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Several studies have indicated that the oral and gut microbiota may exhibit differences in patients with cirrhosis. Less is known about the microbiota in the stomach, which is located between the oral cavity and the intestinal tract. In this study, the gastric mucosal microbiota of patients with liver cirrhosis and controls were analyzed with 16S ribosomal RNA (rRNA) pyrosequencing. Cirrhotic patients had significantly lower Helicobacter pylori (H. pylori) infection rates, as confirmed by both the histological method and the pyrosequencing method. In H. pylori-negative subjects, gastric bacterial communities of healthy and cirrhosis cohorts were clustered into four clusters based on bacterial compositions: Cluster_1 and Cluster_2 (mostly cirrhosis), Cluster_3 (mostly healthy), and Cluster_4 (around half of each). Compositional and functional differences were observed among these different clusters. At the genus level, Cluster_1 and Cluster_2 showed enrichment of Neisseria and Streptococcus, respectively. Functionally, Cluster_2 was characterized as depleted of genetic information processing, as well as of modules related to glycan biosynthesis and metabolism. Patients in Cluster_2 had more severe gastrointestinal symptoms and a higher rate of previous endoscopic variceal ligation (EVL) therapy than patients in other clusters. Our findings suggest that the colonization of both H. pylori and non-H. pylori is influenced in liver cirrhosis. Although the H. pylori-negative gastric mucosal microbiota showed considerable heterogeneity, associations between specific gastric microbiota and clinical characteristics could be observed. Previous EVL therapy might lead to a distinct structure of the gastric mucosal microbiota, thus aggravating the gastrointestinal symptoms in H. pylori-negative cirrhotic patients.

Lactobacillus salivarius Li01 improved TAA‐induced acute liver injury and hyperammonemia which was mediated by restoring destroyed gut microbiota and barrier function, improving TAA‐induced liver damage and systemic inflammation, and alleviating hyperammonaemia, neuro‐inflammation and damaged cognitive function., Summary The gut microbiota plays pivotal roles in liver disease onset and progression. The protective effects of Lactobacillus salivarius Li01 on liver diseases have been reported. In this study, we aimed to detect the protective effect of L. salivarius Li01 on thioacetamide (TAA)‐induced acute liver injury and hyperammonaemia. C57BL/6 mice were separated into three groups and given a gavage of L. salivarius Li01 or phosphate‐buffered saline for 7 days. Acute liver injury and hyperammonaemia were induced with an intraperitoneal TAA injection. L. salivarius Li01 decreased mortality and serum transaminase levels and improved histological liver damage caused by TAA. Serum inflammatory cytokine and chemokine and lipopolysaccharide‐binding protein (LBP) concentrations, nuclear factor κB (NFκB) pathway activation and macrophage and neutrophil infiltration into the liver were significantly alleviated by L. salivarius Li01. L. salivarius Li01 also reinforced gut barrier and reshaped the perturbed gut microbiota by upregulating Bacteroidetes and Akkermansia richness and downregulating Proteobacteria, Ruminococcaceae_UCG_014 and Helicobacter richness. Plasma and faecal ammonia levels declined noticeably in the Li01 group, accompanied by improvements in cognitive function, neuro‐inflammation and relative brain‐derived neurotrophic factor (BDNF) gene expression. Our results indicated that L. salivarius Li01 could be considered a potential probiotic in acute liver injury and hepatic encephalopathy (HE).

Background Intestinal dysbiosis has been shown to be associated with the pathogenesis of alcoholic liver disease (ALD), which includes changes in the microbiota composition and bacterial overgrowth, but an effective microbe-based therapy is lacking. Pediococcus pentosaceus (P. pentosaceus) CGMCC 7049 is a newly isolated strain of probiotic that has been shown to be resistant to ethanol and bile salts. However, further studies are needed to determine whether P. pentosaceus exerts a protective effect on ALD and to elucidate the potential mechanism. Aim To evaluate the protective effect of the probiotic P. pentosaceus on ethanol-induced liver injury in mice. Methods A new ethanol-resistant strain of P. pentosaceus CGMCC 7049 was isolated from healthy adults in our laboratory. The chronic plus binge model of experimental ALD was established to evaluate the protective effects. Twenty-eight C57BL/6 mice were randomly divided into three groups: The control group received a pair-fed control diet and oral gavage with sterile phosphate buffered saline, the EtOH group received a ten-day Lieber-DeCarli diet containing 5% ethanol and oral gavage with phosphate buffered saline, and the P. pentosaceus group received a 5% ethanol Lieber-DeCarli diet but was treated with P. pentosaceus. One dose of isocaloric maltose dextrin or ethanol was administered by oral gavage on day 11, and the mice were sacrificed nine hours later. Blood and tissue samples (liver and gut) were harvested to evaluate gut barrier function and liver injury-related parameters. Fresh cecal contents were collected, gas chromatography-mass spectrometry was used to measure short-chain fatty acid (SCFA) concentrations, and the microbiota composition was analyzed using 16S rRNA gene sequencing. Results The P. pentosaceus treatment improved ethanol-induced liver injury, with lower alanine aminotransferase, aspartate transaminase and triglyceride levels and decreased neutrophil infiltration. These changes were accompanied by decreased levels of endotoxin and inflammatory cytokines, including interleukin-5, tumor necrosis factor-α, granulocyte colony-stimulating factor, keratinocyte-derived protein chemokine, macrophage inflammatory protein-1α and monocyte chemoattractant protein-1. Ethanol feeding resulted in intestinal dysbiosis and gut barrier disruption, increased relative abundance of potentially pathogenic Escherichia and Staphylococcus, and the depletion of SCFA-producing bacteria, such as Prevotella, Faecalibacterium, and Clostridium. In contrast, P. pentosaceus administration increased the microbial diversity, restored the relative abundance of Lactobacillus, Pediococcus, Prevotella, Clostridium and Akkermansia and increased propionic acid and butyric acid production by modifying SCFA-producing bacteria. Furthermore, the levels of the tight junction protein ZO-1, mucin proteins (mucin [MUC]-1, MUC-2 and MUC-4) and the antimicrobial peptide Reg3β were increased after probiotic supplementation. Conclusion Based on these results, the new strain of P. pentosaceus alleviated ethanol-induced liver injury by reversing gut microbiota dysbiosis, regulating intestinal SCFA metabolism, improving intestinal barrier function, and reducing circulating levels of endotoxin and proinflammatory cytokines and chemokines. Thus, this strain is a potential probiotic treatment for ALD.

