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

• Main Authors: Marianna Parlato, Fabienne Charbit‐Henrion, Jie Pan, Claudio Romano, Rémi Duclaux‐Loras, Marie‐Helene Le Du, Neil Warner, Paola Francalanci, Julie Bruneau, Marc Bras, Mohammed Zarhrate, Bernadette Bègue, Nicolas Guegan, Sabine Rakotobe, Nathalie Kapel, Paola De Angelis, Anne M Griffiths, Karoline Fiedler, Eileen Crowley, Frank Ruemmele, Aleixo M Muise, Nadine Cerf‐Bensussan
• Format: Article
• Language: English
• Published: Wiley 2018-04-01
• Series: EMBO Molecular Medicine
• Subjects: inflammatory bowel diseases; intestinal phosphatase alkaline; monogenic disease
• Online Access: https://doi.org/10.15252/emmm.201708483
• ISSN: 1757-4676; 1757-4684

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.