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.

Microbiota, cirrhosis, and the emerging oral-gut-liver axis

“…Qin et al 2014 (89) See Table 1. Implied that salivary bacteria invade the GI tract and can injure the liver Bajaj et al 2014 (90) See Table 1. PPI therapy increases salivary microbiota in stool, indicating that salivary microbiota in stool are related to suppression of gastric acid and likely an epiphenomenon Bajaj et al, 2015 (53) Reanalysis of Qin et al 2014 (89).…”

“…Omeprazole therapy, possibly through increased gastric and intestinal pH, led to a significant increase in the relative abundance of Streptococcaceae in stool from all controls (1% vs. 5%) and all patients with cirrhosis (0% vs. 9%). The elevated levels of Streptococcaceae, which are typically limited to the oral microbiome, in stool after omeprazole correlated with serum gastrin levels, which increased as the result of PPI use (90). While these results are intriguing, current evidence does not directly prove distal migration of oral bacteria to the gut in cirrhotic patients.…”

Acid suppression therapy and allergic reactions

“…Gastric acid reduction is known to change the intestinal micro bial composition [102]. On the one hand, PPIs substantially increase the number of bacteria in the oral cavity and the upper gastrointestinal tract due to lack of gastric acidity [103,104].…”

Bile acids in drug induced liver injury: Key players and surrogate markers

“…DCA, being a relatively cytotoxic BA, provoked DNA damage and cellular senescence in hepatic stellate cells, which consequently released inflammatory and tumor-promoting factors in the liver, facilitating hepatocellular carcinoma development in mice previously exposed to a chemical carcinogen [57]. Drugs that impair the intestinal microflora can therefore indirectly affect the liver by altering the BA profile and BA induced cellular effects [58,59].…”