Gastric signet ring cell carcinoma (SRCC) and colorectal SRCC are the most aggressive histological types of carcinoma related to a poor prognosis, and place a heavy burden on public health. We undertook a population-based study to analyze the metastatic patterns of SRCC and further estimate its contribution to the cancer-specific survival of gastric SRCC and colorectal SRCC. Data from eligible patients diagnosed with gastric or colorectal SRCC between 2010 and 2012 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Chi-squared tests were used to clarify the clinical features in patients with metastatic disease compared with those without metastatic disease. Survival differences of patients with different metastatic sites were compared with a Kaplan–Meier analysis, and other prognostic factors were examined by Cox proportional hazards models. A total of 4055 patients with gastric SRCC or colorectal SRCC were included in our cohort. Among them, 2905 were diagnosed with gastric SRCC, and the remaining 1150 patients were diagnosed with colorectal SRCC. In gastric SRCC, distant lymph nodes were the most common metastatic sites. Furthermore, patients with brain metastases had the worst prognosis. In colorectal SRCC, the liver was the most common metastatic site, and patients with distant lymph node metastases had the highest mortality. In summary, metastasis is a major contributor to cancer mortality in SRCC. The results from our study provide some information for developing follow-up strategies in future studies.

Background Despite the ongoing spread of coronavirus disease 2019 (COVID-19), knowledge about factors affecting prolonged viral excretion is limited. Methods In this study, we retrospectively collected data from 99 hospitalized patients with coronavirus disease 2019 (COVID-19) between 19 January and 17 February 2020 in Zhejiang Province, China. We classified them into 2 groups based on whether the virus test results eventually became negative. Cox proportional hazards regression was used to evaluate factors associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding. Results Among 99 patients, 61 patients had SARS-CoV-2 clearance (virus-negative group), but 38 patients had sustained positive results (virus-positive group). The median duration of SARS-CoV-2 excretion was 15 (interquartile range, 12–19) days among the virus-negative patients. The shedding time was significantly increased if the fecal SARS-CoV-2 RNA test result was positive. Male sex (hazard ratio [HR], 0.58 [95% confidence interval {CI}, .35–.98]), immunoglobulin use (HR, 0.42 [95% CI, .24–.76]), APACHE II score (HR, 0.89 [95% CI, .84–.96]), and lymphocyte count (HR, 1.81 [95% CI, 1.05–3.1]) were independent factors associated with a prolonged duration of SARS-CoV-2 shedding. Antiviral therapy and corticosteroid treatment were not independent factors. Conclusions SARS-CoV-2 RNA clearance time was associated with sex, disease severity, and lymphocyte function. The current antiviral protocol and low-to-moderate dosage of corticosteroid had little effect on the duration of viral excretion.

Background Probiotics are effective to rectify the imbalanced gut microbiota in the diseased cohorts. Two Bifidobacterium strains (LI09 and LI10) were found to alleviate D-galactosamine-induced liver damage (LD) in rats in our previous work. A series of bioinformatic and statistical analyses were performed to determine the vital bacteria in the gut microbiotas altered by the LI09 or LI10 in rats. Results Two groups of representative phylotypes could distinguish the gut microbiotas of LI09 or LI10 groups from the other groups. Among them, OTU170_Porphyromonadaceae acted as a gatekeeper in LI09 group, while OTU12_Bacteroides was determined with multiple correlations in the gut network of LI10 group. Multiple reduced OTUs associated with LC and increased OTUs associated with health were determined in LI09 or LI10 groups, among which, increased OTU51_Barnesiella and reduced OTU99_Barnesiella could be associated with the protective effects of both the two probiotics. The gut microbiotas in LI09, LI10 and positive control groups were clustered into three clusters, i.e., Cluster_1_Microbiota, Cluster_2_Microbiota and Cluster_3_Microbiota, by Partition Around Medoids clustering analysis. Cluster_2_Microbiota was determined at least dysbiotic status due to its greatest LD dysbiosis ratio, lowest levels of liver function variables and plasma cytokines compared with the two other clustered microbiotas, suggesting the treated rats in Cluster_2 were at better health status. Conclusion Our findings suggest that OTU170_Porphyromonadaceae and OTU12_Bacteroides are vital in the gut microbiotas altered by LI09 and LI10. Characteristics of the LD cohorts treated by LI09 or LI10 at different gut microbial colonization states could help monitor the cohorts’ health status.

Summary The gut microbiota is considered a key factor in pathogenesis and progression of inflammatory bowel disease (IBD). The bacterium Pediococcus pentosaceus LI05 alleviated host inflammation by maintaining the gut epithelial integrity, modulating the host immunity, gut microbiota and metabolism, but its effect on IBD remains unclear. The present study aimed to investigate the role and mechanisms of P. pentosaceus LI05. Mice were administered P. pentosaceus LI05 or phosphate‐buffered saline once daily by oral gavage for 14 days, and colitis was induced by providing mice 2% DSS‐containing drinking water for 7 days. P. pentosaceus LI05 ameliorated colitis in mice and reduced the body weight loss, disease activity index (DAI) scores, colon length shortening, intestinal permeability and the proinflammatory cytokine levels. Furthermore, a significantly altered gut microbiota composition with increased diversity and short‐chain fatty acid (SCFA) production was observed in mice treated with P. pentosaceus LI05. Several genera, including Akkermansia and Faecalibacterium, were differentially enriched in the P. pentosaceus LI05‐treated mice and were negatively correlated with colitis indices and positively correlated with gut barrier markers and SCFA levels. The P. pentosaceus LI05 treatment alleviated intestinal inflammation by maintaining the intestinal epithelial integrity and modulating the immunological profiles, gut microbiome and metabolite composition. Based on our findings, P. pentosaceus LI05 might be applied as potential preparation to ameliorate colitis., The P. pentosaceus LI05 treatment alleviated intestinal inflammation by maintaining the intestinal epithelial integrity and modulating the immunological profiles, gut microbiome and metabolite composition. Based on our findings, P. pentosaceus LI05 might be applied as potential preparation to ameliorate colitis.

