This study aimed to evaluate the influence of the intestinal microbiota of rats treated with liraglutide (GLP-1 analogue) in order to prevent cardiotoxicity induced by doxorubicin.
Doxorubicin is an effective drug to treat several types of malignancies. However, it can cause toxicity in the gastrointestinal tract, limiting treatment and worsening quality of life. The pathophysiology is multifactorial and result from direct damage to enterocytes  and gut microbiota dysbiosis. Glucagon-like peptide type 1 (GLP-1) analogs appear to improve the depth of intestinal crypts, enhance cellular junctions, stimulate mucus production, and modify the gut microbiota. The objective of this study was to evaluate the effects of liraglutide, a GLP-1 analog, in acute doxorubicin-induced gut toxicity in rats. Sixty male Wistar rats were allocated into 4 groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received a subcutaneous injection of 0.6 mg/kg liraglutide daily, while C and D received saline for 2 weeks. Afterward, D and DL received a single intraperitoneal injection of 20 mg/kg doxorubicin. Feces were collected before and after treatment to analyze the microbiota and quantify short-chain fatty acids. After 48 h, the rats were euthanized, large intestine and blood samples were collected and stored at -80 °C. Doxorubicin caused structural loss of intestinal crypts, goblet cell reduction, and apoptosis. a-diversity did not change between the two study periods, but the ß-diversity differed between C, L, and D groups after the treatment. The abundance of the Bacteroidetes phylum was lower in groups D and L than in group C, while the Proteobacteria phylum was more abundant in the rats treated with doxorubicin. There was an increase in the Arcanobacterium and Clavibacter genera in group D, in Corynebacterium and Actinobaculum in L compared to C, and an increase in Arcanobacterium in DL compared to L. Acetic, propionic, and butyric acid 22 concentrations were lower in the animals treated with doxorubicin. Expression of tumor necrosis factor-a, nuclear transcription factor-?B, B-cell lymphoma 2 and toll-like receptor 4 and activity of antioxidant enzymes did not differ between the groups. In conclusion, acute doxorubicin toxicity causes significant structural damage to the large intestine, microbiota dysfunction, and a reduction in fecal short-chain fatty acids. Liraglutide pretreatment does modify the gut microbiota, but without attenuating doxorubicin-induced intestine toxicity.