title: Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function.
abstract: Proton pump inhibitors (PPI) have been associated with infectious complications in cirrhosis, but their impact on distal gut microbiota composition and function is unclear. We aimed to evaluate changes in stool microbiota composition and function in patients with cirrhosis and healthy controls after omeprazole therapy. Both 15 compensated cirrhotic patients and 15 age-matched controls underwent serum gastrin measurement, stool microbiota profiling with multitagged pyrosequencing, and urinary metabolic profiling with NMR spectroscopy to assess microbial cometabolites before/after a 14-day course of 40 mg/day omeprazole under constant diet conditions. Results before (pre) and after PPI were compared in both groups, compared with baseline by systems biology techniques. Adherence was >95% without changes in diet or MELD (model for end-stage liver disease) score during the study. Serum gastrin concentrations significantly increased after PPI in cirrhosis (pre 38.3 ± 35.8 vs. 115.6 ± 79.3 pg/ml P < 0.0001) and controls (pre 29.9 ± 14.5 vs. 116.0 ± 74.0 pg/ml, P = 0.001). A significant microbiota change was seen in both controls and cirrhosis after omeprazole (QIIME P < 0.0001). Relative Streptococcaceae abundance, normally abundant in saliva, significantly increased postomeprazole in controls (1 vs. 5%) and cirrhosis (0 vs. 9%) and was correlated with serum gastrin levels (r = 0.4, P = 0.005). We found significantly reduced hippurate in cirrhosis vs. controls both pre- and postomeprazole and increased lactate in both groups post vs. preomeprazole, whereas dimethylamine (DMA) decreased in cirrhosis only. On correlation network analysis, significant changes in linkages of bacteria with metabolites (hippurate/DMA/lactate) were found postomeprazole, compared with pre-PPI in cirrhosis patients. In conclusion, omeprazole is associated with a microbiota shift and functional change in the distal gut in patients with compensated cirrhosis that could set the stage for bacterial overgrowth.
authors.affiliation: Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center and Virginia Commonwealth University, Richmond, Virginia; jsbajaj@vcu.edu.
authors.forename: Jasmohan S
authors.initials: JS
authors.lastname: Bajaj
authors.affiliation: Institute of Hepatology London, Foundation for Liver Research, London, United Kingdom;
authors.forename: I Jane
authors.initials: IJ
authors.lastname: Cox
authors.affiliation: Microbiome Analysis Center, George Mason University, Manassas, Virginia;
authors.forename: Naga S
authors.initials: NS
authors.lastname: Betrapally
authors.affiliation: Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center and Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Heuman
authors.affiliation: Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center and Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Schubert
authors.affiliation: Department of Medicine, Imperial College London, London, United Kingdom; and.
authors.forename: Maiyuran
authors.initials: M
authors.lastname: Ratneswaran
authors.affiliation: Microbiology, McGuire VA Medical Center and Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.affiliation: Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center and Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Melanie B
authors.initials: MB
authors.lastname: White
authors.affiliation: Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center and Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Kalyani
authors.initials: K
authors.lastname: Daita
authors.affiliation: Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center and Virginia Commonwealth University, Richmond, Virginia;
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Noble
authors.affiliation: Microbiome Analysis Center, George Mason University, Manassas, Virginia;
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Sikaroodi
authors.affiliation: Institute of Hepatology London, Foundation for Liver Research, London, United Kingdom;
authors.forename: Roger
authors.initials: R
authors.lastname: Williams
authors.affiliation: Department of Medicine, Imperial College London, London, United Kingdom; and.
authors.forename: Mary M E
authors.initials: MM
authors.lastname: Crossey
authors.affiliation: Department of Medicine, Imperial College London, London, United Kingdom; and.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Taylor-Robinson
authors.affiliation: Microbiome Analysis Center, George Mason University, Manassas, Virginia;
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gillevet
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives / Q000652:urine; D015415:Biomarkers / Q000097:blood / Q000652:urine; D016022:Case-Control Studies; D005243:Feces / Q000382:microbiology; D005260:Female; D005755:Gastrins / Q000097:blood; D006626:Hippurates / Q000652:urine; D006801:Humans; D007422:Intestines / Q000187:drug effects* / Q000382:microbiology; D019344:Lactic Acid / Q000652:urine; D008103:Liver Cirrhosis / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000382:microbiology* / Q000652:urine; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics; D064307:Microbiota / Q000187:drug effects*; D008875:Middle Aged; D009853:Omeprazole / Q000009:adverse effects*; D054328:Proton Pump Inhibitors / Q000009:adverse effects*; D012307:Risk Factors; D049490:Systems Biology / Q000379:methods; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D005755:Gastrins; D006626:Hippurates; D054328:Proton Pump Inhibitors; C487735:dimethylarginine; D019344:Lactic Acid; D001120:Arginine; D009853:Omeprazole; C030514:hippuric acid
keywords: gastrin; gut barrier; infection; metabolomics; microbiome; proton pump inhibitor