Alterations of the intestinal mucus layer correlate with dysbiosis and immune dysregulation in human Type 1 Diabetes

Background In preclinical models of Type 1 Diabetes (T1D) the integrity of the gut barrier (GB) is instrumental to avoid dysregulated crosstalk between the commensal microbiota and immune cells and to prevent autoimmunity. The GB is composed of the intestinal epithelial barrier (IEB) and of the mucus layer containing mucins and anti-microbial peptides (AMPs) that are crucial to maintain immune tolerance. In preclinical models of T1D the alter-ations of the GB primarily affect the mucus layer. In human T1D increased gut permeability and IEB damage have been demonstrated but the integrity of the mucus layer was never assessed.Methods We evaluated GB integrity by measuring serological markers of IEB damage (serological levels of zonulin) and bacterial translocation such as lipopolysaccharide binding protein (LBP) and myeloid differentiation protein 2 (MD2), and mRNA expression of tight junction proteins, mucins and AMPs in intestinal tissue of T1D patients and healthy controls (HC). Simultaneously, we performed immunological profiling on intestinal tissue and 16S rRNA analysis on the mucus-associated gut microbiota (MAGM).Findings Our data show a GB damage with mucus layer alterations and reduced mRNA expression of several mucins (MUC2, MUC12, MUC13, MUC15, MUC20, MUC21) and AMPs (HD4 and HD5) in T1D patients. Mucus layer alterations correlated with reduced relative abundance of short chain fatty acids (SCFA)-producing bacteria such as Bifidobacterium dentium, Clostridium butyricum and Roseburia intestinalis that regulate mucin expression and intestinal immune homeostasis. In T1D patients we also found intestinal immune dysregulation with higher percentages of effector T cells such as T helper (Th) 1, Th17 and TNF-alpha+ T cells.Interpretation Our data show that mucus layer alterations are present in T1D subjects and associated with dysbiosis and immune dysregulation. 2023;91: Published https://doi.org/10. 1016/j.ebiom.2023. 104567

Automated summary

The study reveals that alterations in the mucus layer of the gut are associated with dysbiosis and immune dysregulation in patients with Type 1 Diabetes (T1D).