Morphine use induces gastric microbial dysbiosis driving gastric inflammation through TLR2 signalling which is attenuated by proton pump inhibition

Background and Purpose Opioids are the standard drug for pain management; however, their effects on gastric dysfunction are relatively understudied. Opioid users have a higher incidence of gastric pathology leading to increased hospitalization. Herein, we investigated the consequences of morphine use on gastric pathology and the underlying mechanisms. We further investigated the therapeutic benefit of proton pump inhibition to overcome morphine‐mediated gastric inflammation. Experimental Approach Mice were implanted with 25 mg slow‐release morphine and placebo pellets. Gastric microbiome analyses were performed. Gastric damage was assayed. Gastric pH was measured. Germ‐free and TLR2KO mice were used to investigate the mechanisms. Gastroprotective studies were performed with the proton pump inhibitor (PPI) omeprazole. Key Results Chronic morphine treatment alters gastric microbial composition and induces preferential expansion of pathogenic bacterial communities such as Streptococcus and Pseudomonas. Morphine causes disruption of the gastric mucosal layer, increases apoptosis, and elevates inflammatory cytokines. Moreover, morphine‐mediated gastric pathology was significantly attenuated in germ‐free mice, and reconstitution of morphine gastric microbiome in germ‐free mice resulted gastric inflammation. In addition, morphine‐mediated gastric inflammation was attenuated in TLR2KO mice. Morphine causes a decrease in gastric pH, which contributes to gastric dysbiosis leads to gastric inflammation. Omeprazole treatment inhibits gastric acidity, rescuing morphine‐induced gastric dysbiosis and preventing inflammation. Conclusion and Implications This study attributes morphine‐induced gastric acidity as a driver of gastric dysbiosis and pathology and proposes the therapeutic use of PPI as an inexpensive approach for the clinical management of morphine‐associated pathophysiology. Morphine treatment increases gastric acid secretion which causes dysbiosis of gastric microbiome. The dysbiotic gastric microbiome induces gastric inflammation through TLR2‐mediated signaling. Omeprazole prevents morphine‐induced gastric damage by regulating gastric acid secretion and restoring normal gastric microbiota.