The role of host-microbiota interactions in primary biliary cholangitis (PBC) has received increased attention. However, the impact of PBC on the oral microbiota and contribution of the oral microbiota to PBC are unclear. In this study, thirty-nine PBC patients without other diseases and 37 healthy controls (HCs) were enrolled and tested for liver functions and haematological variables. Saliva specimens were collected before and after brushing, microbiota was determined using 16S rDNA sequencing, metabolomics was profiled using Gas Chromatography-Mass Spectrometer (GC-MS), 80 cytokines were assayed using biochips, and inflammation inducibility was evaluated using OKF6 keratinocytes and THP-1 macrophages. Finally, the effect of ultrasonic scaling on PBC was estimated. Compared with HCs, PBC saliva had enriched taxa such as Bacteroidetes, Campylobacter, Prevotella and Veillonella and depleted taxa such as Enterococcaceae, Granulicatella, Rothia and Streptococcus. PBC saliva also had enriched sCD163, enriched metabolites such as 2-aminomalonic acid and 1-dodecanol, and depleted metabolites such as dodecanoic acid and propylene glycol. sCD163, 4-hydroxybenzeneacetic acid and 2-aminomalonic acid were significantly correlated with salivary cytokines, bacteria and metabolites. Salivary Veillonellaceae members, 2-aminomalonic acid, and sCD163 were positively correlated with liver function indicators such as serum alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PBC salivary microbes induced more soluble interleukin (IL)-6 receptor α (sIL-6Rα), sIL-6Rβ and tumour necrosis factor ligand superfamily (TNFSF)13B from OKF6 keratinocytes, and PBC salivary supernatant induced more IL-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine (C-C motif) ligand (CCL)13, C-X-C motif chemokine (CXC)L1 and CXCL16 from THP-1 macrophages. Toothbrushing significantly reduced the expression of inflammatory cytokines such as IL-1β, IL-8 and TNF-α and harmful metabolites such as cadaverine and putrescine in PBC but not HC saliva after P‐value correction. The levels of ALP and bilirubin in PBC serum were decreased after ultrasonic scaling. Together, PBC patients show significant alterations in their salivary microbiota, likely representing one cause and treatment target of oral inflammation and worsening liver functions.

Aims: Racial disparities in cancer mortality persist despite rapid developments in cancer treatment strategies. In recent decades, an increased frequency of patients with young-onset cancer has been reported. However, few studies have assessed racial disparities in clinical features and overall survival among young-onset patients with colorectal, breast, and testicular cancer. Therefore, we evaluated racial disparities in cancer mortality for these three cancer types. Methods: We extracted the data of eligible patients from the Surveillance, Epidemiology and End Results (SEER) database from 1973 to 2014. Overall and cancer-specific survival rates were compared among races using Kaplan-Meier curves. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated, and the association of race with survival was influenced by marital status, surgery and disease stage in Cox proportional hazard models. Results: We collected the data of 19,574 patients with colorectal cancer, 68,733 with breast cancer, and 26,410 with testicular cancer; all were aged 25-40 years. A higher proportion of Blacks presented with a distant stage at diagnosis compared to Whites and Others (colorectal cancer: 18.0%, 18.5% and 18.4%, respectively, P = 0.004; breast cancer: 3.5%, 6.3% and 4.0%, respectively, P < 0.001; testicular cancer: 6.9%, 10.8% and 8.6%, respectively, P < 0.001). Multivariate analysis showed that Blacks had the highest overall mortality rate (colorectal cancer, HR, 1.277, 95% CI: 1.198, 1.361, P < 0.001; breast cancer, HR, 1.471, 95% CI: 1.420, 1.525, P < 0.001; testicular cancer, HR, 1.887, 95% CI: 1.562, 2.281, P < 0.001). In stratified analyses, Unmarried Blacks had a higher mortality rates (colorectal cancer, HR, 1.318, 95% CI: 1.211, 1.435, P < 0.001; breast cancer, HR, 1.465, 95% CI: 1.394, 1.541, P < 0.001; testicular cancer, HR, 1.944, 95% CI: 1.544, 2.447, P < 0.001). Furthermore, Blacks with colorectal and breast cancer had a higher risk of mortality than Whites at every disease stage, with greatest disparities occurred among individuals at localized stage. The influence of racial disparities on survival was consistent among patients who accepted surgery, but was weak among those who did not undergo surgery for colorectal cancer (Blacks, HR, 1.027, 95% CI: 0.866, 1.219, P = 0.758; Others, HR, 0.919, 95% CI: 0.760, 1.112, P = 0.386) and testicular cancer (Blacks, HR, 1.039, 95% CI: 0.538, 2.007, P = 0.909; Others, HR, 0.772, 95% CI: 0.388, 1.533, P = 0.459). Conclusions: We demonstrated that Blacks had a worse prognosis for young-onset colorectal, breast, and testicular cancer. Marital status, cancer-directed surgery and disease stage may influence the association of race with the risk of mortality. Equal access to high-quality medical care among races, greater social support and comprehensive interventions are required. Moreover, further studies need to clarify the effects of biological properties like genetic differences between races on cancer patient survival.

