Dataset Information

Distinctly altered gut microbiota in the progression of liver disease.

ABSTRACT: Recent studies underscore important roles of intestinal microbiota and the bacterial lipopolysaccharides (LPS) production in the pathogenesis of liver disease. However, how gut microbiota alters in response to the development of steatosis and subsequent progression to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remains unclear. We aimed to study the gut microbial changes over liver disease progression using a streptozotocin-high fat diet (STZ-HFD) induced NASH-HCC C57BL/6J mouse model that is highly relevant to human liver disease. The fecal microbiota at various liver pathological stages was analyzed by 16S rDNA gene pyrosequencing. Both UniFrac analysis and partial least squares-discriminant analysis showed significant structural alterations in gut microbiota during the development of liver disease. Co-abundance network analysis highlighted relationships between genera. Spearman correlation analysis revealed that the bacterial species, Atopobium spp., Bacteroides spp., Bacteroides vulgatus, Bacteroides acidifaciens, Bacteroides uniformis, Clostridium cocleatum, Clostridium xylanolyticum and Desulfovibrio spp., markedly increased in model mice, were positively correlated with LPS levels and pathophysiological features. Taken together, the results showed that the gut microbiota was altered significantly in the progression of liver disease. The connection between the gut microbial ecology and the liver pathology may represent potential targets for the prevention and treatment of chronic liver disease and HCC.

SUBMITTER: Xie G

PROVIDER: S-EPMC4991388 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Distinctly altered gut microbiota in the progression of liver disease.

Xie Guoxiang G Wang Xiaoning X Liu Ping P Wei Runmin R Chen Wenlian W Rajani Cynthia C Hernandez Brenda Y BY Alegado Rosanna R Dong Bing B Li Defa D Jia Wei W

Oncotarget 20160401 15

Recent studies underscore important roles of intestinal microbiota and the bacterial lipopolysaccharides (LPS) production in the pathogenesis of liver disease. However, how gut microbiota alters in response to the development of steatosis and subsequent progression to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remains unclear. We aimed to study the gut microbial changes over liver disease progression using a streptozotocin-high fat diet (STZ-HFD) induced NASH-HCC C57B ...[more]

PMID: 27036035

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Project description:Disturbance of the gut microbiota is common in liver cirrhosis (LC) patients, the underlying mechanisms of which are yet to be unfolded. This study aims to explore the relationship between small bowel transit (SBT) and gut microbiota in LC patients. Cross-sectional design was applied with 36 LC patients and 20 healthy controls (HCs). The gut microbiota was characterized by 16S rRNA gene sequencing. The Firmicutes/Bacteroidetes (F/B) ratio and the Microbial Dysbiosis index (MDI) were used to evaluate the severity of microbiota dysbiosis. The scintigraphy method was performed in patients to describe the objective values of SBT. Patients were then subdivided according to the Child-Pugh score (threshold = 5) or SBT value (threshold = 0.6) for microbiota analysis. LC patients were characterized by an altered gut microbiota; F/B ratios and MDI were higher than HC in both Child_5 (14.00 ± 14.69 vs. 2.86 ± 0.99, p < 0.01; 0.49 ± 0.80 vs. -0.47 ± 0.69, p < 0.01) and Child_5+ (15.81 ± 15.11 vs. 2.86±0.99, p < 0.01; 1.11 ± 1.05 vs. -0.47 ± 0.69, p < 0.01) sub-groups in patients. Difference in the gut microbiota between Child_ 5 and Child_5+ patients was inappreciable, but the SBT was relatively slower in Child_5+ patients (43 ± 26% vs. 80 ± 15%, p < 0.05). Compared with the Child-Pugh score indicators, SBT showed stronger associations with bacterial genera. A clear difference in the gut microbiota was observed between SBT_0.6- and SBT_0.6+ patients [Pr(>F) = 0.0068, pMANOVA], with higher F/B ratios and MDI in SBT_0.6- patients (19.71 ± 16.62 vs. 7.33 ± 6.65, p < 0.01; 1.02 ± 0.97 vs. 0.20 ± 0.58, p < 0.01). Similar results were observed between the SBT_0.6- and SBT_0.6+ sub-groups of patients with normal liver function and a Child-Pugh score of 5. SBT was negatively correlated with both the F/B ratio and MDI (r = -0.34, p < 0.05; r = -0.38, p < 0.05). Interestingly, an increased capacity for the inferred pathway "bacterial invasion of epithelial cells" in patients, was highly negatively correlated with SBT (r = -0.57, p < 0.01). The severity of microbiota dysbiosis in LC patients depends on SBT rather than Child-Pugh score. SBT per se might be significantly related to the gut microbiota abnormalities observed in patients with LC.

