J Leukoc Biol. 2021 Jun;109(6):1147-1154. doi: 10.1002/JLB.5AB1219-699RR. Epub 2020 Sep 15.

Anu Goenka ^1 2 3, John A Doherty ¹, Tariq Al-Farsi ², Christopher Jagger ¹, Siddharth Banka ^4 5, Edmund Cheesman ⁶, Andrew Fagbemi ⁷, Stephen M Hughes ^1 2, Robert F Wynn ⁸, Tracy Hussell ¹, Peter D Arkwright ^1 2

Author information

¹Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK.

²Department of Paediatric Allergy & Immunology, Royal Manchester Children's Hospital, Manchester, UK.

³School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.

⁴Division of Evolution and Genomic Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.

⁵Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester, UK.

⁶Department of Paediatric Histopathology, Royal Manchester Children's Hospital, Manchester, UK.

⁷Department of Paediatric Gastroenterology, Royal Manchester Children's Hospital, Manchester, UK.

⁸Department of Paediatric Haematology Royal Manchester Children's Hospital, Manchester, UK.

Abstract

The glucose-6-phosphatase catalytic subunit 3 (G6PC3) encodes a ubiquitously expressed enzyme that regulates cytoplasmic glucose availability. Loss-of-function biallelic G6PC3 mutations cause severe congenital neutropenia and a diverse spectrum of extra-hematological manifestations, among which inflammatory bowel disease (IBD) has been anecdotally reported. Neutrophil function and clinical response to granulocyte colony-stimulating factor (G-CSF) and hematopoietic stem cell transplantation (HSCT) were investigated in 4 children with G6PC3 deficiency-associated IBD. G6PC3 deficiency was associated with early-onset IBD refractory to treatment with steroids and infliximab. The symptoms of IBD progressed despite G-CSF treatment. In vitro studies on the patients' blood showed that neutrophils displayed higher levels of activation markers (CD11b, CD66b, and CD14), excessive IL-8 and reactive oxygen species, and increased apoptosis and secondary necrosis. Secondary necrosis was exaggerated after stimulation with Escherichia coli and could be partially rescued with supplemental exogenous glucose. HSCT led to normalization of neutrophil function and remission of gastrointestinal symptoms. We conclude that neutrophils in G6PC3 deficiency release pro-inflammatory mediators when exposed to gut bacteria, associated with intestinal inflammation, despite treatment with G-CSF. HSCT is an effective therapeutic option in patients with G6PC3 deficiency-associated IBD refractory to immune suppressants.