Many Pediococcus spp. have health-promoting benefits, and Pediococcus pentosaceus LI05 is one such species that was proved to be beneficial in previous studies. Our research aimed to determine the immune and metabolic effects of P. pentosaceus LI05 on germ-free rats. Germ-free rats were gavaged with P. pentosaceus LI05 suspensions (1 × 109 CFU) for 2 weeks, and 3 weeks later, blood, spleen, intestine and liver samples were gathered for metabolome, intestine morphology, immunity, and transcriptomics analyses. Oral gavage of P. pentosaceus LI05 reduced the bodyweight of rats, which manifested as increased fecal carbohydrate concentrations, decreased intestinal fat intake and the hepatic fat synthesis gene expression, and accelerated fat-to-glycogen conversion. In addition, P. pentosaceus LI05 exhibited an anti-inflammatory ability, reducing serum proinflammatory cytokine levels and increasing intestinal subepidermal CD4+ cell levels. Furthermore, administration of P. pentosaceus LI05 increased the antimicrobial ability and enhanced the liver detoxification function. These results indicate that as a probiotic, P. pentosaceus LI05 ameliorates the hampered immune response of GF animals and improves the metabolism of fat and toxic substances.

The gut microbiota plays an important role in multifaceted physiological functions in the host. Previous studies have assessed the probiotic effects of Lactobacillus salivarius LI01. In this study, we aimed to investigate the potential effects and putative mechanism of L. salivarius LI01 in immune modulation and metabolic regulation through the monocolonization of germ-free (GF) Sprague-Dawley (SD) rats with L. salivarius LI01. The GF rats were separated into two groups and administered a gavage of L. salivarius LI01 or an equal amount of phosphate-buffered saline. The levels of serum biomarkers, such as interleukin (IL)-1α, IL-5, and IL-10, were restored by L. salivarius LI01, which indicated the activation of Th0 cell differentiation toward immune homeostasis. L. salivarius LI01 also stimulated the immune response and metabolic process by altering transcriptional expression in the ileum and liver. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed significant enrichment of the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, which indicated that L. salivarius LI01 exerts an effect on energy accumulation. The LI01 group showed alterations in fecal carbohydrates accompanied by an increased body weight gain. In addition, L. salivarius LI01 produced indole-3-lactic acid (ILA) and enhanced arginine metabolism by rebalancing the interconversion between arginine and proline. These findings provide evidence showing that L. salivarius LI01 can directly impact the host by modulating immunity and metabolism. KEY POINTS : • Lactobacillus salivarius LI01 conventionalizes the cytokine profile and activates the immune response. • LI01 modulates carbohydrate metabolism and arginine transaction. • LI01 generates tryptophan-derived indole-3-lactic acid. • The cytochrome P450 family contributes to the response to altered metabolites.

The aim of this research was to develop a quantitative method for clinicians to predict the probability of improved prognosis in patients with coronavirus disease 2019 (COVID-19). Data on 104 patients admitted to hospital with laboratory-confirmed COVID-19 infection from 10 January 2020 to 26 February 2020 were collected. Clinical information and laboratory findings were collected and compared between the outcomes of improved patients and non-improved patients. The least absolute shrinkage and selection operator (LASSO) logistics regression model and two-way stepwise strategy in the multivariate logistics regression model were used to select prognostic factors for predicting clinical outcomes in COVID-19 patients. The concordance index (C-index) was used to assess the discrimination of the model, and internal validation was performed through bootstrap resampling. A novel predictive nomogram was constructed by incorporating these features. Of the 104 patients included in the study (median age 55 years), 75 (72.1%) had improved short-term outcomes, while 29 (27.9%) showed no signs of improvement. There were numerous differences in clinical characteristics and laboratory findings between patients with improved outcomes and patients without improved outcomes. After a multi-step screening process, prognostic factors were selected and incorporated into the nomogram construction, including immunoglobulin A (IgA), C-reactive protein (CRP), creatine kinase (CK), acute physiology and chronic health evaluation II (APACHE II), and interaction between CK and APACHE II. The C-index of our model was 0.962 (95% confidence interval (CI), 0.931-0.993) and still reached a high value of 0.948 through bootstrapping validation. A predictive nomogram we further established showed close performance compared with the ideal model on the calibration plot and was clinically practical according to the decision curve and clinical impact curve. The nomogram we constructed is useful for clinicians to predict improved clinical outcome probability for each COVID-19 patient, which may facilitate personalized counselling and treatment.

Additional file 1 Figure S1. Flow chart of study design.

Additional file 3 Figure S2. Illustration of correlation between microbial abundance and metabolite concentration.

Additional file 2 Table S1. Significantly differentially abundant microbial genera between tumour and normal colon tissues from CRC patients (n = 36).

Additional file 4 Table S2. Significantly differentially methylated probes that located within the differentially expressed genes between tumour and normal colon tissues from CRC patients (n = 4).

Acute liver failure is a drastic, unpredictable clinical syndrome with high mortality. Various preventive and adjuvant therapies based on modulating the gut flora have been proposed for hepatic injury. We aimed to explore the preventive and therapeutic effects of Bifidobacterium adolescentis CGMCC15058 on rat liver failure, as well as the potential microecological and immunological mechanisms of those effects. B. adolescentis CGMCC15058 (3 × 109 CFU), isolated from healthy human stool, was gavaged to Sprague–Dawley rats for 14 days. Acute liver injury was induced on the 15th day by intraperitoneal injection of d-galactosamine. After 24 h, liver and terminal ileum histology, liver function, plasma cytokines, bacterial translocation and gut microbiota composition were assessed. We found that pretreatment with B. adolescentis significantly relieved elevated serum levels of alanine aminotransferase (ALT), total bile acid and lipopolysaccharide-binding protein and enhanced the expression of mucin 4 and the tight junction protein zonula occludens-1. B. adolescentis exhibited anti-inflammatory properties as indicated by decreased levels of mTOR and the inflammatory cytokines TNF-α and IL-6, as well as elevated levels of the anti-inflammatory cytokine interleukins-10 in the liver. Similar anti-inflammatory signs were also found in plasma. B. adolescentis significantly altered the microbial community, depleting the common pathogenic taxon Proteus and markedly enriching the taxa Coriobacteriaceae, Bacteroidales and Allobaculum, which are involved in regulating the metabolism of lipids and aromatic amino acids. Our findings not only suggest B. adolescentis acts as a prospective probiotic against liver failure but also provide new insights into the prevention and treatment of liver disease.

