Goblet cells and the mucus barrier in intestinal inflammation

• Applicant: Dr. Aline Azabdaftari
• Subject Area: Pediatric and Adolescent Medicine ; Gastroenterology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 501883972

• Final Report Year: 2025

Final Report Abstract

Analysis of rare human monogenic disease models can help to understand the pathophysiological pathways that control barrier function and immunity. Biallelic Anterior gradient 2 (AGR2) loss-of-function variants in humans cause infantile-onset inflammatory bowel disease, alongside histological changes of the gastric epithelium and a depletion of goblet cell. The underlying mechanisms of AGR2 defects on epithelial development and function are not yet well understood. We show that AGR2-deficiency represents a genetic model of precancerous intestinal metaplastic lesions and goblet cell dysfunction with high endoplasmic reticulum (ER)-stress. An apparent depletion of goblet cells was found in AGR2-deficiency and ulcerative colitis, but this is a histological artefact, representing a reduction of stored mucins. This study highlights the role of AGR2-deficiency as a relevant protein in epithelial cell differentiation causing the development of metaplastic enterocytes in the stomach, while affecting goblet cell function in the colon. Histological goblet cell depletion in AGR2-deficiency is caused by a dysfunction of mucin stores in goblet cells. Similarly in ulcerative colitis, an apparent goblet cell “depletion” is a misrepresentation since single-cell analysis showed maintained goblet cell numbers with high ER-stress. The inflammatory consequences of AGR2-deficiency highlight the relevance of goblet cell ER-stress and mucus production as a pathogenic mechanism for intestinal inflammation.

Publications

• Paneth cell dysfunction and the intestinal microbiome in XIAP deficiency. Science Immunology, 6(65).
  Azabdaftari, Aline & Uhlig, Holm H.
  
• Monogenic inflammatory bowel disease-genetic variants, functional mechanisms and personalised medicine in clinical practice. Human Genetics, 142(5), 599-611.
  Azabdaftari, Aline; Jones, Kelsey D. J.; Kammermeier, Jochen & Uhlig, Holm H.
  
• NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures. Gut, 72(4), 654-662.
  Hsu, Nai-Yun; Nayar, Shikha; Gettler, Kyle; Talware, Sayali; Giri, Mamta; Alter, Isaac; Argmann, Carmen; Sabic, Ksenija; Thin, Tin Htwe; Ko, Huai-Bin Mabel; Werner, Robert; Tastad, Christopher; Stappenbeck, Thaddeus; Azabdaftari, Aline; Uhlig, Holm H.; Chuang, Ling-Shiang & Cho, Judy H.
  
• Biallelic known and novel DCDC2 variants in cholestatic liver disease: Phenotype–genotype observations in four children. Liver International, 43(5), 1089-1095.
  Azabdaftari, Aline; Sczakiel, Henrike L.; Danyel, Magdalena; Kohlmaier, Benno; Mache, Christoph J.; Stalke, Amelie; Pfister, Eva‐Doreen; Thumfart, Julia; Henning, Stephan; Knisely, A. S. & Bufler, Philip
  
• Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity. Frontiers in Immunology, 14.
  Kröhn, Laura; Azabdaftari, Aline; Heuberger, Julian; Hudert, Christian; Zilbauer, Matthias; Breiderhoff, Tilman & Bufler, Philip
  
• Phosphomannomutase 2 (PMM2) variants leading to hyperinsulinism-polycystic kidney disease are associated with early-onset inflammatory bowel disease and gastric antral foveolar hyperplasia. Human Genetics, 142(5), 697-704.
  Kiparissi, Fevronia; Dastamani, Antonia; Palm, Liina; Azabdaftari, Aline; Campos, Luis; Gaynor, Edward; Grünewald, Stephanie; Uhlig, Holm H.; Kleta, Robert; Böckenhauer, Detlef & Jones, Kelsey D. J.
  
• Abstracts der 39. Jahrestagung der Gesellschaft für Pädiatrische Gastroenterologie und Ernährung (GPGE) e.V.. Pädiatrie, 36(1), 62-62.
  Kampmann, Kristina; Kathemann, Simone; Lainka, Elke; Pilic, Denisa & Prusinskas, Benas
  
• Cellular and molecular basis of proximal small intestine disorders. Nature Reviews Gastroenterology & Hepatology, 21(10), 687-709.
  Bildstein, Tania; Charbit-Henrion, Fabienne; Azabdaftari, Aline; Cerf-Bensussan, Nadine & Uhlig, Holm H.
  
• Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn’s Disease. Gut, 73(9), 1464-1477.
  Dennison, Thomas W.; Edgar, Rachel D.; Payne, Felicity; Nayak, Komal M.; Ross, Alexander D. B.; Cenier, Aurelie; Glemas, Claire; Giachero, Federica; Foster, April R.; Harris, Rebecca; Kraiczy, Judith; Salvestrini, Camilla; Stavrou, Georgia; Torrente, Franco; Brook, Kimberley; Trayers, Claire; Elmentaite, Rasa; Youssef, Gehad; Tél, Bálint ... & Zilbauer, Matthias