GUT MICROBIOME CHANGES ASSOCIATED WITH INFLIXIMAB RESPONSE IN PEDIATRIC IBD

Abstract BACKGROUND Infliximab is a first line therapy for severe pediatric IBD, but only 50% of patients achieve and maintain clinical remission by 1 year. We investigated the gut microbiome in pediatric IBD patients to determine its impact on Infliximab response. METHODS 100 pediatric IBD patients on maintenance Infliximab therapy were enrolled and prospectively followed over a two-year period at a tertiary children’s hospital from 2021-2024. Disease activity was evaluated using the Harvey-Bradshaw Index (HBI) in CD patients or the Pediatric Ulcerative Colitis Activity Index (PUCAI) in UC patients and stool samples were collected every 1-2 months as patients presented to the infusion clinic. The difference in beta-diversity and abundance of individual taxa of the gut microbiome were evaluated in 40 patients (29 with CD 11 with UC) 1 year post Infliximab and 36 patients (29 CD, 7 UC) 3-5 years post Infliximab using 16s rRNA sequencing. Patients were classified into biochemical remission or persistent inflammation by clinical activity index score (Remission: HBI < 5, PUCAI < 10) and fecal calprotectin level (Remission: < 250 υg/g in CD, < 150 υg/g in UC). RESULTS At one year post Infliximab, there were 25 patients in remission (22 CD, 3 UC) with mean calprotectin 28.6 υg/g (95% CI 9.9, 47.4) and 15 patients with persistent inflammation (7 CD, 8 UC) with mean calprotectin 486.3 υg/g (95% CI 355.6, 616.9). At 3-5 years post Infliximab, there were 26 patients in remission (23 CD, 3 UC) with mean calprotectin 34.4 υg/g (95% CI 12.6, 56.2) and 10 patients with persistent inflammation (6 CD, 4 UC) with mean calprotectin 985.1 υg/g (95% CI 304.7, 1665.5). There were no differences in beta diversity identified by non-metric multidimensional scaling at either 1-year or 3-5 years post Infliximab between patients in remission vs those with persistent inflammation. Significant differences in the abundance in the taxa Faecalitalea and Faecalibacterium were found at 1 year post Infliximab (Figure 1) and in the taxa Hungatella, Parabacteroides, and Eisenbergiella at 3-5 years post Infliximab (Figure 2). CONCLUSIONS The overall composition of gut microbiota in pediatric IBD patients on maintenance Infliximab therapy was similar between patients achieving remission and those with persistent inflammation; however, in patients with persistent inflammation there were decreased Short Chain Fatty Acid (SCFA) producing taxa (Faecalitalea, Parabacteroides) and increased mucous degrading taxa (Hungatella) which have been implicated in the pathogenesis of IBD. Further evaluation with metagenomic and metabolomic approaches may uncover the functional mechanisms through which these taxonomic differences determine the response to Infliximab in pediatric IBD. Figure 1. Taxonomic abundance 1 year post Infliximab. Figure 2. Taxonomic abundance 3-5 years post Infliximab.