Alterations of the intestinal mucus layer correlate with dysbiosis and immune dysregulation in human Type 1 Diabetes
Marta Lo Conte, Ilaria Cosorich, Roberto Ferrarese, Martina Antonini Cencicchio, Angelica Nobili, Vittoria Palmieri, Luca Massimino, Luigi Antonio Lamparelli, Wenjie Liang, Michela Riba, Elisabetta Devecchi, Andrea Mario Bolla, Erika Pedone, Marina Scavini, Emanuele Bosi, Alessio Fasano, Federica Ungaro, James S. Diana, Nicasio Mancini, Marika Falcone
Abstract
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 antimicrobial peptides (AMPs) that are crucial to maintain immune tolerance. In preclinical models of T1D the alterations 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: T cells. INTERPRETATION: Our data show that mucus layer alterations are present in T1D subjects and associated with dysbiosis and immune dysregulation. FUNDING: Research Grants from the Juvenile Diabetes Foundation (Grant 1-INO-2018-640-A-N to MF and 2-SRA-2019-680-S-B to JD) and from the Italian Ministry of Health (Grant RF19-12370721 to MF).