Individual variability shapes ex vivo responses to resistant starch in inflammatory bowel disease derived microbiomes.

Fiber-based therapies focus on butyrate production, a process often dysregulated in inflammatory bowel disease (IBD), but seldomly examine other metabolites or functional pathways. Here, we systematically profiled ex vivo responses of 66 pediatric IBD microbiomes to nine resistant starches (RS), with extensive multi-omic characterization in a subset. Our study demonstrates that inter-individual variability dominates over RS-specific effects, yielding consistent yet highly personalized fermentation phenotypes, microbial compositional shifts, and metabolite outputs. Beyond butyrate, we identify previously unreported RS fermentation metabolites, revealing hidden functional pathways and cross-feeding interactions not captured by conventional short chain fatty acid-focused analyses. Metaproteomic profiling further revealed a coordinated shift from host mucin-degrading activity toward RS utilization. Together, these findings show that RS fermentation is shaped by both RS type and participant microbiome composition, and establish the RapidAIM ex vivo platform as a fiber personalization pipeline fit for interventions aimed at restoring microbial functions disrupted in human diseases.