To investigate changes in gut microbiota and metabolism during nonalcoholic steatohepatitis (NASH) development in mice fed a methionine-choline-deficient (MCD) diet.Twenty-four male C57BL/6J mice were equally divided into four groups and fed a methionine-choline-sufficient diet for 2 wk (Control 2w group,The mice fed the MCD diet presented with simple hepatic steatosis and slight intestinal barrier deterioration after 2 wk. After 4 wk of feeding with the MCD diet, however, the mice developed prominent NASH with liver fibrosis, and the intestinal barrier was more impaired. Compared with the control diet, the MCD diet induced gradual gut microbiota dysbiosis, as evidenced by a marked decrease in the abundance ofThe MCD diet induced persistent alterations in the gut microbiota and metabolome.

// Yating Li 1 , Hong Xu 2 , Wenrui Wu 1 , Jianzhong Ye 1 , Daiqiong Fang 1 , Ding Shi 1 and Lanjuan Li 1 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People’s Republic of China 2 Department of Orthopaedics, Tianjin Medical University General Hospital, Heping District, Tianjin 300052, People’s Republic of China Correspondence to: Lanjuan Li, email: ljli@zju.edu.cn Keywords: NAFLD (non-alcoholic fatty liver disease); ARBs (angiotensin receptor blockers); liver fibrosis; liver inflammation; meta-analysis Received: September 19, 2017 Accepted: October 27, 2017 Epub: January 02, 2018 Published: May 08, 2018 ABSTRACT Objective: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, ranging from simple steatosis to progressive steatohepatitis and cirrhosis. Because of their anti-inflammatory and anti-fibrotic effects, angiotensin receptor blockers (ARBs) are potential therapeutic agents for NAFLD. The present systematic review assessed the effectiveness of ARBs in NAFLD management. Results: Accounting for data overlap and exclusion criteria, randomized controlled trial -based and single-arm meta-analyses were conducted for four studies with 362 patients and eight studies with 525 patients, respectively. Although alanine aminotransferase levels were not significantly affected by ARB treatment (standardized mean difference 0.20; 95% confidence interval (CI) [−0.04, 0.44]; P = 0.10), a fixed-effect model revealed a decreasing trend in alanine transaminase levels. Low-density lipoprotein levels were reduced by ARB treatment (MD 5.21; 95% CI [3.01, 7.40]; P < 0.00001), and total cholesterol also decreased in response to ARBs (MD 2.10; 95% CI [−0.37, 4.57]; P = 0.10). However, the fibrosis score and NAFLD activity score were not significantly improved by ARB treatment (MD 0.10; 95% CI [−0.58, 0.78]; P = 0.77) (MD −0.25; 95% CI [−1.05, 0.55]; P = 0.53). Materials and Methods: Keywords were used to identify studies in PubMed, EMBASE, CENTRAL, Web of Science and CNKI published up to July 31, 2017. Single-arm and RCT-based meta-analyses of the available data were performed using RevMan (version 5.3). Conclusions: Although ARBs significantly decreased plasma low-density lipoprotein and total cholesterol levels, the current evidence is insufficient to support the efficacy of ARBs in managing fibrosis in NAFLD patients.

Wenrui Wu,1,2 Daiqiong Fang,1,2 Ding Shi,1,2 Xiaoyuan Bian,1,2 Lanjuan Li1,2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People’s Republic of China Purpose: It is well demonstrated that being married is associated with a better prognosis in multiple types of cancer. However, whether the protective effect of marital status varied across race/ethnicity and gender in patients with hepatocellular carcinoma remains unclear. Therefore, we aimed to evaluate the roles of race/ethnicity and gender in this relationship.Patients and methods: We identified eligible patients from Surveillance, Epidemiology and End Results (SEER) database during 2004–2012. Overall and cancer-specific survival differences across marital status were compared by Kaplan–Meier curves. We also estimated crude hazard ratios (CHRs) and adjusted hazard ratios (AHRs) with 95% confidence intervals (CIs) for marital status associated with survival by race/ethnicity and gender in Cox proportional hazard models.Results: A total of 12,168 eligible patients diagnosed with hepatocellular carcinoma were included. We observed that married status was an independent protective prognostic factor for overall and cancer-specific survival. In stratified analyses by race/ethnicity, the AHR of overall mortality (unmarried vs married) was highest for Hispanic (AHR =1.25, 95% CI, 1.13–1.39; P

The gut microbiota is altered in liver diseases, and several probiotics have been shown to reduce the degree of liver damage. We hypothesized that oral administration of specific Bifidobacterium strains isolated from healthy guts could attenuate liver injury. Five strains were tested in this study. Acute liver injury was induced by D-galactosamine after pretreating Sprague-Dawley rats with the Bifidobacterium strains, and liver function, liver and ileum histology, plasma cytokines, bacterial translocation and the gut microbiome were assessed. Two strains, Bifidobacterium pseudocatenulatum LI09 and Bifidobacterium catenulatum LI10, conferred liver protection, as well as alleviated the increase in plasma M-CSF, MIP-1α and MCP-1 and bacterial translocation. They also ameliorated ileal mucosal injury and gut flora dysbiosis, especially the enrichment of the opportunistic pathogen Parasutterella and the depletion of the SCFA-producing bacteria Anaerostipes, Coprococcus and Clostridium XI. Negative correlations were found between MIP-1α / MCP-1 and Odoribacter (LI09 group) and MIP-1α / M-CSF and Flavonifractor (LI10 group). Our results indicate that the liver protection effects might be mediated through gut microbiota modification, which thus affect the host immune profile. The desirable characteristics of these two strains may enable them to serve as potential probiotics for the prevention or adjuvant treatment of liver injury.

