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Relationship between intestinal microbial dysbiosis and primary liver cancer

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Hepatobiliary & Pancreatic Diseases International 2019年第2期18卷 149-157页

作者： Lei Zhang Yong-Na Wu Tuo Chen Cheng-Hui Ren Xun Li Guang-Xiu Liu Key Laboratory of Desert and Desertification Northwest Institute of Eco-Environment and Resources Chinese Academy of Sciences Key Laboratory of Extreme Environmental Microbial Resources and Engineering of Gansu Province University of Chinese Academy of Sciences The First Clinical Medical College Lanzhou University The First Hospital of Lanzhou University Lanzhou University Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province

Background: Intestinal microbial dysbiosis is involved in liver disease pathogenesis. However, its role in primary liver cancer(PLC), particularly in hepatocarcinogenesis remains unclear. The present study aimed to study the changes in intestinal flora at various stages of PLC and clarify the relationship between intestinal microbes and PLC. Methods: Twenty-four patients with PLC(PLC group), 24 patients with liver cirrhosis(LC group), and 23 healthy control individuals(HC group) were enrolled from October 2016 to October 2017. Stool specimens of the participants were collected and the genomic DNA of fecal bacteria was isolated. High-throughput pyrosequencing of 16 S r DNA was used to identify differences in gut bacterial diversity among HC, LC, and PLC groups. We also analyzed the relationship between clinical factors and intestinal microorganisms in LC and PLC groups. Results: Diversity of Firmicutes tended to decrease from the HC to LC and PLC groups at the phylum level. Among species, Enterobacter ludwigii displayed an increasing trend in the PLC group, wherein the relative abundance of Enterobacter ludwigii in the PLC group was 100 times greater than that in the HC and LC groups. The ratio of Firmicutes/Bacteroidetes was significantly decreased with the disease progression. In addition, the linear discriminant analysis effect size method indicated that Clostridia were predominant in the gut microbiota of the HC group, whereas Enterococcaceae, Lactobacillales, Bacilli and Gammaproteobacteria may be used as diagnostic markers of PLC. Redundancy analysis showed a correlation between intestinal microbial diversity and clinical factors AST, ALT, and AFP. Veillonella showed a significant positive correlation with AFP in the PLC group, whereas Subdoligranulum showed a negative correlation with AFP. Conclusions: This study indicates that dysbiosis of the gut microbiota might be involved in PLC development and progression.

关键词： Gut microbiota Microbial dysbiosis Hepatocarcinogenesis 16S rDNA

Characteristic dysbiosis of gut microbiota of Chinese patients with diarrhea-predominant irritable bowel syndrome by an insight into the pan-microbiome

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Chinese Medical Journal 2019年第8期132卷 889-904页

作者： Zhe Wang Cong-Min Xu Yi-Xuan Liu Xiao-Qi Wang Lu Zhang Mo Li Shi-Wei Zhu Zhong-Jie Xie Pei-Hong Wang Li-Ping Duan Huai-Qiu Zhu State Key Laboratory for Turbulence and Complex Systems and Department of Biomedical Engineering College of Engineering Peking University Beijing 100871 China Center for Quantitative Biology Peking University Beijing 100871 China Department of Gastroenterology Peking University Third Hospital Beijing 100191 China

Background:Irritable bowel syndrome(IBS)is reported associated with the alteration of gut microbial composition termed as dysbiosis.However,the pathogenic mechanism of IBS remains unclear,while the studies of Chinese individuals are scarce.This study aimed to understand the concept of dysbiosis among patients with Chinese diarrhea-predominant IBS(IBS-D),as a degree of variance between the gut microbiomes of IBS-D population and that of a healthy population.Methods:The patients with IBS-D were recruited(assessed according to the Rome III criteria,by IBS symptom severity score)from the Outpatient Department of Gastroenterology of Peking University Third Hosp让al,and volunteers as healthy controls(HCs)were enrolled,during 2013.The 16S rRNA sequences were extracted from fecal samples.Ribosomal database project resources,basic local alignment search tool,and SparCC software were used to obtain the phylotype composition of samples and the internal interactions of the microbial community.Herein,the non-parametric test,Wilcoxon rank-sum test was carried out to find the statistical significance between HC and IBS-D groups.All the P values were adjusted to q values to decrease the error rate.Results:The study characterized the gut microbiomes of Chinese patients with IBS-D,and demonstrated that the dysbiosis could be characterized as directed alteration of the microbiome composition leading to greater disparity between relative abundance of two phyla,Bacteroidetes(Z=4.77,q=1.59×10^-5)and Firmicutes(Z=-3.87,q=5.83×10^-4).Moreover,it indicated that the IBS symptom features were associated with the dysbiosis of whole gut microbiome,instead of one or several certain genera even they were dominating.Two genera,Bacteroides and Lachnospiracea incertae sedis,were identified as the core genera,meanwhile,the non-core genera contribute to a larger pan-microbiome of the gut microbiome.Furthermore,the dysbiosis in patients with IBS-D was associated with a reduction of network complexity of the interacted microbial community(HC us.IBS-D:

