Transcriptome, glycome, and mucinome analysis reveal zinc is essential for the composition of mucus in the human goblet cell model HT-29-MTX

Zinc deficiency impacts roughly 1 billion individuals globally, leading to severe health issues such as heightened infection risk, inflammation, and diarrhea. This condition weakens the intestinal defense barrier, resulting in epithelial destruction and alterations in mucus composition. However, the precise mechanisms by which Zn deficiency influences mucin synthesis in intestinal goblet cells (GCs) remain unclear.

To address this knowledge gap, researchers conducted an investigation into the influence of Zn deficiency on mucin expression and glycosylation in the human GC model HT-29-MTX. Zn deprivation demonstrated alterations in the GC transcriptome, affecting genes related to Zn transport, mucin synthesis, and glycosylation. Consequently, the mucus profile in Zn-deficient GCs showed significant modifications, with MUC2 and MUC17 exhibiting increased mRNA and protein levels.

Multiple Zn transporters, primarily those involved in the early secretory pathway (ESP), exhibited dysregulation, indicating an adaptive response to cellular Zn homeostasis. Moreover, free Zn levels in the ESP, a crucial site for glycosylation, were considerably reduced. The Zn deficit profoundly altered mucin glycosylation, characterized by an increase in sialylation and a substantial decrease in complex N-glycans.

These changes were linked to widespread dysregulation of glycosyltransferase expression, notably an increase in COSMC, a Zn-binding chaperone vital for core 1 O-glycan formation. Overall, these in vitro findings underscore the critical role of Zn in mucin production and glycosylation within GCs. The study suggests that Zn deficiency may compromise the protective and functional attributes of intestinal mucus, elevating the risk of infections and potentially disrupting host-microbiome interactions.

This research was supported by the Deutsche Forschungsgemeinschaft (DFG MA 9681/1-1) and the French National Agency (ENIGMncA project, ANR-21-CE14-0049-01).