The gut microbiota plays an important role in colorectal cancer (CRC), and the use of probiotics might be a promising intervention method. The aim of our study was to investigate the beneficial effect of Bifidobacterium bifidum CGMCC 15068 on an azoxymethane (AOM)/dextran sulphate sodium (DSS)-induced colitis-associated CRC (CAC) mouse model. CAC was induced by an intra-peritoneal injection of AOM (10 mg/kg) and three 7-day cycles of 2% DSS in drinking water with a 14-day recovery period between two consecutive DSS administrations. B. bifidum CGMCC 15068 (3 × 109 CFU/mL) was gavaged once daily during the recovery period. Then, the faecal microbial composition and metabolome were profiled using the 16S rRNA sequencing technology and gas chromatography-mass spectrometry (GC-MS), respectively. The administration of B. bifidum CGMCC 15068 attenuated tumourigenesis in the CAC mouse model. In addition, B. bifidum CGMCC 15068 pre-treatment increased the relative abundance of Akkermansia, Desulfovibrionaceae, Romboutsia, Turicibacter, Verrucomicrobiaceae, Ruminococcaceae_UCG_013, Lachnospiraceae_UCG_004, and Lactobacillus. Meanwhile, B. bifidum CGMCC 15068 altered metabolites involved in the citrate cycle (TCA cycle), glycolysis, butyrate metabolism, fatty acid biosynthesis, and galactose metabolism. Several significant correlations were identified between the differentially abundant microbes and metabolites. These findings supported the beneficial role of B. bifidum CGMCC 15068 in intestinal health by modulating dysbiosis and the gut metabolic profile. The manipulation of the gut microbial composition using probiotics might be a promising prevention strategy for CRC. Long-term and large-scale clinical trials are warranted for the potential clinical applications of this strategy in the future.

// Wenrui Wu 1, 2 , Feifei Guo 1, 2 , Jianzhong Ye 1, 2 , Yating Li 1, 2 , Ding Shi 1, 2 , Daiqiong Fang 1, 2 , Jing Guo 1, 2 , Lanjuan Li 1, 2 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China 2 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China Correspondence to: Lanjuan Li, email: ljli@zju.edu.cn Keywords: physical activity, pre-diagnosis, post-diagnosis, colorectal cancer Received: April 03, 2016 Accepted: June 29, 2016 Published: July 18, 2016 ABSTRACT Objective: Physical activity is associated with reduced risk of colorectal cancer. However, whether physical activity could impart cancer patients’ survival benefits remains uncertain. The aim of this study is to systematically evaluate the relationship between physical activity and colorectal cancer mortality. Results: Our meta-analysis included 11 studies involving 17,295 patients with a follow-up period ranging from 3.8 to 11.9 years. Results indicated that physical activity was inversely associated with overall (RR = 0.81, 95% CI = 0.72–0.91) and colorectal cancer-specific mortality (RR = 0.79, 95% CI = 0.71–0.89) before the diagnosis of cancer, respectively. For physical activity after diagnosis, the pooled RRs of colorectal cancer-specific and total mortality were 0.77 (95% CI, 0.63–0.94) and 0.71 (95% CI, 0.63–0.81), respectively. Similar inverse associations between exercise and prognosis were found among colorectal cancer survivors who had high-level exercise compared with those who had low-level exercise or were inactive. There was no obvious evidence for publication bias among studies. Materials and Methods: We performed a systematic data search in PubMed, Cochrane Library databases and Web of Science for relevant articles before Jan 2016. We adopted adjusted estimates to calculate pooled relative risks (RRs) with 95% confidence intervals (CI) by the random-effects model. The publication bias was assessed by Begg’s test. Conclusions: Our meta-analysis provides comprehensive evidence that physical activity, whether before or after the diagnosis of colorectal cancer, is related to reduced overall and cancer-specific mortality. Our findings may have significant public health implications and more prospective randomized clinical trials should be warranted to certify this protective association.

We selected 42 early-stage primary biliary cirrhosis (PBC) patients and 30 healthy controls (HC). Metagenomic sequencing of the 16S rRNA gene was used to characterize the fecal microbiome. UPLC-MS/MS assaying of small molecules was used to characterize the metabolomes of the serum, urine and feces. Liquid chip assaying of serum cytokines was used to characterize the immune profiles. The gut of PBC patients were depleted of some potentially beneficial bacteria, such as Acidobacteria, Lachnobacterium sp., Bacteroides eggerthii and Ruminococcus bromii, but were enriched in some bacterial taxa containing opportunistic pathogens, such as γ-Proteobacteria, Enterobacteriaceae, Neisseriaceae, Spirochaetaceae, Veillonella, Streptococcus, Klebsiella, Actinobacillus pleuropneumoniae, Anaeroglobus geminatus, Enterobacter asburiae, Haemophilus parainfluenzae, Megasphaera micronuciformis and Paraprevotella clara. Several altered gut bacterial taxa exhibited potential interactions with PBC through their associations with altered metabolism, immunity and liver function indicators, such as those of Klebsiella with IL-2A and Neisseriaceae with urinary indoleacrylate. Many gut bacteria, such as some members of Bacteroides, were altered in their associations with the immunity and metabolism of PBC patients, although their relative abundances were unchanged. Consequently, the gut microbiome is altered and may be critical for the onset or development of PBC by interacting with metabolism and immunity.

Background: Ascites bacterial burden is associated with poor clinical outcomes in patients with end-stage liver disease. However, the impact of ascitic microbial composition on clinical course was still not clear. In this study, the ascitic microbiota composition of 100 cirrhotic patients with culture-negative and nonneutrocytic ascites were researched. Results: By characterizing the ascitic microbial composition, two distinct microbial clusters were observed, Cluster 1 (86 patients) and Cluster 2 (14 patients). Cluster 1 showed lower microbial richness than Cluster 2. At the phylum level, Cluster 1 had greater abundance of Bacteroidetes and Firmicutes, but less abundance of Proteobacteria and Actinobacteria than Cluster 2. At the family level, family Bacteroidales S24-7 group, Prevotellaceae, Lachnospiraceae, Lactobacillaceae, Rikenellaceae, and Vibrionaceae were found over-represented in Cluster 1. And family Acetobacteraceae, Erysipelotrichaceae, Rickettsiaceae, and Streptococcaceae were found enriched in Cluster 2. The levels of plasma cytokine IL-17A, IL-7, and PDGF-BB were found significantly higher in Cluster 1 than in Cluster 2. There were four OTUs closely correlated with plasma cytokines, which were OTU 140 and OTU 271 (both from Bacteroidales S24-7 group), OTU 68 (Veillonellaceae), and OTU 53 (Helicobacteraceae). Patients from Cluster 1 showed significant higher short-term mortality than patients from Cluster 2. Conclusion: Our study demonstrated that the microbial composition of culture-negative and nonneutrocytic ascites in cirrhotic patients is associated with short-term clinical outcomes. The results here offer a rational for the identification of patients with high risk, and provide references for selective use of prophylactic methods.

