Dataset Information

Altered Microbiota Diversity and Bile Acid Signaling in Cirrhotic and Noncirrhotic NASH-HCC.

ABSTRACT: OBJECTIVES:The precipitous increase in nonalcoholic steatohepatitis (NASH) is accompanied by a dramatic increase in the incidence of NASH-related hepatocellular carcinoma (HCC). HCC in NASH has a higher propensity to arise without pre-existing cirrhosis compared with other chronic liver diseases. METHODS:To identify the potential links between liver and gut in NASH-related hepatocarcinogenesis, we compared the gut microbiota and mediators of bile acid (BA) signaling in the absence or presence of cirrhosis through the analysis of stool and serum samples from patients with NASH non-HCC and NASH-HCC and healthy volunteers. RESULTS:Serum levels of total and individual BA were higher in NASH compared with healthy controls. Furthermore, serum levels of the primary conjugated BAs glycine-conjugated cholic acid, taurine-conjugated cholic acid, glycine-conjugated chenodeoxycholic acid, and taurine-conjugated chenodeoxycholic acid were significantly increased in cirrhotic vs noncirrhotic patients, independent of the occurrence of HCC. By contrast, serum FGF19 levels were higher in patients with NASH-HCC and associated with tumor markers as well as an attenuation of BA synthesis. Specific alterations in the gut microbiome were found for several bacteria involved in the BA metabolism including Bacteroides and Lactobacilli. Specifically, the abundance of Lactobacilli was associated with progressive disease, serum BA levels, and liver injury in NASH and NASH-HCC. DISCUSSION:Here, we demonstrate a clear association of the altered gut microbiota and primary conjugated BA composition in cirrhotic and noncirrhotic patients with NASH-HCC. Microbiota-associated alterations in BA homeostasis and farnesoid X receptor signaling, via FGF19, might thus contribute to fibrogenesis, liver injury, and tumorigenesis in NASH-HCC.

SUBMITTER: Sydor S

PROVIDER: S-EPMC7145043 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Altered Microbiota Diversity and Bile Acid Signaling in Cirrhotic and Noncirrhotic NASH-HCC.

Sydor Svenja S Best Jan J Messerschmidt Insa I Manka Paul P Vilchez-Vargas Ramiro R Brodesser Susanne S Lucas Christina C Wegehaupt Annemarie A Wenning Chiara C Aßmuth Sophia S Hohenester Simon S Link Alexander A Faber Klaas Nico KN Moshage Han H Cubero Francisco Javier FJ Friedman Scott L SL Gerken Guido G Trauner Michael M Canbay Ali A Bechmann Lars P LP

Clinical and translational gastroenterology 20200301 3

<h4>Objectives</h4>The precipitous increase in nonalcoholic steatohepatitis (NASH) is accompanied by a dramatic increase in the incidence of NASH-related hepatocellular carcinoma (HCC). HCC in NASH has a higher propensity to arise without pre-existing cirrhosis compared with other chronic liver diseases.<h4>Methods</h4>To identify the potential links between liver and gut in NASH-related hepatocarcinogenesis, we compared the gut microbiota and mediators of bile acid (BA) signaling in the absence ...[more]

PMID: 32352707

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Project description:The co-occurrence of gut microbiota dysbiosis and bile acid (BA) metabolism alteration has been reported in several human liver diseases. However, the gut microbiota dysbiosis in infantile cholestatic jaundice (CJ) and the linkage between gut bacterial changes and alterations of BA metabolism have not been determined. To address this question, we performed 16S rRNA gene sequencing to determine the alterations in the gut microbiota of infants with CJ, and assessed their association with the fecal levels of primary and secondary BAs. Our data reveal that CJ infants show marked declines in the fecal levels of primary BAs and most secondary BAs. A decreased ratio of cholic acid (CA)/chenodeoxycholic acid (CDCA) in infants with CJ indicated a shift in BA synthesis from the primary pathway to the alternative BA synthesis pathway. The bacterial taxa enriched in infants with CJ corresponded to the genera Clostridium, Gemella, Streptococcus, and Veillonella and the family Enterobacteriaceae and were negatively correlated with the fecal BA level and the CDCA/CA ratio but positively correlated with the serological indexes of impaired liver function. An increased ratio of deoxycholic acid (DCA)/CA was observed in a proportion of infants with CJ. The bacteria depleted in infants with CJ, including Bifidobacterium and Faecalibacterium prausnitzii, were positively and negatively correlated with the fecal levels of BAs and the serological markers of impaired liver function, respectively. In conclusion, the reduced concentration of BAs in the gut of infants with CJ is correlated with gut microbiota dysbiosis. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs.IMPORTANCE Liver health, fecal bile acid (BA) concentrations, and gut microbiota composition are closely connected. BAs and the microbiome influence each other in the gut, where bacteria modify the BA profile, while intestinal BAs regulate the growth of commensal bacteria, maintain the barrier integrity, and modulate the immune system. Previous studies have found that the co-occurrence of gut microbiota dysbiosis and BA metabolism alteration is present in many human liver diseases. Our study is the first to assess the gut microbiota composition in infantile cholestatic jaundice (CJ) and elucidate the linkage between gut bacterial changes and alterations of BA metabolism. We observed reduced levels of primary BAs and most secondary BAs in infants with CJ. The reduced concentration of fecal BAs in infantile CJ was associated with the overgrowth of gut bacteria with a pathogenic potential and the depletion of those with a potential benefit. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs. Our study provides a new perspective on potential targets for gut microbiota intervention directed at the management of infantile CJ.

