14 days. Throughout the experiment, the weight and the food intake of each mouse were recorded once weekly. Serum LPS and diamine oxidase (DAO), jejunal morphology, jejunal tight junction proteins and nutrient transporters, colonic inflammatory cytokines, gut microbiota and its antibiotic resistance gene (ARG) were examined at euthanasia. The results showed that UA treatment significantly increased average daily food intake (ADFI) of mice. Notably, UA increased the jejunal villi height, decreased the jejunal crypt depth and promoted the expression of jejunum nutrient transporters. UaT group had higher villi height, lower crypt depth and higher nutrient transporter mRNA expression in jejunum than NatR group. Besides, UA decreased serum DAO content, upregulated mRNA expression of ZO-1, claudin-1 and occludin and downregulated TNF-α and IL-6. The mRNA abundances of ZO-1, claudin-1 and occludin and TNF-α and IL-6 in UaT group were, respectively upregulated and downregulated than NatR group. Furthermore, an analysis of 16S rDNA sequences demonstrated that UA increased the abundance of beneficial bacteria in the gut. And the results of ARG test showed that UA downregulated the expression of antibiotic-induced resistance genes. The UaT group inhibited the increase of harmful bacteria abundance and suppressed the mRNA abundances of ARG compared to the NatR group. In conclusion, considering the positive effects of UA on the growth performance and intestinal mucosal barrier, we anticipate that these findings could be a stepping stone for developing UA as a novel substitute of antibiotics.
| S-EPMC8195277 | biostudies-literature
Project description:Rapid shifts in microbial composition frequently occur during intestinal inflammation, but the mechanisms underlying such changes remain elusive. Here we demonstrate that an increased caecal sialidase activity is critical in conferring a growth advantage for some bacteria including Escherichia coli (E. coli) during intestinal inflammation in mice. This sialidase activity originates among others from Bacteroides vulgatus, whose intestinal levels expand after dextran sulphate sodium administration. Increased sialidase activity mediates the release of sialic acid from intestinal tissue, which promotes the outgrowth of E. coli during inflammation. The outburst of E. coli likely exacerbates the inflammatory response by stimulating the production of pro-inflammatory cytokines by intestinal dendritic cells. Oral administration of a sialidase inhibitor and low levels of intestinal α2,3-linked sialic acid decrease E. coli outgrowth and the severity of colitis in mice. Regulation of sialic acid catabolism opens new perspectives for the treatment of intestinal inflammation as manifested by E. coli dysbiosis.
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Project description:Background and Aims: Continuous development will evolve into end-stage liver disease. Profibrotic factors NOX4 and RhoA participate in the activation of HSC and accelerate the development of liver fibrosis. Abnormal intrahepatic metabolism during liver fibrosis interferes with intestinal homeostasis through the liver-gut axis. Methods: Wild-type (WT), NOX4 knockout, RhoA expression inhibition C57BL/6 mice were randomly divided into 6 groups as follows: control group, CCl4 group, NOX4-/- group, AP group, RhoAi group, and FA group. Results: The results of alpha-diversity suggest that the diversity and abundance of intestinal flora in liver fibrosis mice is lower than that in normal mice, but there is some recovery in liver fibrosis mice with NOX4 or RhoA intervention. The flora structure showed that the intestinal flora of the control group, NOX4-/- group, AP group, RhoAi group, and FA group belonged to one type, while the intestinal flora of the CCl4 group belonged to another type. In addition, analysis of the composition of the flora at the level of the phylum and genus also suggested the decline in Firmicutes and Lactobacillus caused by liver fibrosis has partially restore in the liver fibrosis mice with NOX4 or RhoA intervention. In terms of functional prediction, the "Secondary metabolites biosynthesis, transport and catabolism," "Infectious diseases," and "Xenobiotics biodegradation and metabolism" signaling pathways are mainly enriched in liver fibrosis mice, and the "Energy production and conversion," "Defense mechanisms," and "Carbohydrate metabolism" signaling pathways are mainly enriched in the NOX4 and RhoA intervention groups. Conclusion: In the case of liver fibrosis, the intestinal flora is disordered, and the disorder is related to NOX4 and RhoA. This study provides theoretical support for a better understanding of the underlying mechanisms of liver fibrosis development.
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Project description:Individuals with cystic fibrosis (CF) often experience gastrointestinal (GI) abnormalities. In recent years, the intestinal microbiome has been postulated as a contributor to the development of CF-associated GI complications, hence representing a potential therapeutic target for treatment. We recently developed a rabbit model of CF, which is shown to manifest many human patient-like pathological changes, including intestinal obstruction. Here, we investigated the feces microbiome in young CF rabbits in the absence of antibiotics treatment. Stool samples were collected from seven- to nine-week-old CF rabbits (n = 7) and age-matched wild-type (WT) rabbits (n = 6). Microbiomes were investigated by iTag sequencing of 16S rRNA genes, and functional profiles were predicted using PICRUSt. Consistent with reports of those in pediatric CF patients, the fecal microbiomes of CF rabbits are of lower richness and diversity than that of WT rabbits, with a marked taxonomic and inferred functional dysbiosis. Our work identified a new CF animal model with the manifestation of intestinal dysbiosis phenotype. This model system may facilitate the research and development of novel treatments for CF-associated gastrointestinal diseases.
| S-EPMC7920415 | biostudies-literature
Project description:Intestinal ischaemia/reperfusion (I/R) severely disrupts gut barriers and leads to high mortality in the critical care setting. Transforming growth factor (TGF)-β1 plays a pivotal role in intestinal cellular and immune regulation. However, the effects of TGF-β1 on intestinal I/R injury remain unclear. Thus, we aimed to investigate the effects of TGF-β1 on gut barriers after intestinal I/R and the molecular mechanisms. Intestinal I/R model was produced in mice by clamping the superior mesenteric artery for 1 hr followed by reperfusion. Recombinant TGF-β1 was intravenously infused at 15 min. before ischaemia. The results showed that within 2 hrs after reperfusion, intestinal I/R disturbed intestinal immunoglobulin A class switch recombination (IgA CSR), the key process of mucosal IgA synthesis, and resulted in IgA dysfunction, as evidenced by decreased production and bacteria-binding capacity of IgA. Meanwhile, the disruptions of intestinal microflora and mucosal structure were exhibited. Transforming growth factor-β1 activated IgA CSR as evidenced by the increased activation molecules and IgA precursors. Strikingly, TGF-β1 improved intestinal mucosal IgA dysfunction, dysbiosis and epithelial damage at the early stage after reperfusion. In addition, SB-431542, a specific inhibitor of activating mothers against decapentaplegic homologue (SMAD) 2/3, totally blocked the inductive effect of TGF-β1 on IgA CSR and almost abrogated the above protective effects on intestinal barriers. Taken together, our study demonstrates that TGF-β1 protects intestinal mucosal IgA immunity, microbiota and epithelial integrity against I/R injury mainly through TGF-β receptor 1/SMAD 2/3 pathway. Induction of IgA CSR may be involved in the protection conferred by TGF-β1.
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