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

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 RuemmeleAleixo M Muise, Nadine Cerf-Bensussan

Research output: Contribution to journalArticle

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.

Original languageEnglish
Number of pages12
JournalEMBO Molecular Medicine
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 2018

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    Parlato, M., Charbit-Henrion, F., Pan, J., Romano, C., Duclaux-Loras, R., Le Du, M-H., Warner, N., Francalanci, P., Bruneau, J., Bras, M., Zarhrate, M., Bègue, B., Guegan, N., Rakotobe, S., Kapel, N., De Angelis, P., Griffiths, A. M., Fiedler, K., Crowley, E., ... Cerf-Bensussan, N. (2018). Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis. EMBO Molecular Medicine, 10(4). https://doi.org/10.15252/emmm.201708483