Oral delivery of Clostridium butyricum using selective antibacterial lipids for enhanced treatment of Fusobacterium nucleatum-associated intestinal diseases

Abstract

The gut microbiota plays a crucial role in host immune modulation and maintaining homeostasis. An abnormal increase in certain pathogens such as Fusobacterium nucleatum (Fn) can break homeostasis and drive the progression of various intestinal diseases. Supplementing probiotics can partially counteract these effects without flora disturbance. However, broad-spectrum antibacterial treatments are not compatible with probiotic therapy in a therapeutic system due to their non-selective damage on both probiotics and the overall gut microbiota. Herein, we screen and identify lauric acid (LA)-derived lipid, S12, from a combinatorial library of 12 chemically diverse lipids for its selective antibacterial activity against Fn over probiotic Clostridium butyricum (Cb). This lipid is then utilized as a single-cell carrier to orally deliver Cb (Cb@S12) for enhanced treatment of Fn-associated intestinal diseases. The surface arming of S12 effectively protects Cb from simulated gastric and intestinal fluids, thus significantly prolonging its intestinal retention in mice. Oral administration of Cb@S12 has demonstrated impressive therapeutic outcomes against Fn-aggravated inflammatory bowel disease and orthotopic colorectal cancer by selectively eliminating Fn while preserving the probiotic activity of Cb. This study introduces a robust approach using selectively antibacterial lipids for probiotic encapsulation, offering an antibiotic-free “probiotic-antagonistic” combination therapeutic strategy for intestinal diseases.