Microbiome and liver diseases
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1 Klinik und Poliklinik für Innere Medizin I Microbiome and liver diseases Bernd Schnabl, M.D. Department of Medicine I have no financial relationship relevant to my presentation AND my presentation does not include discussion of off-label or investigational use.
2 Overview 1. Microbiome and NAFLD/NASH 2. Microbiome and alcoholic liver disease
3 Metabolic changes linked to non-alcoholic fatty liver disease Non-alcoholic fatty liver disease is a multifactorial disease including various genetic, metabolic and environmental factors. Among the environmental factors, diet is the most important. It s role is more complex than one of simply inducing fat accumulation in the liver and involves interactions with the microbiota.
4 Obesity alters gut microbial ecology in humans Obese humans (n=12) on diet: Ley, Nature 2006
5 How does the microbiota influence non-alcoholic fatty liver disease? Enhanced extraction of calories from intestinal contents. Buck, PNAS 2006 Turnbaugh, Nature 2006 Tremaroli, Nature 2012
6 Microbiome in pediatric obese and NASH patients Zhu, Hepatology 2013
7 Microbiome in pediatric obese and NASH patients Zhu, Hepatology 2013
8 SIBO and intestinal permeability in non-alcoholic fatty liver disease Miele, Hepatology 2009
9 How does the microbiota influence non-alcoholic steatohepatitis? Microbial regulation of intestinal permeability and inflammation Henao-Mejia, Nature 2012 Tremaroli, Nature 2012
10 Choline deficiency results in hepatic steatohepatitis Miura,Schnabl,Seki Gastroenterology 2010
11 Gut microbiota reduces choline availability Choline TMA TMA TMAO Heart disease High-fat foods Gut NASH Blood vessel Dumas, PNAS 2006 Wang, Nature 2011 Tang, NEJM 2013 Adapted from Rak, Nature 2011
12 How does the microbiota influence NAFLD/NASH? Schnabl, Gastroenterology 2014
13 Overview 1. Microbiome and NAFLD/NASH 2. Microbiome and alcoholic liver disease
14 Bacterial translocation in patients with alcoholic liver disease PEG 4000 Endotoxin % of ingested amount pg/ml Controls ALD1 ALD2 ALD3 0 Controls ALD1 ALD2 ALD3 Parlesak, J Hepatol 2000
15 Intestinal bacterial overgrowth in patients with alcoholic liver disease p<0.025 p< Controls Alcoholics CFUs (log10) Anaerobics Aerobics Bode, Hepatogastroenterology 1984
16 Intestinal bacterial overgrowth in alcoholic liver disease CFUs/Segment Aerobic bacteria Control 3w Alcohol 3w Fold induction Total bacteria 10 6 Proximal Mid Small Intestine Distal Cecum Colon 0.0 Control Alcohol 3 weeks Yan, Schnabl, Hepatology 2011
17 Intestinal dysbiosis in alcoholic liver disease Taxa Verrucomicrobia Akkermansia TM7 Betaproteobacteria Proteobacteria Proteobacteria Erysipelotrichaceae Incertae Sedis Erysipelotrichaceae Ruminococcaceae Incertae Sedis Anaerotruncus Ruminococcaceae Lachnospiraceae Incertae Sedis Dorea Bryantella Lachnospiraceae Clostridiales Clostridia Firmicutes Lactococcus Leuconostoc Pediococcus Lactobacillus Lactobacillaceae Enterococcus Lactobacillales Bacilli Firmicutes Alistipes Rikenellaceae Porphyromonadaceae Bacteroidetes Bacteroides Bacteroidales Bacteroidetes Eggerthella Actinobacteria Coriobacteriaceae Actinobacteria Bacteria OTUs [% of total] Alcohol 3 weeks Control 3 weeks % Bacteria 80% 60% 40% 20% 0% Control 3 weeks Alcohol 3 weeks Verrucomicrobia TM7 Proteobacteria Firmicutes Bacteroidetes Actinobacteria Yan, Schnabl, Hepatology 2011
