Blautia luti reduces neratinib-induced diarrhea in a rat model.

Abstract

Purpose: Neratinib is a pan-human epidermal growth factor receptor (HER) tyrosine kinase inhibitor (TKI) used in the treatment of HER2+ breast cancer. Diarrhea is the most commonly reported toxicity, with the majority experiencing at least some grade of diarrhea. The mechanisms behind neratinib-induced diarrhea are yet to be fully defined, but have been linked to gut microbiome changes, specifically decreased levels of the genera Blautia. This study aimed to investigate the efficacy of Blautia luti (B.luti) administered as a daily probiotic on neratinib-induced diarrhea, and its effects on the gut microbiome in a well-established rat model.

Methods: Female albino Wistar (AW) rats (n = 40) were randomly allocated to groups including; vehicle control (VC), neratinib alone, B.luti alone and neratinib + B.luti in different schedules (Pre, Pre & Post or Post). Daily oral gavage administration of B.luti (10⁷CFU/ml) was given according to corresponding schedules, alongside a 28-day cycle of neratinib (50 mg/kg). Diarrhea was graded daily, and faecal samples collected for gut microbiome analysis at study end. Ileum and colon samples were collected for intestinal analysis. 16S rRNA gene sequencing was performed on faecal samples and H&E performed on intestinal tissue for injury evaluation.

Results: Grade 3 diarrhea was reduced in the Post group when compared to the neratinib alone group (p = 0.0122). No significant differences were seen in the tissue injury scores of the ileum or colon. There was no significant change in microbial composition with B.luti administration.

Conclusion: This study demonstrated that administration of B.luti supplementation, was effective in reducing neratinib-induced diarrhea severity when consumed concurrently. This administration schedule may have a protective role in the intestines through immunomodulation.