Alterations in the gut microbiome have been reported in liver cirrhosis, and probiotic interventions are considered a potential treatment strategy. This study aimed to evaluate the effects and mechanisms of Lactobacillus salivarius LI01, Pediococcus pentosaceus LI05, Lactobacillus rhamnosus GG, Clostridium butyricum MIYAIRI and Bacillus licheniformis Zhengchangsheng on CCl4-induced cirrhotic rats. Only administration of LI01 or LI05 prevented liver fibrosis and down-regulated the hepatic expression of profibrogenic genes. Serum endotoxins, bacterial translocations (BTs), and destruction of intestinal mucosal ultrastructure were reduced in rats treated with LI01 or LI05, indicating maintenance of the gut barrier as a mechanism; this was further confirmed by the reduction of not only hepatic inflammatory cytokines, such as TNF-α, IL-6, and IL-17A, but also hepatic TLR2, TLR4, TLR5 and TLR9. Metagenomic sequencing of 16S rRNA gene showed an increase in potential beneficial bacteria, such as Elusimicrobium and Prevotella, and a decrease in pathogenic bacteria, such as Escherichia. These alterations in gut microbiome were correlated with profibrogenic genes, gut barrier markers and inflammatory cytokines. In conclusion, L. salivarius LI01 and P. pentosaceus LI05 attenuated liver fibrosis by protecting the intestinal barrier and promoting microbiome health. These results suggest novel strategies for the prevention of liver cirrhosis.

Accumulating evidence indicates that gut microbiota participates in the pathogenesis and progression of liver diseases. The severity of immune-mediated liver injury is associated with different microbial communities. Akkermansia muciniphila can regulate immunologic and metabolic functions. However, little is known about its effects on gut microbiota structure and function. This study investigated the effect of A. muciniphila on immune-mediated liver injury and potential underlying mechanisms. Twenty-two C57BL/6 mice were assigned to three groups (N = 7–8 per group) and continuously administrated A. muciniphila MucT or PBS by oral gavage for 14 days. Mouse feces were collected for gut microbiota analysis on the 15th day, and acute liver injury was induced by Concanavalin A (Con A, 15 mg/kg) injection through the tail vein. Samples (blood, liver, ileum, colon) were assessed for liver injury, systemic inflammation, and intestinal barrier function. We found that oral administration of A. muciniphila decreased serum ALT and AST and alleviated liver histopathological damage induced by Con A. Serum levels of pro-inflammatory cytokines and chemokines (IL-2, IFN-γ, IL-12p40, MCP-1, MIP-1a, MIP-1b) were substantially attenuated. A. muciniphila significantly decreased hepatocellular apoptosis; Bcl-2 expression increased, but Fas and DR5 decreased. Further investigation showed that A. muciniphila enhanced expression of Occludin and Tjp-1 and inhibited CB1 receptor, which strengthened intestinal barriers and reduced systemic LPS level. Fecal 16S rRNA sequence analysis indicated that A. muciniphila increased microbial richness and diversity. The community structure of the Akk group clustered distinctly from that of mice pretreated with PBS. Relative abundance of Firmicutes increased, and Bacteroidetes abundance decreased. Correlation analysis showed that injury-related factors (IL-12p40, IFN-γ, DR5) were negatively associated with specific genera (Ruminococcaceae_UCG_009, Lachnospiraceae_UCG_001, Akkermansia), which were enriched in mice pretreated with A. muciniphila. Our results suggested that A. muciniphila MucT had beneficial effects on immune-mediated liver injury by alleviating inflammation and hepatocellular death. These effects may be driven by the protective profile of the intestinal community induced by the bacteria. The results provide a new perspective on the immune function of gut microbiota in host diseases.

Cirrhosis-associated duodenal dysbiosis is not yet clearly defined. In this research, duodenal mucosal microbiota was analyzed in 30 cirrhotic patients and 28 healthy controls using 16S rRNA gene pyrosequencing methods. The principal coordinate analysis revealed that cirrhotic patients were colonized by remarkable different duodenal mucosal microbiota in comparison with controls. At the genus level, Veillonella, Megasphaera, Dialister, Atopobium, and Prevotella were found overrepresented in cirrhotic duodenum. And the duodenal microbiota of healthy controls was enriched with Neisseria, Haemophilus, and SR1 genera incertae sedis. On the other hand, based on predicted metagenomes analyzed, gene pathways related to nutrient absorption (e.g. sugar and amino acid metabolism) were highly abundant in cirrhosis duodenal microbiota, and functional modules involved in bacterial proliferation and colonization (e.g. bacterial motility proteins and secretion system) were overrepresented in controls. When considering the etiology of cirrhosis, two operational taxonomic units (OTUs), OTU-23 (Neisseria) and OTU-36 (Gemella), were found discriminative between hepatitis-B-virus related cirrhosis and primary biliary cirrhosis. The results suggest that the structure of duodenal mucosa microbiota in cirrhotic patients is dramatically different from healthy controls. The duodenum dysbiosis might be related to alterations of oral microbiota and changes in duodenal micro-environment.

