Role of liraglutide on cardiotoxicity and gut microbiota changes induced by doxorubicin in rats

Abstract Background Cancer is one of the main causes of morbidity and mortality worldwide. Despite doxorubicin (DOX) being an effective chemotherapy drug, DOX-induced cardiotoxicity is the most severe side effect, limiting its use. There is no effective treatment for preventing DOX-induced cardiotoxicity. Gut microbiota seems to have a role in cardiovascular disease. Glucagon like peptide-1 (GLP-1) analogs such as liraglutide have shown benefits in cardiovascular diseases and seem to affect gut microbiota. Purpose To evaluate the role of liraglutide in modulating acute DOX-induced cardiotoxicity and gut microbiota. Methods Sixty male Wistar rats were allocated into four groups: Control (C), DOX (D), Liraglutide (L), and DOX + Liraglutide (DL). Animals in L and DL groups received a subcutaneous injection of 0.6 mg/kg liraglutide daily for 2 weeks. After 12 days, D and DL groups received an intraperitoneal injection of DOX (20 mg/kg). Rats were subjected to echocardiogram and isolated heart functional study 48 hours after DOX injection. At the end of the experiment, feces were collected to evaluate microbiota and short chain fatty acid concentration. Statistical analyses: Generalized linear model (GLM), ANCOVA and PERMANOVA (p<0.05). Results DOX-treated rats had worse cardiac function than rats that did not receive DOX in both echocardiography and isolated heart study; liraglutide did not change any functional parameters (Table). In feces, the phylum Bacteroidota was reduced in D and L groups compared to C and the phylum Pseudomonadota was increased in D and DL compared to C and L. Alpha-diversity did not differ between groups. Beta-diversity differed between C, D and L groups, and was similar between D and DL (Figure). Feces short chain fatty acid concentration was reduced in DOX-treated rats, with no effect from liraglutide (Figure). Conclusion DOX altered the function and composition of gut microbiota and caused acute cardiotoxicity; liraglutide changed gut microbiota and did not improve cardiac function.Table.Left ventricular functional dataFigure.Microbiota