The gut microbiome plays a central role in inflammatory bowel diseases (IBDs) pathogenesis and propagation. To determine whether the gut microbiome may predict responses to IBD therapy, we conducted a prospective study with Crohn’s disease (CD) or ulcerative colitis (UC) patients initiating anti-integrin therapy (vedolizumab). Disease activity and stool metagenomes at baseline, and weeks 14, 30, and 54 after therapy initiation were assessed. Community α-diversity was significantly higher, and Roseburia inulinivorans and a Burkholderiales species were more abundant at baseline among CD patients achieving week 14 remission. Several significant associations were identified with microbial function; 13 pathways including branched chain amino acid synthesis were significantly enriched in baseline samples from CD patients achieving remission. A neural network algorithm, vedoNet, incorporating microbiome and clinical data, provided highest classifying power for clinical remission. We hypothesize that the trajectory of early microbiome changes may be a marker of response to IBD treatment. Display omitted •Stool metagenomes of IBD patients starting biologic therapy were prospectively assessed•Higher abundance of butyrate producers at baseline in therapy-responsive CD patients•Baseline enrichment of 13 microbial pathways in therapy-responsive CD patients•Early microbial changes at week 14 persist up to 1 year in responders Gut microbiome may predict responses to clinical therapy. Ananthakrishnan et al. conducted a prospective study with IBD patients initiating anti-integrin therapy. Higher abundance of butyrate producers and enrichment of 13 microbial pathways at baseline in therapy-responsive CD patients was observed. Early microbial changes persist up to 1 year in responders.