Microbiome Profile and Molecular Pathways Alterations in Gastrointestinal Tract by Hydrogen Sulfide-Releasing Nonsteroidal Anti-Inflammatory Drug (ATB-352): Insight into Possible Safer Polypharmacy
Urszula Głowacka, Katarzyna Magierowska, Dagmara Wójcik, Jerzy Hankus, Małgorzata Szetela, Jakub Cieszkowski, Edyta Korbut, Aleksandra Danielak, Marcin Surmiak, Anna Chmura, John L. Wallace, Marcin Magierowski
Abstract
Aims: Nonsteroidal anti-inflammatory drugs, including ketoprofen, induce adverse effects within the gastrointestinal (GI)-tract. Hydrogen sulfide (H 2 S) is an antioxidative gaseous mediator contributing to GI-protection. We aimed to evaluate the GI safety of a novel H 2 S-releasing derivative of ketoprofen (ATB-352) versus classic ketoprofen and the molecular mechanisms of their activity after chronic treatment in experimental animal models. Results: Ketoprofen (10 mg/kg/day) administered intragastrically for 7 days in contrast with ATB-352 (14 mg/kg/day) reduced mucosal H 2 S content inducing GI damage with significantly increased injury score, altered intestinal microbiome profile, and modulation of more than 50% of 36 investigated molecular sensors ( e.g ., mammalian target of rapamycin or suppressor of cytokine signaling 3 [SOCS3]). Polypharmacy with aspirin (10 mg/kg/day) enhanced ketoprofen toxicity not affecting GI safety of ATB-352. Omeprazole (20 mg/kg/day) decreased ketoprofen-induced injury to the level of ATB-352 alone. Both compounds combined or not with aspirin or omeprazole maintained the ability to inhibit cyclooxygenase (COX) activity manifested by decreased prostaglandin production. Innovation and Conclusions: Ketoprofen-induced H 2 S-production decrease and intestinal microbiome profile alterations lead to GI toxicity observed on macro-/microscopic and molecular levels. Ketoprofen but not ATB-352 requires concomitant treatment with omeprazole to eliminate GI adverse effects. ATB-352 applied alone or in a polypharmacy setting with aspirin effectively inhibited COX and maintained GI safety due to H 2 S-release. Neither compound affected DNA oxidation in the GI mucosa, but ATB-352 had lower impact on molecular oxidative/inflammatory response pathways and intestinal microbiome. The GI safety of ATB-352 could be due to the involvement of heme oxygenase 1 and SOCS3 pathway activation. Antioxid. Redox Signal . 36, 189–210.