AbstractPurposeRoux-en-Y gastric bypasses (RYGB) are frequently accompanied by long-term gastrointestinal (GI) symptoms. Direct mechanistic insight into the causation of these symptoms is lacking, but changes in the intestinal microbiome have been proposed to play a role. With this study, we aimed to investigate whether a microbial predisposition exists before RYGB which is associated with GI symptoms during follow-up and to evaluate which microbial groups are involved.Materials and MethodsIn total, 67 RYGB patients were included. Shotgun metagenomic sequencing was performed on fecal samples obtained just before and 1 year after surgery. To assess GI symptoms, patients filled out Gastrointestinal Quality of Life Index (GIQLI) questionnaires and were divided into groups based on their total GIQLI score and change in score (postsurgery versus baseline). Extremely randomized tree predictor models were used to identify the most distinctive microbial species associated with postoperative GI symptoms.ResultsBeta diversity differed significantly between baseline and 1-year post-surgery samples, with the post-surgery microbiome resembling a more dysbiotic profile. The most predictive species regarding total GIQLI (AUC 0.77) or delta GIQLI score (AUC 0.83) were identified. Many of these species are known butyrate producers or species known to support them and/or species with anti-inflammatory properties, includingCoprococcus eutactus,Faecalibacterium prausnitzii, andRuminococcus callidus.ConclusionBeneficial commensal gut microbiota related to a high GI score were associated to adequate intestinal fermentative capacity, suggesting these species might have protective properties against postoperative GI malfunctioning.Graphical AbstractSupplementary InformationThe online version contains supplementary material available at 10.1007/s11695-023-06610-6.