Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Authors

Marianna Parlato, l'Institut des Maladies Génétiques Imagine
Fabienne Charbit-Henrion, l'Institut des Maladies Génétiques Imagine
Jie Pan, Hospital for Sick Children University of Toronto
Claudio Romano, GENIUS group from ESPGHAN
Rémi Duclaux-Loras, l'Institut des Maladies Génétiques Imagine
Marie Helene Le Du, Institut de Biologie Intégrative de la Cellule
Neil Warner, Hospital for Sick Children University of Toronto
Paola Francalanci, IRCCS Ospedale Pediatrico Bambino Gesù
Julie Bruneau, Université Paris Cité
Marc Bras, Université Paris Cité
Mohammed Zarhrate, Inserm
Bernadette Bègue, l'Institut des Maladies Génétiques Imagine
Nicolas Guegan, l'Institut des Maladies Génétiques Imagine
Sabine Rakotobe, l'Institut des Maladies Génétiques Imagine
Nathalie Kapel, AP-HP Assistance Publique - Hopitaux de Paris
Paola De Angelis, IRCCS Ospedale Pediatrico Bambino Gesù
Anne M. Griffiths, Hospital for Sick Children University of Toronto
Karoline Fiedler, Hospital for Sick Children University of Toronto
Eileen Crowley, Hospital for Sick Children University of Toronto
Frank Ruemmele, l'Institut des Maladies Génétiques Imagine
Aleixo M. Muise, Hospital for Sick Children University of Toronto
Nadine Cerf-Bensussan, l'Institut des Maladies Génétiques Imagine

Document Type

Article

Publication Date

4-1-2018

Journal

EMBO Molecular Medicine

Volume

10

Issue

4

URL with Digital Object Identifier

10.15252/emmm.201708483

Abstract

Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients’ biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host–microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.