Project description:Background & aimsBesides their physiological role in bile formation and fat digestion, bile acids (BAs) synthesised from cholesterol in hepatocytes act as signalling molecules that modulate hepatocellular carcinoma (HCC). Trafficking of cholesterol to mitochondria through steroidogenic acute regulatory protein 1 (STARD1) is the rate-limiting step in the alternative pathway of BA generation, the physiological relevance of which is not well understood. Moreover, the specific contribution of the STARD1-dependent BA synthesis pathway to HCC has not been previously explored.MethodsSTARD1 expression was analyzed in a cohort of human non-alcoholic steatohepatitis (NASH)-derived HCC specimens. Experimental NASH-driven HCC models included MUP-uPA mice fed a high-fat high-cholesterol (HFHC) diet and diethylnitrosamine (DEN) treatment in wild-type (WT) mice fed a HFHC diet. Molecular species of BAs and oxysterols were analyzed by mass spectrometry. Effects of NASH-derived BA profiles were investigated in tumour-initiated stem-like cells (TICs) and primary mouse hepatocytes (PMHs).ResultsPatients with NASH-associated HCC exhibited increased hepatic expression of STARD1 and an enhanced BA pool. Using NASH-driven HCC models, STARD1 overexpression in WT mice increased liver tumour multiplicity, whereas hepatocyte-specific STARD1 deletion (Stard1ΔHep) in WT or MUP-uPA mice reduced tumour burden. These findings mirrored the levels of unconjugated primary BAs, β-muricholic acid and cholic acid, and their tauroconjugates in STARD1-overexpressing and Stard1ΔHep mice. Incubation of TICs or PMHs with a mix of BAs mimicking this profile stimulated expression of genes involved in pluripotency, stemness and inflammation.ConclusionsThe study reveals a previously unrecognised role of STARD1 in HCC pathogenesis, wherein it promotes the synthesis of primary BAs through the mitochondrial pathway, the products of which act in TICs to stimulate self-renewal, stemness and inflammation.Lay summaryEffective therapy for hepatocellular carcinoma (HCC) is limited because of our incomplete understanding of its pathogenesis. The contribution of the alternative pathway of bile acid (BA) synthesis to HCC development is unknown. We uncover a key role for steroidogenic acute regulatory protein 1 (STARD1) in non-alcoholic steatohepatitis-driven HCC, wherein it stimulates the generation of BAs in the mitochondrial acidic pathway, the products of which stimulate hepatocyte pluripotency and self-renewal, as well as inflammation.

Project description:BackgroundMounting evidences have demonstrated that HCC patients with or without cirrhosis possess different clinical characteristics, tumor development and prognosis. However, few studies directly investigated the underlying molecular mechanisms between non-cirrhotic HCC and cirrhotic HCC.MethodsThe clinical information and RNA-seq data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) of HCC with or without cirrhosis were obtained by R software. Functional annotation and pathway enrichment analysis were performed by Enrichr. Protein-protein interaction (PPI) network was established through STRING and mapped to Cytoscape to identify hub genes. MicroRNAs were predicted through miRDB database. Furthermore, correlation analysis between selected genes and miRNAs were conducted via starBase database. MiRNAs expression levels between HCC with or without cirrhosis and corresponding normal liver tissues were further validated through GEO datasets. Finally, expression levels of key miRNAs and target genes were validated through qRT-PCR.ResultsBetween 132 non-cirrhotic HCC and 79 cirrhotic HCC in TCGA, 768 DEGs were acquired, mainly involved in neuroactive ligand-receptor interaction pathway. According to the result from gene expression analysis in TCGA, CCL19, CCL25, CNR1, PF4 and PPBP were renamed as key genes and selected for further investigation. Survival analysis indicated that upregulated CNR1 correlated with worse OS in cirrhotic HCC. Furthermore, ROC analysis revealed the significant diagnostic values of PF4 and PPBP in cirrhotic HCC, and CCL19, CCL25 in non-cirrhotic HCC. Next, 517 miRNAs were predicted to target the 5 key genes. Correlation analysis confirmed that 16 of 517 miRNAs were negatively regulated the key genes. By detecting the expression levels of these key miRNAs from GEO database, we found 4 miRNAs have high research values. Finally, potential miRNA-mRNA networks were constructed based on the results of qRT-PCR.ConclusionIn silico analysis, we first constructed the miRNA-mRNA regulatory networks in non-cirrhotic HCC and cirrhotic HCC.