Project description:Nonalcoholic fatty liver disease (NAFLD), largely studied as a condition of overnutrition, also presents in undernourished populations. Like NAFLD, undernutrition disrupts systemic metabolism and has been linked to gut microbiota dysbiosis. Indeed, chronic exposures to fecal microbes contribute to undernutrition pathology in regions with poor sanitation. Despite a growing prevalence of fatty liver disease, the influence of undernutrition and the gut microbiota remain largely unexplored. Here, we utilize an established murine model (C57BL/6J mice placed on a malnourished diet that received iterative Escherichia coli/Bacteroidales gavage [MBG mice]) that combines a protein/fat-deficient diet and iterative exposure to specific, fecal microbes. Fecal-oral contamination exacerbates triglyceride accumulation in undernourished mice. MBG livers exhibit diffuse lipidosis accompanied by striking shifts in fatty acid, glycerophospholipid, and retinol metabolism. Multiomic analyses revealed metabolomic pathways linked to the undernourished gut microbiome and hepatic steatosis, including phenylacetate metabolism. Intriguingly, fatty liver features were observed only in the early-life, but not adult, MBG model despite similar liver metabolomic profiles. Importantly, we demonstrate that dietary intervention largely mitigates aberrant metabolomic and microbiome features in MBG mice. These findings indicate a crucial window in early-life development that, when disrupted by nutritional deficiency, may significantly influence liver function. Our work provides a multifaceted study of how diet and gut microbes inform fatty liver progression and reversal during undernutrition.IMPORTANCE Nonalcoholic fatty liver disease (NAFLD) remains a global epidemic, but it is often studied in the context of obesity and aging. Nutritional deficits, however, also trigger hepatic steatosis, influencing health trajectories in undernourished pediatric populations. Here, we report that exposure to specific gut microbes impacts fatty liver pathology in mice fed a protein/fat-deficient diet. We utilize a multiomics approach to (i) characterize NAFLD in the context of early undernutrition and (ii) examine the impact of diet and gut microbes in the pathology and reversal of hepatic steatosis. We provide compelling evidence that an early-life, critical development window facilitates undernutrition-induced fatty liver pathology. Moreover, we demonstrate that sustained dietary intervention largely reverses fatty liver features and microbiome shifts observed during early-life malnutrition.

Project description:Dysbiosis of gut microbiota and metabolome is a frequently encountered condition in liver cirrhosis (LC) patients. The severity of liver dysfunction was found to be correlated with the degree of microbial dysbiosis. Several clinical studies have indicated liver function improvement after therapeutic splenectomy for LC-induced hypersplenism. We sought to determine whether such post-splenectomy outcome is pertinent to modulation of the abnormal gut microenvironment in LC patients. A cross-sectional study including 12 LC patients and 16 healthy volunteers was first conducted, then a before-after study in the cohort of patients was carried out before and 6 months after splenectomy. Fecal samples were collected in hospital. Temporal bacterial (n = 40) and metabolomics (n = 30) profiling was performed using 16s rRNA gene sequencing and ultra performance liquid chromatography/mass spectrometer (UPLC/MS), respectively. Our results revealed that microbial composition in patients was clearly different from that in healthy controls (HCs), evidenced by considerable taxonomic variation. Along with improved liver function (Child-Pugh score), the patients also displayed similar gut microbiota profile and predicted metagenome function to that of HCs after splenectomy. Enterobacteriaceae and Streptococcaceae, two LC-enriched families showing positive relation with Child-Pugh score, exhibited significantly decreased abundance after splenectomy. At the genus level, 11 genera were differentially abundant between patients and HCs, but 9 genera of them restituted to normal levels by certain degree after splenectomy. PICRUSt analysis showed that the relative abundance of 17 KEGG pathways was partially restored after splenectomy. Four of them were amino acid-related pathways: lysine degradation, tryptophan degradation, amino acid metabolism, and protein digestion and absorption. These findings were supported by metabonomics results which showed that relative abundance of amino acid and corresponding catabolites changed toward normal. In addition to the variations in the relative abundances of bacteria and metabolites, the correlation between them also altered in patients after splenectomy. Dysbiosis in gut microbiome and related metabolism of LC patients was partially corrected after splenectomy. Whether the improved gut microenvironment could prevent LC-related complications and delay the progress of LC is a propitious objective for future study. TRIAL REGISTRATION:ChiCTR-OOB-15007409. Registered November 15, 2015.

Project description:BackgroundThe human gut microbiota directly affects human health, and its alteration can lead to gastrointestinal abnormalities and inflammation. Rett syndrome (RTT), a progressive neurological disorder mainly caused by mutations in MeCP2 gene, is commonly associated with gastrointestinal dysfunctions and constipation, suggesting a link between RTT's gastrointestinal abnormalities and the gut microbiota. The aim of this study was to evaluate the bacterial and fungal gut microbiota in a cohort of RTT subjects integrating clinical, metabolomics and metagenomics data to understand if changes in the gut microbiota of RTT subjects could be associated with gastrointestinal abnormalities and inflammatory status.ResultsOur findings revealed the occurrence of an intestinal sub-inflammatory status in RTT subjects as measured by the elevated values of faecal calprotectin and erythrocyte sedimentation rate. We showed that, overall, RTT subjects harbour bacterial and fungal microbiota altered in terms of relative abundances from those of healthy controls, with a reduced microbial richness and dominated by microbial taxa belonging to Bifidobacterium, several Clostridia (among which Anaerostipes, Clostridium XIVa, Clostridium XIVb) as well as Erysipelotrichaceae, Actinomyces, Lactobacillus, Enterococcus, Eggerthella, Escherichia/Shigella and the fungal genus Candida. We further observed that alterations of the gut microbiota do not depend on the constipation status of RTT subjects and that this dysbiotic microbiota produced altered short chain fatty acids profiles.ConclusionsWe demonstrated for the first time that RTT is associated with a dysbiosis of both the bacterial and fungal component of the gut microbiota, suggesting that impairments of MeCP2 functioning favour the establishment of a microbial community adapted to the costive gastrointestinal niche of RTT subjects. The altered production of short chain fatty acids associated with this microbiota might reinforce the constipation status of RTT subjects and contribute to RTT gastrointestinal physiopathology.

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Distinctly altered gut microbiota in the progression of liver disease.

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Distinctly altered gut microbiota in the progression of liver disease.

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