Modified Gut Microbiome Induced by Sleeve Gastrectomy Promotes Colitis-associated Colorectal Cancer
James N. Luo, Renuka S. Haridas, Tammy Lo, Andrei Moscalu, Cullen F. Roberts, Ali Tavakkoli, James Yoo, Eric G. Sheu
Laboratory for Surgical and Metabolic Research, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School
Background: Colitis-associated colorectal cancer (CAC) is characterized by rapid progression and high mortality. Mechanistically, the phenotypic impact of obesity and bariatric surgery remains highly controversial. Recent evidence has implicated the gut microbiome as a key mediator linking obesity, bariatric surgery, and colorectal cancer. Here, we examine sleeve gastrectomy (SG)'s effect on CAC development via alterations in the gut microbiome.
Methods: Murine CAC model was established as outlined in Fig-1A. 16S rRNA sequencing was used to profile the microbiome. To isolate the causal role of the microbiome, cecal microbiota transplant (CMT) was performed between these and age- and weight-matched germ-free (GF) mice, then challenged with AOM-DSS (Fig-1F).
Results: SG significantly increased tumor development (Fig-1B, -C). 16S rRNA profiling showed a distinct segregation of the microbial populations between SG and sham (Fig-1D). SG mice exhibited key species-level changes including marked enrichment of the colitis-promoting taxa Akkermansia and Bacteroides (Fig-1E). CMT was sufficient to replicate SG’s effect. Ex-GF mice conventionalized with SG donor exhibited a 5-fold increase in tumor burden (Fig-1G).
Conclusion: For the first time in vivo, we showed SG catalyzes a colitogenic transformation of the gut microbiome and promotes CAC development. Transplant of this modified microbiome was sufficient to independently recreate SG’s tumorigenic phenotype, confirming that the gut microbiome plays a key causal role in promoting CAC following SG.
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