关键词： Irritable bowel syndrome Gut microbiome dysbiosis Microbial diversity Community network complexity

Fecal microbial dysbiosis in Chinese patients with inflammatory bowel disease

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World Journal of Gastroenterology 2018年第13期24卷 1464-1477页

作者： Hai-Qin Ma Ting-Ting Yu Xiao-Jing Zhao Yi Zhang Hong-Jie Zhang Department of Gastroenterology First Affiliated Hospital of Nanjing Medical University

AIM To analyze the alterations of fecal microbiota in Chinese patients with inflammatory bowel disease(IBD).METHODS Fecal samples from 15 patients with Crohn's disease(CD)(11 active CD, 4 inactive CD), 14 patients with active ulcerative colitis(UC) and 13 healthy individuals were collected and subjected to 16 S ribosomal DNA(rDNA) gene sequencing. The V4 hypervariable regions of 16 S rDNA gene were amplified from all samples and sequenced by the Illumina Mi Seq platform. Quality control and operational taxonomic units classification of reads were calculated with QIIME software. Alpha diversity and beta diversity were displayed with R software.RESULTS Community richness(chao) and microbial structure in both CD and UC were significantly different from those in normal controls. At the phyla level, analysis of the microbial compositions revealed a significantly greater abundance of Proteobacteria in IBD as compared to that in controls. At the genera level, 8 genera in CD and 23 genera in UC(in particular, the Escherichia genus) showed significantly greater abundance as compared to that in normal controls. The relative abundance of Bacteroidetes in the active CD group was markedly lower than that in the inactive CD group. The abundance of Proteobacteria in patients with active CD was nominally higher than that in patients with inactive CD; however, the difference was not statistically significant after correction. Furthermore, the relative abundance of Bacteroidetes showed a negative correlation with the CD activity index scores.CONCLUSION Our study profiles specific characteristics and microbial dysbiosis in the gut of Chinese patients with IBD. Bacteroidetes may have a negative impact on inflammatory development.

关键词： Crohn’s disease Ulcerative colitis Chinese Microbial dysbiosis 16S ribosomal DNA

Microbiome dysbiosis and alcoholic liver disease

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Liver Research 2019年第3期3卷 218-226页

作者： Fengyuan Li Craig J.McClain Wenke Feng Department of Medicine Department of Pharmacology and ToxicologyAlcohol Research CenterUniversity of LouisvilleLouisvilleKYUSA

Microbiome dysbiosis is strongly associated with alcoholic liver disease(ALD).Recent studies on comprehensive analyses of microbiome compositional and functional changes have begun to uncover the mechanistic relation between microbiome and the pathogenesis of ALD.Importantly,targeting the microbiome has become a potential strategy for the prevention and treatment of ALD.In this review,we summarize the clinical evidence of microbiome dysbiosis in ALD patients,and experimental advances in microbiome and metabolomic functional changes in animals with different species and genetic backgrounds in ALD.We also summarize the studies in humanized intestinal microbiome and fecal microbiota transplantation in mice.We introduce new developments in the studies on the role of the circulating bacterial microbiome,oral bacterial microbiome and fungal microbiome in the development of ALD.We highlight the potential mechanisms by which microbiome dysbiosis contributes to ALD,including short chain fatty acid changes,bile acid metabolism,intestinal barrier function,release of bacterial and fungal products,and inflammation.In addition,we summarize the recent developments targeting the microbiome in prevention and treatment of ALD,including dietary nutrient interference,herbal medicine,antibiotics,anti-fungal agents,probiotics,engineered bacterial therapy,fecal transplantation and oral hygiene.Although recent preclinical studies have advanced our understanding of the microbiome and ALD,clinical studies,especially prospective studies with large samples,are needed to better understand the cause-effect of microbiome dysbiosis in ALD.Identifying new precision-based strategies targeting the microbiome are expected to be developed as more effective therapies in ALD.©2019 The Third Affiliated Hospital of Sun Yat-sen University.Publishing Services by Elsevier B.V.on behalf of KeAi Communications Co.,Ltd.This is an open access article under the CC BY-NC-ND license.

