(PTFS14-05-26) Multiomics Approach to Regionally Profile Zinc-Driven Host-Gut Microbiome Interactions in the Intestinal Tract

Objectives: Zinc (Zn) is an essential micronutrient that regulates epithelial barrier integrity, immune signaling, and host–microbiome interactions in the gastrointestinal tract. Although Zn deficiency (ZnD) is associated with metabolic and inflammatory diseases with gut dysbiosis, how Zn availability shapes host–microbiome dynamics across intestinal regions remains unclear. Using integrative multi-omics, this work examines how dietary Zn status regulates regional Zn distribution, epithelial transcriptional programs, and gut microbial composition across the intestine and colon.

Methods: C57BL/6 mice were fed zinc-adequate or zinc-deficient (ZnD) diets for three weeks. Luminal contents from the small intestine, cecum, and colon underwent shotgun metagenomic sequencing to profile microbial composition and function. Host transcriptional responses to Zn status in the small intestine and colon were examined using bulk RNA-seq, and host–microbe interactions under ZnD were assessed using Spearman correlations.

Results: Multi-omics profiling revealed spatial differences in host and microbial responses to ZnD. Shotgun metagenomics showed distinct microbial communities across intestinal regions, with lower diversity in the small intestine than in the cecum and colon. ZnD shifted specific taxa and metabolic pathways in the colon driven by Bacteroides, Clostridioides, and Hungatella. Transcriptomics revealed region-specific host responses, with altered epithelial and antimicrobial programs in the small intestine and suppression of epithelial structural genes in the colon.

Conclusions: By integrating metagenomic and transcriptomic analyses, this study reveals coordinated host–microbiome adaptations to altered Zn availability in a region-specific manner, providing new insight into how micronutrient status shapes intestinal biology and may influence susceptibility to inflammatory and metabolic disease.

Funding Sources: This work was supported by Cornell University Division of Nutritional Sciences funds and a Center for Vertebrate Genomics Seed Grant to T.B.A., National Institutes of Health training grant T32-DK007158 and a Cornell University Center for Vertebrate Genomics Seed Grant to S.B.M., and a Crohn’s and Colitis Foundation Student Research Fellowship to S.S.