Lactobacillus gasseri prevents ibrutinib-associated atrial fibrillation through butyrate

Abstract

Ibrutinib, a widely used anti-cancer drug, is known to significantly increase the susceptibility to atrial fibrillation (AF). While it is recognized that drugs can reshape the gut microbiota, influencing both therapeutic effectiveness and adverse events, the role of gut microbiota in ibrutinib-induced AF remains largely unexplored. Utilizing 16S rRNA gene sequencing, fecal microbiota transplantation, metabonomics, electrophysiological examination, and molecular biology methodologies, we sought to validate the hypothesis that gut microbiota dysbiosis promotes ibrutinib-associated AF and to elucidate the underlying mechanisms. We found that ibrutinib administration predisposes rats to AF. Interestingly, ibrutinib-associated microbial transplantation conferred increased susceptibility to AF in rats. Notably, ibrutinib induced a significantly decrease in the abundance of Lactobacillus gasseri (L. gasseri), and oral supplementation of L. gasseri or its metabolite, butyrate, effectively prevented rats from ibrutinib-induced AF. Mechanistically, butyrate inhibits the generation of reactive oxygen species (ROS), thereby ameliorating atrial structural remodeling. Furthermore, we demonstrated that ibrutinib inhibited the growth of L. gasseri by disrupting the intestinal barrier integrity. Collectively, our findings provide compelling experimental evidence supporting the potential efficacy of targeting gut microbes in preventing ibrutinib-associated AF, opening new avenues for therapeutic interventions.