关键词： Microbiome dysbiosis Alcoholic liver disease(ALD)

Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis

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World Journal of Gastroenterology 2023年第6期29卷 967-996页

作者： Ryutaro Kuraji Takahiko Shiba Tien S Dong Yukihiro Numabe Yvonne L Kapila Department of Periodontology The Nippon Dental University School of Life Dentistry at TokyoTokyo 102-0071Japan Department of Orofacial Sciences University of California San FranciscoSan FranciscoCA 94143United States Department of Oral Medicine Infectionand ImmunityHarvard School of Dental MedicineBostonMA 02115United States Department of Periodontology Tokyo Medical and Dental UniversityTokyo 113-8549Japan The Vatche and Tamar Manoukian Division of Digestive Diseases University of California Los AngelesDepartment of MedicineUniversity of California David Geffen School of MedicineLos AngelesCA 90095United States Department of Periodontology The Nippon Dental University School of Life Dentistry at TokyoTokyo 102-8159Japan Sections of Biosystems and Function and Periodontics Professor and Associate Dean of ResearchFelix and Mildred Yip Endowed Chair in DentistryUniversity of California Los AngelesLos AngelesCA 90095United States

A growing body of evidence from multiple areas proposes that periodontal disease,accompanied by oral inflammation and pathological changes in the microbiome,induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease(NAFLD).A subgroup of NAFLD patients have a severely progressive form,namely nonalcoholic steatohepatitis(NASH),which is characterized by histological findings that include inflammatory cell infiltration and fibrosis.NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma.The oral microbiota may serve as an endogenous reservoir for gut microbiota,and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis.Gut dysbiosis increases the production of potential hepatotoxins,including lipopolysaccharide,ethanol,and other volatile organic compounds such as acetone,phenol and cyclopentane.Moreover,gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall,leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation.In particular,many animal studies support that oral administration of Porphyromonas gingivalis,a typical periodontopathic bacterium,induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis.NAFLD,also known as the hepatic phenotype of metabolic syndrome,is strongly associated with metabolic complications,such as obesity and diabetes.Periodontal disease also has a bidirectional relationship with metabolic syndrome,and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively.In this review,we will describe the link between periodontal disease and NAFLD with a focus on basic,epidemiological,and clinical studies,and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome.In conclusion,it is presumed that the pathogenesis of N

关键词： Periodontal disease Nonalcoholic fatty liver disease Microbiota dysbiosis Metabolic syndrome Probiotics

Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice

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World Journal of Gastroenterology 2022年第17期28卷 1814-1829页

作者： Flavia Maria Silva-Veiga Carolline Santos Miranda Isabela Macedo Lopes Vasques-Monteiro Henrique Souza-Tavares Fabiane Ferreira Martins Julio Beltrame Daleprane Vanessa Souza-Mello Department of Anatomy Institute of BiologyState University of Rio de JaneiroLaboratory of MorphometryMetabolism and Cardiovascular DiseasesRio de Janeiro 20551-030Brazil Department of Clinical and Toxicology Analysis State University of Rio de JaneiroNutrition InstituteState University of Rio de JaneiroNutrition InstituteUniversity of Sao PauloRio de Janeiro 20551-030Brazil

