Background: Bariatric surgery is highly effective in achieving weight loss in children and adolescents with severe obesity, however the underlying mechanisms are incompletely understood, and gut microbiome changes are unknown. Objectives: 1) To comprehensively examine gut microbiome and metabolome changes after laparoscopic vertical sleeve gastrectomy (VSG) in adolescents and 2) to assess whether the microbiome/metabolome changes observed with VSG influence phenotype using germ-free murine models. Design: 1) A longitudinal observational study in adolescents undergoing VSG with serial stool samples undergoing shotgun metagenomic microbiome sequencing and metabolomics (polar metabolites, bile acids and short chain fatty acids) and 2) a human-to-mouse fecal transplant study. Results: We show adolescents exhibit significant gut microbiome and metabolome shifts several months after VSG, with increased alpha diversity and notably with enrichment of oral-associated taxa. To assess causality of the microbiome/metabolome changes in phenotype, pre-VSG and post-VSG stool was transplanted into germ-free mice. Post-VSG stool was not associated with any beneficial outcomes such as adiposity reduction compared pre-VSG stool. However, post-VSG stool exhibited an inflammatory phenotype with increased intestinal Th17 and decreased regulatory T cells. Concomitantly, we found elevated fecal calprotectin and an enrichment of proinflammatory pathways in a subset of adolescents post-VSG. Conclusion: We show that in some adolescents, microbiome changes post-VSG may have inflammatory potential, which may be of importance considering the increased incidence of inflammatory bowel disease post-VSG.

B.A.S. is a former SomaLogic, Inc. (Boulder, CO, USA) employee and a company shareholder. All other authors declare that they have no competing interests.

This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under the Division of Intramural Research, NIAID, NIH (Hourigan), BCBB Support Services Contract HHSN316201300006W/75N93022F00001 to Medical Science & Computing (McCauley, Subramanian, McCauley), the Thrasher Research Fund Early Career Award #01484 (Akagbosu), and the American Pediatric Association Research in Academic Pediatrics Initiative on Diversity (RAPID) grant with funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant R25DK096944 (Akagbosu). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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All data generated or analyzed during this study are included in this published article and its online supplemental information files. Sequencing reads for human and murine analyses are deposited in the Sequence Read Archive (SRA) under accession number PRJNA1093424 at the following reviewer link: https://dataview.ncbi.nlm.nih.gov/object/PRJNA1093424?reviewer=gbe14pmjol31cvc64bn6vh4f4r.