Abstract
The use/misuse of antibiotics leads to pathological features referring to antibiotic-induced intestinal injury (AIJ), a clinical issue that plays a prominent role in the development of severe digestive disturbances. AIJ is characterized by loss of intestinal architecture and function, dysbiosis and bacterial translocation into the liver, triggering hepatic inflammation. This study aimed at determining the beneficial effect of N-(1-carbamoyl-2-phenylethyl) butyramide (FBA), a butyrate releasing compound, in ceftriaxone-induced intestinal injury. To this purpose, mice receiving ceftriaxone (8 g∙kg−1/die, per os) for five days, were treated with FBA (212,5 mg∙kg−1/die, per os) for five or fifteen days. FBA modulated key players of innate immunity in antibiotic-injured gut tissues, reducing inflammatory process and improving the anti-inflammatory and resolving pattern. FBA also improved colonic architecture and intestinal integrity. Interestingly, we also observed a remodeling of gut microbiota composition related to an increase of metabolic pathways related to lactate and butyrate production. At mechanistic level, FBA induced histone acetylation and increased the expression of GPR43 and monocarboxylate transporter 1 in colon. Our data clearly demonstrated that FBA has multiple converging mechanisms in limiting intestinal and hepatic alterations to counteract AIJ.
Highlights
Antibiotics are one of the most used drug classes to manage infectious disorders
We demonstrated the efficacy of FBA, a butyrate-releasing compound, in limiting intestinal injury induced by oral administration of ceftriaxone and its capability in remodeling gut microbiota
We provide a comprehensive picture of gut perturbations in terms of serum and colon inflammation, liver alteration and microbial dysbiosis and the modulating effect of FBA on all these pathological features consistently associated to antibiotic exposure
Summary
The discovery of antibiotics represents the breakthrough in medicine history, over the years, the medical overuse of broad spectrum agents has dramatically increased[1,2] as well as the exposure to low levels of antibiotics contained in food and water[3] These drugs can induce several gastrointestinal (GI) adverse events, commonly ascribed to their ability of altering gut microbiota composition and diversity, the so-called dysbiosis. We studied its capability in reducing gut inflammation, analyzing colonic cytokines, proteins involved in epithelium repair and integrity, colon responsiveness thorough TLRs expression, and liver innate response and in modulating gut microbiota composition, trying to obtain an overall picture on the early and late phases of antibiotic-induced injury and their pharmacological control by FBA. We tried to shed light on the mechanisms underlying FBA treatment, addressing the expression of proteins related to butyrate effects
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