18 Fecal Lactobacillus in patients with liver cirrhosis Cirrhotics Healthy Lactobacillus fermentum Lactobacillus salivarius Lactobacillus reuteri Lactobacillus plantarum Lactobacillus rhamnosus Lactobacillus paracasei Lactobacillus crispatus Lactobacillus gasseri Lactobacillus acidophilus Copy numbers/g feces Chen Y, Microbial Ecology 2011 Chen Y, Hepatology 2011
19 Lactobacillus GG treatment ameliorates alcoholic steatohepatitis in rats Forsyth CB, Alcohol 2009
![[IU/L] Hepatic](/docs-images/72/67298440/images/20-3.jpg "Triglyceride [mg/g")
![liver] 120 80 40 0 25](/docs-images/72/67298440/images/20-4.jpg "20 15 10 5 0 Control")
20 Alcoholic liver disease is prevented in mice treated with non-absorbable antibiotics EtOH + ABX EtOH Control ALT [IU/L] Hepatic Triglyceride [mg/g liver] Control EtOH EtOH + ABX Control EtOH EtOH + ABX Chen, Schnabl, Hepatology 2014
21 The enteric metagenome following chronic ethanol administration Unchanged Down in alcohol Up in alcohol
22 Chronic ethanol administration reduces bacterial biosynthesis of saturated fatty acids in mice Acetyl - CoA FabD, FabH Acetyl - [ACP]; Malonyl - [ACP] FabF 3 - oxo --- decanoyl - [ACP] FabG (R) Hydroxy --- decanoyl - [ACP] Fold Change fabf Genomic DNA fabf Genomic DNA 1.5 Fold Change fabg Genomic DNA Fold Change fabg Genomic DNA 1.5 fabd Genomic DNA Non-Alcoholics Alcoholics Control EtOH Fas, FabL Saturated fatty acid Fold Change Fold Change
23 The enteric metabolome following chronic ethanol administration Z value SCFA MCFA LCFA C2:0 C3:0 C4:0 C5:0 Iso C5:0 C6:0 C7:0 C8:0 C9:0 C10:0 C11:0 C12:0 C13:0 C14:0 C15:0 C16:0 C17:0 C18:0 0 High [nmol/mg] Control EtOH Short Chain Medium Chain Long Chain [nmol/mg] 20 C13:0 C14:0 C15:0 15 C16:0 C17:0 10 C18:0 5 0 Control EtOH
![EtOH 300 200 100 0 USF SF Hepatic Triglyceride [mg/g liver] 30 Control](/docs-images/72/67298440/images/24-1.jpg "EtOH 20 10 0 USF SF Hepatic TBARS [µm/g liver] 0.4 Control EtOH 0.3 0.2 0.")
24 Supplementation of saturated long-chain fatty acids reduces alcoholic liver disease in mice Alcohol + USF Alcohol + SF ALT [U/L] 400 Control EtOH USF SF Hepatic Triglyceride [mg/g liver] 30 Control EtOH USF SF Hepatic TBARS [µm/g liver] 0.4 Control EtOH USF SF
25 Supplementation of diet with saturated fatty acids prevents alcohol-induced dysbiosis Fold Change 4 Control EtOH Fold Change Control EtOH 0 USF SF Intestinal bacteria 0.0 USF SF Lactobacillus Peng, Schnabl, Gastroenterology 2014
26 Host microbiome interactions in alcoholic liver disease Adapted from Schnabl, Gastroenterology 2014
27 Acknowledgments Schnabl Lab Peng Chen Lirui Wang Cristina Llorente Phillipp Hartmann An-Ming Yan Maggie Mazagova Hui Wang Arthur Yan Collaborators David Brenner UCSD Justin Tan UCSD Mallory Embree UCSD Karsten Zengler USCD Rohit Loomba UCSD Samuel B. Ho UCSD Hide Tsukamoto USC Derrick Fouts JCVI Manolito Torralba JCVI Jessica DePew JCVI Karen Nelson JCVI Jasmohan Bajaj VCU Ece Mutlu Rush Univ Ali Keshavarzian Rush Univ
28 Funding NIDDK (K08) NIAAA (R01, U01) VA Merit ABMRF/The Foundation for Alcohol Research
29 Thank you
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