Liraglutide alters gut microbiota but fails to mitigate doxorubicin-induced gastrointestinal toxicity in rats

Doxorubicin, a potent chemotherapeutic, is limited by severe gastrointestinal toxicity, including mucositis, which significantly impairs patient quality of life and treatment adherence. Current supportive care often falls short in fully preventing or treating these side effects. Liraglutide, a GLP-1 analog, is known to influence gut physiology and has been hypothesized to exert protective effects through its modulation of the gut microbiome. This study investigated whether liraglutide's ability to reshape microbial profiles could offer a therapeutic strategy against acute doxorubicin-induced gut damage, addressing a critical unmet need in oncology supportive care.

Sixty male Wistar rats were divided into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). Groups L and DL received liraglutide 0.6 mg/kg s.c. daily for 14 days. Groups D and DL received a single doxorubicin 20 mg/kg i.p. injection. After 48 hours, distal colon tissue, fecal samples, and blood were collected. Primary endpoints included assessment of intestinal structural damage, goblet cell count, apoptosis, fecal short-chain fatty acids (SCFAs), and levels of inflammatory markers (TNF-α, NF-κB, TLR4), anti-apoptotic protein (Bcl-2), and antioxidant enzymes. Gut microbiota composition was analyzed using 16S rRNA gene sequencing.

Acute doxorubicin administration induced significant intestinal damage, characterized by crypt disruption, substantial goblet cell loss, and increased apoptosis. This was accompanied by a reduction in fecal short-chain fatty acids. Doxorubicin also significantly altered gut microbiota composition, reducing Bacteroidetes and increasing Proteobacteria, with notable increases in Arcanobacterium and Clavibacter genera. Liraglutide alone also modified the microbiota, decreasing Bacteroidetes and increasing Corynebacterium and Actinobaculum genera. However, despite these microbial shifts, liraglutide failed to protect against doxorubicin's toxic effects. Levels of inflammatory markers (TNF-α, NF-κB, TLR4), Bcl-2, and antioxidant enzymes remained unchanged across all groups, indicating no attenuation of inflammation or oxidative stress by liraglutide.

Combined liraglutide and doxorubicin treatment showed no significant effects on intestinal damage or inflammatory markers, indicating liraglutide did not attenuate acute doxorubicin-induced gut toxicity.