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

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.