(PTFS14-01-26) Microbial Complexity Shapes the Host Colonic Transcriptome in Response to Processed Diet Feeding

Objectives: Higher intake of ultra-processed foods is associated with increased inflammatory bowel disease (IBD) risk, but mechanisms remain unclear. In line, we observed increased colitis in mice fed a processed ingredient diet (PID) compared to those fed whole grain-based diet (GBD). We hypothesized that PID modulates host intestinal pathways that contribute to increased colitis susceptibility, and that microbial complexity amplifies this effect.

Methods: Wild-type mice were assigned to either a GBD or PID diet and maintained on their respective diets for 5 weeks prior to euthanasia. Colonic tissue was collected for RNA sequencing, and cecal content was collected for NMR-based metabolomics and targeted bile acid profiling. Two cohorts were studied, consisting of conventional microbiota mice and gnotobiotic mice colonized with a defined 12-member consortium. A germ-free cohort was maintained as a microbiome-independent control.

Results: PID exacerbated dextran sulfate sodium (DSS)-induced colitis in both conventional and gnotobiotic mice. Our mechanistic investigation in healthy cohorts (diet intervention only, no DSS) revealed marked colonic transcriptional remodeling in PID-fed mice compared with the GBD group. This effect was pronounced most in conventional mice (1,738 differentially expressed [DE] genes; 4.25% DE pathways), with minimal changes in 12-member consortium mice (45 DE genes; 0.07% DE pathways) and germ-free mice (28 DE genes; 1.33% DE pathways). Despite these differences in transcriptional magnitude, PID consistently enriched succinate and fumarate in microbiota-bearing mice and depleted butyrate across all groups. PID also altered bile acid composition across cohorts. Notably, increasing microbial complexity amplified bile acid remodeling and transcriptional pathway activation.

Conclusions: PID increases susceptibility to colitis and alters microbial metabolism, while a complex microbiota amplifies transcriptional and metabolic remodeling. Our data indicate that microbiome metabolite–driven priming may be a vital mechanism linking ultra-processed diet intake to colitis risk, and further investigation is required to assess whether broad host transcriptional reprogramming is necessary for ultra-processed diet -induced IBD susceptibility.

Funding Sources: NIH-NIDDK