Nutrient Metabolism by the Gut Microbiome Within the Context of Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is characterized by gut microbial dysbiosis, yet most studies rely on genus- and species-level taxonomic profiling that cannot capture strain-level composition or functional heterogeneity. Although functional studies have provided insight into IBD pathogenesis, the metabolic potential and phenotypic diversity of clinically relevant bacterial strains isolated directly from the IBD gut microbiome remain poorly understood. I hypothesized that the metabolic capacity of the gut microbial community is altered in individuals with IBD and is mediated, at least in part, by previously uncharacterized bacterial strains that contribute to either disease pathogenesis or gut health.

I employed three distinct yet complementary objectives using an integrated functional-genomic approach combining culture-based phenotypic profiling with the isolation and genomic characterization of clinical strains obtained from pediatric IBD stool and mucosal luminal interface (MLI) microbiome samples. First, I optimized an in vitro enrichment assay to identify resistant starch (RS)-associated bacteria in 21 pediatric IBD participants and demonstrated that Agathobacter emerged as a predominant taxon associated with RS metabolism. I subsequently isolated A. rectalis H10.1 from the IBD gut microbiome and identified an expanded repertoire of carbohydrate-active enzymes (CAZymes) involved in RS degradation, including the unique presence of CBM74. These findings suggest that this A. rectalis H10.1 may represent a previously unappreciated RS degrader with potential relevance for personalized dietary interventions in IBD.

Second, using Biolog phenotypic profiling and multi-platform sequencing approaches across 57 MLI samples from 23 participants, I identified a UC specific metabolic signature characterized by increased glycerol utilization that correlated with the increased abundance of the genus Citrobacter. These findings support the presence of disease-associated metabolic specialization within UC microbiomes and link specific bacterial taxa to altered substrate utilization patterns.

Third, I developed a strain-specific qPCR assay to investigate the abundance of gut-derived clinical isolate Lancefieldella parvula TI19E08 across the IBD cohort and demonstrated that its abundance positively correlated with inflammation severity in IBD, establishing its potential as a prognostic bacterial biomarker. Altogether, these findings advance the current understanding of IBD pathogenesis beyond taxonomic descriptions to strain-level and metabolic characterization of clinically relevant gut bacteria. This work highlights the clinical importance of gut-derived clinical isolates and identifies potential targets for personalized microbiome modulating therapies and dietary interventions in IBD management.