Project description:Bacterial infections are among the major factors that cause stress and intestinal diseases in piglets. Lipopolysaccharide (LPS), a major component of the Gram-negative bacteria outer membrane, is commonly employed for inducing an immune response in normal organisms for convenience. The association between LPS stimulation and gut immunity has been reported. However, the effects of gut immunity on microbial homeostasis and metabolism of host, especially bile acid and lipid metabolism in piglets, remain unclear. Hence, in the current study, we elucidated the effect of gut immunity on microbial balance and host metabolism. Twenty-one-day-old healthy piglets (male) were randomly assigned into the CON and LPS groups. After 4 hours of treatment, related tissues and cecal contents were obtained for further analysis. The obtained results showed that stimulated LPS considerably damaged the morphology of intestinal villi and enhanced the relative expression of proinflammatory cytokines. Besides, LPS partially changed the microbial structure as indicated by β-diversity and increased operational taxonomic units (OTUs) related to Oxalobacter and Ileibacterium. Furthermore, bile acid, a large class of gut microbiota metabolites, was also assessed by many proteins related to the enterohepatic circulation of bile acids. It was also revealed that LPS markedly inhibited the mRNA and protein expression of TGR5 and FXR (bile acid receptors) in the ileum, which expressed negative feedback on bile acid de novo synthesis. Additionally, results indicated upregulated mRNA of genes associated with the production of bile acid in the liver tissues. Moreover, LPS reduced the expression of bile acid transporters in the ileum and liver tissues and further disturbed the normal enterohepatic circulation. Taken together, gut immunity and microbial dysbiosis are associated with altered bile acid metabolism in LPS-challenged piglets, which provided theoretical basis for revealing the potential mechanism of intestinal inflammation in swine and seeking nutrients to resist intestinal damage.

Project description:Background & aimsPlasma bile acids (BAs) have been extensively studied as pathophysiological actors in non-alcoholic steatohepatitis (NASH). However, results from clinical studies are often complicated by the association of NASH with type 2 diabetes (T2D), obesity, and insulin resistance (IR). Here, we sought to dissect the relationship between NASH, T2D, and plasma BA levels in a large patient cohort.MethodsFour groups of patients from the Biological Atlas of Severe Obesity (ABOS) cohort (Clinical Trials number NCT01129297) were included based on the presence or absence of histologically evaluated NASH with or without coincident T2D. Patients were matched for BMI, homeostatic model assessment 2 (HOMA2)-assessed IR, glycated haemoglobin, age, and gender. To study the effect of IR and BMI on the association of plasma BA and NASH, patients from the HEPADIP study were included. In both cohorts, fasting plasma BA concentrations were measured.ResultsPlasma BA concentrations were higher in NASH compared with No-NASH patients both in T2D and NoT2D patients from the ABOS cohort. As we previously reported that plasma BA levels were unaltered in NASH patients of the HEPADIP cohort, we assessed the impact of BMI and IR on the association of NASH and BA on the combined BA datasets. Our results revealed that NASH-associated increases in plasma total cholic acid (CA) concentrations depend on the degree of HOMA2-assessed systemic IR, but not on β-cell function nor on BMI.ConclusionsPlasma BA concentrations are elevated only in those NASH patients exhibiting pronounced IR.Lay summaryNon-alcoholic steatohepatitis (NASH) is a progressive liver disease that frequently occurs in patients with obesity and type 2 diabetes. Reliable markers for the diagnosis of NASH are needed. Plasma bile acids have been proposed as NASH biomarkers. Herein, we found that plasma bile acids are only elevated in patients with NASH when significant insulin resistance is present, limiting their utility as NASH markers.

Dataset Information

Altered Microbiota Diversity and Bile Acid Signaling in Cirrhotic and Noncirrhotic NASH-HCC.

Publications

Altered Microbiota Diversity and Bile Acid Signaling in Cirrhotic and Noncirrhotic NASH-HCC.

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