Assistant Clinical Investigator Zhejiang University School of Medicine, United States
Introduction/Rationale: Goblet cell mucins are indispensable for maintaining intestinal homeostasis, and their dysfunction is a pivotal factor in inflammatory bowel disease (IBD). However, the precise molecular mechanisms governing this critical barrier remain elusive. The metal ion transporter SLC39A8, bearing missense variant A391T, was identified as an IBD susceptibility locus by GWAS. Here, we investigated the role of SLC39A8 in goblet cells and mucus barrier, aiming to elucidate insights into IBD pathogenesis.
Methods: Human IBD scRNA-seq datasets were analyzed and validated by collected clinical samples. The villin-creERT2-SLC39A8flox/flox mice was generated, followed by the induction of DSS-colitis to assess disease progression. Samples were analyzed via RNA-seq, ICP-MS, TEM and GALNT6 activity assays. The underlying mechanism of SLC39A8 in regulating mucin secretion was further explored in vitro and in vivo.
Results: We found that SLC39A8 expression was selectively decreased in goblet cells from patients with IBD rather than in other epithelial subpopulations. Conditional SLC39A8 knockout (KO) in intestinal epithelium resulted in partial embryonic lethality; therefore, we generated a Tamoxifen-inducible IEC-specific SLC39A8-KO mice (Slc39a8ΔIEC) to investigate its function in the gut. The results revealed that epithelial SLC39A8 deficiency enhances susceptibility to DSS-induced colitis, accompanied by defective mucin O-glycosylation and severe mucus barrier damage. Mechanistically, SLC39A8 deletion induced a profound deficiency of Mn2+. This Mn2+ loss led to both reduced expression (up to 8-fold by RNA-seq) and impaired activity of the key O-glycosylation enzyme GALNT6, which led to defective mucin O-glycosylation and secretory granule exocytosis, ultimately compromising inner mucus layer.
Conclusion: Our study establishes SLC39A8-Mn2+-GALNT6 axis as a crucial determinant of O-glycosylation and mucus barrier function, offering a mechanistic basis for IBD pathogenesis and therapeutic potential for mucosal healing.