Lactobacillus salivarius LI01, isolated from healthy humans, has demonstrated probiotic properties in the prevention and treatment of liver failure. Tolerance to bile stress is crucial to allow lactobacilli to survive in the gastrointestinal tract and exert their benefits. In this work, we used a Digital Gene Expression transcriptomic and iTRAQ LC-MS/MS proteomic approach to examine the characteristics of LI01 in response to bile stress. Using culture medium with or without 0.15% ox bile, 591 differentially transcribed genes and 347 differentially expressed proteins were detected in LI01. Overall, we found the bile resistance of LI01 to be based on a highly remodeled cell envelope and a reinforced bile efflux system rather than on the activity of bile salt hydrolases. Additionally, some differentially expressed genes related to regulatory systems, the general stress response and central metabolism processes, also play roles in stress sensing, bile-induced damage prevention and energy efficiency. Moreover, bile salts appear to enhance proteolysis and amino acid uptake (especially aromatic amino acids) by LI01, which may support the liver protection properties of this strain. Altogether, this study establishes a model of global response mechanism to bile stress in L. salivarius LI01. Biological significance L. salivarius strain LI01 exhibits not only antibacterial and antifungal properties but also exerts a good health-promoting effect in acute liver failure. As a potential probiotic strain, the bile-tolerance trait of strain LI01 is important, though this has not yet been explored. In this study, an analysis based on DGE and iTRAQ was performed to investigate the gene expression in strain LI01 under bile stress at the mRNA and protein levels, respectively. To our knowledge, this work also represents the first combined transcriptomic and proteomic analysis of the bile stress response mechanism in L. salivarius.

We report a draft genome sequence of Lactobacillus panis DSM 6035 T , isolated from sourdough. The genome of this strain is 2,082,789 bp long, with 47.9% G+C content. A total of 2,047 protein-coding genes were predicted.

Bacterial translocation from the gut plays an important role in the pathophysiology of acute-on-chronic liver failure (ACLF). However, gut dysbiosis in ACLF was not widely documented in previous studies.This research characterized the fecal microbiota in patients with ACLF and analyzed the temporal stability of gut microbiota during illness.Fecal microbiota of 79 ACLF patients (42 patients were followed in the next 4 weeks after the first visit for longitudinal study) and 50 healthy controls was analyzed by 16S ribosomal DNA pyrosequencing.There was a marked difference between the ACLF group and the control group. The overall microbial diversity and richness were significantly lower in ACLF than in controls. ACLF patients had lower abundance of Bacteroidaceae, Ruminococcaceae, and Lanchnospiraceae, but higher abundance of Pasteurellaceae, Streptococcaceae, and Enterecoccaceae. The relative abundance of Lachnospiraceae was obviously decreased in ACLF patients with hepatic encephalopathy. The gut microbiota kept relatively stable in a short term after the onset of ACLF. The use of antibiotics only showed moderate impacts on the gut microbiota. The relative abundance of Pasteurellaceae and Model of End Stage Liver Disease score were independent factors predicting mortality rate. Network analysis comparison showed robust correlations between specific bacterial families (Ruminococcaceae and Lachnospiraceae) and inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor alpha, IL-2) in ACLF patients.These data suggest gut dysbiosis in ACLF and its predictive value for mortality. The results thus open up the possibility of designing diagnostic biomarkers and targeted probiotics aimed at decreasing mortality in ACLF.

Summary Objectives The avian influenza H7N9 virus can cause cytokine overproduction and result in severe pneumonia and acute respiratory distress syndrome. Many studies have focused on hypercytokinemia during avian influenza infection. This study examined the association between C-reactive protein (CRP) and cytokines. Methods The plasma cytokine and chemokine profiles of 57 H7N9 patients were investigated using a multiplex immunoassay. The CRP levels of patients with H7N9 and patients with H1N1 were also compared. Further, the association between cytokines and CRP in H7N9 infections was explored. Results Compared with H1N1 virus, it was found that H7N9 virus induced higher expression of CRP, leading to cytokine storms. Several cytokines, including MIP-1β, MCP-1, IP-10, and IL-6, were observed to have significantly positive relationships with CRP levels, whereas IL-17A was negatively associated with CRP levels. Conclusions These findings suggest that CRP may be used as an early indicator to identify high-risk patients, to assess disease progression, and to determine the development of hypercytokinemia.

Background Human gut microbiota plays an important role in the pathogenesis of cirrhosis complications. Although the phylogenetic diversity of intestinal microbiota in patients with liver cirrhosis has been examined in several studies, little is known about their functional composition and structure. Results To characterize the functional gene diversity of the gut microbiome in cirrhotic patients, we recruited a total of 42 individuals, 12 alcoholic cirrhosis patients, 18 hepatitis B virus (HBV)-related cirrhosis patients, and 12 normal controls. We determined the functional structure of these samples using a specific functional gene array, which is a combination of GeoChip for monitoring biogeochemical processes and HuMiChip specifically designed for analyzing human microbiomes. Our experimental data showed that the microbial community functional composition and structure were dramatically distinctive in the alcoholic cirrhosis. Various microbial functional genes involved in organic remediation, stress response, antibiotic resistance, metal resistance, and virulence were highly enriched in the alcoholic cirrhosis group compared to the control group and HBV-related cirrhosis group. Cirrhosis may have distinct influences on metabolic potential of fecal microbial communities. The abundance of functional genes relevant to nutrient metabolism, including amino acid metabolism, lipid metabolism, nucleotide metabolism, and isoprenoid biosynthesis, were significantly decreased in both alcoholic cirrhosis group and HBV-related cirrhosis group. Significant correlations were observed between functional gene abundances and Child-Pugh scores, such as those encoding aspartate-ammonia ligase, transaldolase, adenylosuccinate synthetase and IMP dehydrogenase. Conclusions Functional gene array was utilized to study the gut microbiome in alcoholic and HBV-related cirrhosis patients and controls in this study. Our array data indicated that the functional composition of fecal microbiomes was heavily influenced by cirrhosis, especially by alcoholic cirrhosis. This study provides new insights into the functional potentials and activity of gut microbiota in cirrhotic patients with different etiologies. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-753) contains supplementary material, which is available to authorized users.