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.

Keywords: gastrin; gut barrier; infection; metabolomics; microbiome; proton pump inhibitor.

Copyright © 2014 the American Physiological Society.

Figures

Fig. 1.

Urinary NMR metabolic profiling. Principal component analysis of urinary NMR data sets postomeprazole from controls (gray circles) and cirrhotic patients (black circles) showing clear separation of the groups.

Fig. 2.

Principal component analysis of microbiota before and after omeprazole. Light gray squares, microbiota at baseline; dark gray squares, postomeprazole microbiota. A: significant clustering before omeprazole that changed after omeprazole. B: no clustering before or after omeprazole therapy.

Fig. 3.

Correlation network differences before and after omeprazole. Node colors: light gray, bacterial families; dark gray, unnamed urinary metabolites; white, named urinary metabolites. Edge colors: black dashed, was positive and became negative; black solid, was negative became positive; gray, remained negative but significant change. A: correlation network difference in cirrhotic patients. B: correlation network difference in controls.