BACKGROUND Obesity and comorbidities onset encompass gut dysbiosis,altered intestinal permeability,and endotoxemia.Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease(NAFLD)management.Peroxisome proliferator-activated receptor(PPAR)-alpha activation and dipeptidyl-peptidase-4(DPP-4)inhibition alleviate NAFLD,but the mechanism may involve gut microbiota modulation and merits further investigation.AIM To address the effects of PPAR-alpha activation and DPP-4 inhibition(isolated or combined)upon the gut-liver axis,emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice.METHODS Male C57BL/6J mice were fed a control diet(C,10%of energy as lipids)or a highfat diet(HFD,50%of energy as lipids)for 12 wk,when treatments started,forming the groups:C,HF,HFA(HFD+PPAR-alpha agonist WY14643,2.5 mg/kg body mass),HFL(HFD+DPP-4 inhibitor linagliptin,15 mg/kg body mass),and HFC(HFD+the combination of WY14643 and linagliptin).RESULTS The HFD was obesogenic compared to the C diet.All treatments elicited significant body mass loss,and the HFC group showed similar body mass to the C group.All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations.These metabolic benefits restored Bacteroidetes/Firmicutes ratio,resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups.At the gene level,treated groups showed higher intestinal Mucin 2,Occludin,and Zo-1 expression than the HFD group.The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals.These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol,reassuring the role of the proposed treatments on NAFLD mitigation.CONCLUSION PPAR alpha activation and DPP-4 inhibition(isolated or combined)tackled NAFLD in dietinduced obese mice by restoration of gut-liver axis.The reestablishment of the intestinal barrier a

关键词： Nonalcoholic fatty liver disease High-fat diet Peroxisome proliferator-activated receptor-alpha Dipeptidyl-peptidase-4-inhibitor dysbiosis Inflammation

“Role of exercise in preventing and restoring gut dysbiosis in patients with inflammatory bowel disease”:A letter to the editor

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World Journal of Gastroenterology 2022年第8期28卷 878-880页

作者： Neasa Mc Gettigan Aoibhlinn O'Toole Karen Boland Department of Gastroenterology Beaumont HospitalDublin D09V2N0LeinsterIreland School of Medicine Royal College of SurgeonsDublin D02YN77Ireland

Exercise-induced changes of the microbiome in inflammatory bowel diseases(IBD)is a promising field of research with the potential for personalized exercise regimes as a promising therapeutic adjunct for restoring gut dysbiosis and additionally for regulating immunometabolic pathways in the management of IBD patients.Structured exercise programmes in IBD patients of at least of 12 wk duration are more likely to result in disease-altering changes in the gut microbiome and to harness potential anti-inflammatory effects through these changes along with immunometabolic pathways.

关键词： Inflammatory bowel diseases Microbiota dysbiosis Metabolism Exercise Cytokines

Gut dysbiosis and small intestinal bacterial overgrowth as independent forms of gut microbiota disorders in cirrhosis

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World Journal of Gastroenterology 2022年第10期28卷 1067-1077页

作者： Roman Maslennikov Vladimir Ivashkin Irina Efremova Elena Poluektova Anna Kudryavtseva George Krasnov Department of Internal Medicine Gastroenterology and HepatologySechenov UniversityMoscow 119435Russia Scientific Community for Human Microbiome Research Moscow 119435Russia Department of Internal Medicine 1 Сonsultative and Diagnostic Center 2 of the Moscow City Health DepartmentMoscow 107564Russia Laboratory of Postgenomic Research Engelhardt Institute of Molecular BiologyRussian Academy of SciencesMoscow 119991Russia

BACKGROUND Gut dysbiosis and small intestinal bacterial overgrowth(SIBO)are commonly observed in patients with cirrhosis.Despite the substantial number of articles describing the relations between disorders of gut microbiota and various manifestations of cirrhosis,dysbiosis and SIBO were always studied separately.AIM To study the relationship of gut dysbiosis and SIBO in cirrhosis.METHODS This observational study included 47 in-patients with cirrhosis.Stool microbiome was assessed using 16 S r RNA gene sequencing.SIBO was assessed using the lactulose hydrogen breath test.RESULTS SIBO was found in 24/47(51.1%)patients.Patients with SIBO had a higher abundance of Firmicutes(P=0.017)and Fusobacteria(P=0.011),and a lower abundance of Bacteroidetes(P=0.013)than patients without SIBO.This increase in the abundance of Firmicutes occurred mainly due to an increase in the abundance of bacteria from the genus Blautia(P=0.020)of the Lachnospiraceae family(P=0.047),while the abundance of other major families of this phylum[Ruminococcaceae(P=0.856),Peptostreptococcaceae(P=0.066),Clostridiaceae(P=0.463),Eubacteriaceae(P=0.463),Lactobacillaceae(P=0.413),and Veillonellaceae(P=0.632)]did not differ significantly between the patients with and without SIBO.Reduced level of Bacteroidetes in samples from patients with SIBO was a result of the decrease in bacterial numbers from all the major families of this phylum[Bacteroidaceae(P=0.014),Porphyromonadaceae(P=0.002),and Rikenellaceae(P=0.047)],with the exception of Prevotellaceae(P=0.941).There were no significant differences in the abundance of taxa that were the main biomarkers of cirrhosis-associated gut dysbiosis[Proteobacteria(P=0.790),Bacilli(P=0.573),Enterobacteriaceae(P=0.632),Streptococcaceae(P=0.170),Staphylococcaceae(P=0.450),and Enterococcaceae(P=0.873)]between patients with and without SIBO.CONCLUSION Despite the differences observed in the gut microbiome between patients with and without SIBO,gut dysbiosis and SIBO are most likely independent disorders of gut microbiota

关键词： dysbiosis Gut-liver axis Microbiome Small intestinal bacterial overgrowth Cirrhosis Microbiota

Gut dysbiosis and body composition in cirrhosis

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World Journal of Hepatology 2022年第6期14卷 1210-1225页

作者： Roman Maslennikov Vladimir Ivashkin Aliya Alieva Elena Poluektova Anna Kudryavtseva George Krasnov Maria Zharkova Yuri Zharikov Department of Internal Medicine Gastroenterology and HepatologySechenov UniversityMoscow 119435Russia Scientific Community for Human Microbiome Research Moscow 119435Russia Department of Internal Medicine Сonsultative and Diagnostic Center No.2Moscow City Health DepartmentMoscow 107564Russia Center for Precision Genome Editing and Genetic Technologies for Biomedicine Engelhardt Institute of Molecular BiologyRussian Academy of Sciences119991 MoscowRussia Laboratory of Postgenomic Research Engelhardt Institute of Molecular BiologyRussian Academy of Sciences119991 MoscowRussia Department of Anatomy Sechenov UniversityMoscow 119435Russia

BACKGROUND Gut dysbiosis and changes in body composition(i.e.,a decrease in the proportion of muscle mass and an increase in extracellular fluid)are common in cirrhosis.AIM To study the relationship between the gut microbiota and body composition in cirrhosis.METHODS This observational study included 46 patients with cirrhosis.Stool microbiome was assessed using 16S rRNA gene sequencing.Multifrequency bioelectrical impedance analysis was performed to assess body composition in these patients.RESULTS An increase in fat mass and a decrease in body cell mass were noted in 23/46(50.0%)and 15/46(32.6%)patients,respectively.Changes in the gut microbiome were not independently associated with the fat mass percentage in cirrhosis.The abundance of Bacteroidaceae(P=0.041)and Eggerthella(P=0.001)increased,whereas that of Erysipelatoclostridiaceae(P=0.006),Catenibacterium(P=0.021),Coprococcus(P=0.033),Desulfovibrio(P=0.043),Intestinimonas(P=0.028),and Senegalimassilia(P=0.015)decreased in the gut microbiome of patients with body cell mass deficiency.The amount of extracellular fluid increased in 22/46(47.6%)patients.Proteobacteria abundance(P<0.001)increased,whereas Firmicutes(P=0.023),Actinobacteria(P=0.026),Bacilli(P=0.008),Anaerovoraceceae(P=0.027),Christensenellaceae(P=0.038),Eggerthellaceae(P=0.047),Erysipelatoclostridiaceae(P=0.015),Erysipelotrichaceae(P=0.003),Oscillospiraceae(P=0.024),Rikenellaceae(P=0.002),Collinsella(P=0.030),Hungatella(P=0.040),Peptococcaceae(P=0.023),Slackia(P=0.008),and Senegalimassilia(P=0.024)abundance decreased in these patients.Patients with clinically significant ascites(n=9)had a higher abundance of Proteobacteria(P=0.031)and a lower abundance of Actinobacteria(P=0.019)and Bacteroidetes(P=0.046)than patients without clinically significant ascites(n=37).CONCLUSION Changes in the amount of body cell mass and extracellular fluid are associated with changes in the gut microbiome in cirrhosis patients.

关键词： dysbiosis Microbiome Microbiota Gut-Liver axis Sarcopenia Malnutrition Cirrhosis