(P18-004-25) Inflammatory Bowel Disease-Induced Gastrointestinal Zinc Deficiency and Its Influence on Disease Outcome

Objectives: Zinc (Zn) is an essential micronutrient for almost all living organisms, including microbes. Inflammatory bowel diseases (IBDs) are chronic, complex disorders affecting gastrointestinal health, with nearly half of patients displaying reduced circulating Zn levels. However, the mechanisms driving systemic Zn redistribution, particularly to gastrointestinal tissues, and its impact on disease outcomes remain poorly understood. Furthermore, it is unclear whether the primary effects of disease-induced Zn deficiency directly impact host gastroepithelial health or indirectly occur through gut microbiota changes. We hypothesized that inflammation disrupts gastrointestinal Zn homeostasis, which in turn may exacerbate disease outcomes by influencing gut microbial composition and function.

Methods: We utilized two preclinical models of inflammation (LPS-induced inflammation and DSS-induced colitis) and ex vivo organoid systems to examine the role of Zn transport in IBD. Metallomics analyses were conducted using a plasma-atomic emission spectrometer. Zn transport studies were with ⁶⁵Zn. Gut microbial composition was assessed using shotgun metagenomics sequencing. Zn supplementation was administered orally and intraperitoneally during the pre-disease (preventative) and recovery phases (therapeutic) of colitis.

Results: Metallomics analyses identified the differential distribution of Zn, iron, and manganese, essential elements involved in nutritional immunity. Specifically, inflammation significantly alters gastrointestinal Zn distribution by reducing serosal-to-mucosal Zn transport, creating localized Zn deficiency in affected tissues. Oral Zn supplementation during the recovery phase improved colonic tissue integrity and restored gut microbial diversity, whereas Zn injection showed limited efficacy.

Conclusions: Inflammation disrupts gastrointestinal Zn metabolism through dysregulation of Zn transporters, contributing to colitis severity. Oral Zn supplementation in the recovery phase effectively restores gut Zn homeostasis and microbial diversity, offering a promising therapeutic approach for IBD.

Funding Sources: Cornell University Division of Nutritional Sciences funds
Cornell University Center for Vertebrate Genomics Seed Grant
National Institutes of Health