Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease

Prabha Chandrasekaran; Yu Han; Christa S Zerbe; Theo Heller; Suk See DeRavin; Samantha A Kreuzberg; Beatriz E Marciano; Yik Siu; Drew R Jones; Roshini S Abraham; Michael C Stephens; Amy M Tsou; Scott Snapper; