Manipulating Mi Ma Microbiota in The Hong Kong Association for the - PowerPoint PPT Presentation

The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases Manipulating Mi Ma Microbiota in The Hong Kong Association for the Study of Liver Diseases Liver Dise Li sease The Hong Kong Association for the Study of Liver Diseases Jasmohan S Bajaj, MD The Hong Kong Association for the Study of Liver Diseases Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases

The Hong Kong Association for the Study of Liver Diseases Outline and Out and Que uestions to be be as asked The Hong Kong Association for the Study of Liver Diseases • Why is it relevant to study microbial change in liver disease? The Hong Kong Association for the Study of Liver Diseases • What is lacking in the current microbial therapies for liver disease? The Hong Kong Association for the Study of Liver Diseases • What are the levels of therapy in reducing the severity of liver disease? The Hong Kong Association for the Study of Liver Diseases • Is microbial therapy going to be enough? The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases

The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases Mi Microbial Analysis and Outputs The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases

The Hong Kong Association for the Study of Liver Diseases Phylogenetic Tree of Life: Microbes, Fungi and Humans The Hong Kong Association for the Study of Liver Diseases • Proteobacteria The Hong Kong Association for the Study of Liver Diseases • Gammaproteobacteria Fungi Animals The Hong Kong Association for the Study of Liver Diseases • Enterobacteriales • Enterobacteriaceae The Hong Kong Association for the Study of Liver Diseases • Escherichia The Hong Kong Association for the Study of Liver Diseases • Escherichia coli The Hong Kong Association for the Study of Liver Diseases

The Hong Kong Association for the Study of Liver Diseases Products of bacterial metabolism The Hong Kong Association for the Study of Liver Diseases • Carbohydrates : Short chain fatty acids The Hong Kong Association for the Study of Liver Diseases • Phytochemicals: Phenolic acids • Protein: Phenolic acids, Ammonia, Polyamides The Hong Kong Association for the Study of Liver Diseases • Fat: Bile acids with taurine and secondary bile acids • Xenobiotics: Carcinogens The Hong Kong Association for the Study of Liver Diseases • Alcohol: Acetaldehyde The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases

The Hong Kong Association for the Study of Liver Diseases Mi Microbial Outputs The Hong Kong Association for the Study of Liver Diseases • Type of bacteria The Hong Kong Association for the Study of Liver Diseases • Presence/absence • Richness: count of individual bacterial types The Hong Kong Association for the Study of Liver Diseases • Diversity: count of individual types and their The Hong Kong Association for the Study of Liver Diseases abundance • Relative abundance: percent present compared to the The Hong Kong Association for the Study of Liver Diseases total abundance The Hong Kong Association for the Study of Liver Diseases

The Hong Kong Association for the Study of Liver Diseases Levels of study in microbiome research The Hong Kong Association for the Study of Liver Diseases • Which microbes are present in the GI tract? (culture-dependent or independent techniques) • Stool The Hong Kong Association for the Study of Liver Diseases • GI tract mucosa • In peripheral systems • What are GI tract microbes doing? (metatranscriptomics, metaproteomics, The Hong Kong Association for the Study of Liver Diseases metabonomics/metabolomics). • What microbial genes are present in the GI tract? (metagenomics) The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases Ultimately, the relationship with host state and outcomes is essential The Hong Kong Association for the Study of Liver Diseases

The Hong Kong Association for the Study of Liver Diseases Relevance of f microbial change in liver disease Alcohol with/without Cirrhosis The Hong Kong Association for the Study of Liver Diseases • Liver diseases, especially alcohol and NAFLD, initiate microbial change independent of liver injury The Hong Kong Association for the Study of Liver Diseases • This microbial change could worsen the liver injury phenotype The Hong Kong Association for the Study of Liver Diseases • Cirrhosis of the liver, the end-stage of fibrosis, can affect the microbiota NAFLD with/without Cirrhosis The Hong Kong Association for the Study of Liver Diseases • Microbial change, including bacterial translocation, is associated with systemic and intestinal inflammation The Hong Kong Association for the Study of Liver Diseases Mutlu et al AJP 2012, Hartmann et al Hepatol 2015, Boursier et al Hepatol 2017, Bajaj et Nature 2015 The Hong Kong Association for the Study of Liver Diseases Chen et al Hepatol 2011, Bajaj et al J Hepatol 2014

The Hong Kong Association for the Study of Liver Diseases Bio iosensors: Keystone and In Indic icator organis isms Keystone organisms: that has a The Hong Kong Association for the Study of Liver Diseases disproportionately large effect on its environment relative to its abundance The Hong Kong Association for the Study of Liver Diseases Adequate presence=Good health of the overall ecosystem The Hong Kong Association for the Study of Liver Diseases Indicator organisms : that defines a trait of the environment which are also The Hong Kong Association for the Study of Liver Diseases known as sentinel organisms, i.e. organisms which are ideal for biomonitoring The Hong Kong Association for the Study of Liver Diseases E.g. Coliforms to monitor water quality Ideal Biosensor: Combination of Keystone and Indicator Organisms The Hong Kong Association for the Study of Liver Diseases

The Hong Kong Association for the Study of Liver Diseases The Cirr Th irrhosis is Dysbio iosis is Ratio io Paralle llels ls Cirr irrhosis is Se Severit ity The Hong Kong Association for the Study of Liver Diseases 2.5 2.05 P<0.0001 2 The Hong Kong Association for the Study of Liver Diseases 1.5 0.89 The Hong Kong Association for the Study of Liver Diseases 1 0.66 0.32 0.5 The Hong Kong Association for the Study of Liver Diseases 0 Healthy Controls Compensated Decompensated Infected outpts outpts inpatients The Hong Kong Association for the Study of Liver Diseases Cirrhosis Dysbiosis ratio was also stable over time, worsened with the development of the first episode of hepatic encephalopathy and was worse in those who were subsequently The Hong Kong Association for the Study of Liver Diseases hospitalized Bajaj JS et al J Hepatol 2014, Bajaj JS Sci Rep 2015

The Hong Kong Association for the Study of Liver Diseases Mic icrobial change is is li linked to outcomes in in cir irrhosis Death in Cirrhotic Inpatients • Microbial change can predict inpatient and The Hong Kong Association for the Study of Liver Diseases outpatient outcomes in cirrhotic patients • Microbiota are associated with an altered gut- liver-brain axis resulting in Hepatic The Hong Kong Association for the Study of Liver Diseases encephalopathy (HE) Cognitive function and brain inflammation and edema are related to microbes in cirrhosis= HE The Hong Kong Association for the Study of Liver Diseases Hospitalizations in Outpatients The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases Bajaj et AJP 2011/2013, Chen et al J Gastro Hepatol 2015, Bajaj et al J Hepatol 2014, Bajaj et al Hepatol 2015, Ahluwalia et al Sci Rep 2016

The Hong Kong Association for the Study of Liver Diseases Pathophysiology of HE The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases Bajaj JS Hepatology 2015, Dasarathy et al J Hepatol 2016

The Hong Kong Association for the Study of Liver Diseases Gut micr icrobio iota are re necessary fo for r bra rain in inf infla lammatio ion (micr icrogli lial l and glia lial) l) in in cirrh irrhotic ic mice ice The Hong Kong Association for the Study of Liver Diseases Cerebellum Cortex The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases The Hong Kong Association for the Study of Liver Diseases 4 mouse groups: GF, GF made cirrhotic using CCL4 gavage, Conventional control and Conventional mice made cirrhotic using The Hong Kong Association for the Study of Liver Diseases CCL4 gavage Kang, Bajaj et al Hepatology 2016