RESUMO
Appendectomy impacts the homeostasis of gut microbiome in patients. We aimed to study the role of appendectomy in colorectal cancer (CRC) risk through causing gut microbial dysbiosis. Population-based longitudinal study (cohort 1, n = 129,155) showed a 73.0% increase in CRC risk among appendectomy cases throughout 20 years follow-up (Adjusted sub-distribution hazard ratio (SHR) 1.73, 95% CI 1.49-2.01, P < 0.001). Shotgun metagenomic sequencing was performed on fecal samples from cohort 2 (n = 314). Gut microbial dysbiosis in appendectomy subjects was observed with significant enrichment of 7 CRC-promoting bacteria (Bacteroides vulgatus, Bacteroides fragilis, Veillonella dispar, Prevotella ruminicola, Prevotella fucsa, Prevotella dentalis, Prevotella denticola) and depletion of 5 beneficial commensals (Blautia sp YL58, Enterococcus hirae, Lachnospiraceae bacterium Choco86, Collinsella aerofaciens, Blautia sp SC05B48). Microbial network analysis showed increased correlation strengths among enriched bacteria and their enriched oncogenic pathways in appendectomy subjects compared to controls. Of which, B. fragilis was the centrality in the network of the enriched bacteria. We further confirmed that appendectomy promoted colorectal tumorigenesis in mice by causing gut microbial dysbiosis and impaired intestinal barrier function. Collectively, this study revealed appendectomy-induced microbial dysbiosis characterized by enriched CRC-promoting bacteria and depleted beneficial commensals, signifying that the gut microbiome may play a crucial role in CRC development induced by appendectomy.
Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Animais , Camundongos , Microbioma Gastrointestinal/genética , Disbiose/microbiologia , Apendicectomia/efeitos adversos , Estudos Longitudinais , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologiaRESUMO
A therapeutic strategy that targets multiple proinflammatory factors in inflammatory bowel disease (IBD) with minimal systemic side effects would be attractive. Here, we develop a drug-free, biodegradable nanomedicine that acts against IBD by scavenging proinflammatory cell-free DNA (cfDNA) and reactive oxygen species (ROS). Polyethylenimine (PEI) was conjugated to antioxidative diselenide-bridged mesoporous organosilica nanoparticles (MONs) to formulate nanoparticles (MON-PEI) that exhibited high cfDNA binding affinity and ROS-responsive degradation. In ulcerative colitis and Crohn's disease mouse colitis models, orally administered MON-PEI accumulated preferentially in the inflamed colon and attenuated colonic and peritoneal inflammation by alleviating cfDNA- and ROS-mediated inflammatory responses, allowing a reduced dose frequency and ameliorating colitis even after delayed treatment. This work suggests a new nanomedicine strategy for IBD treatment.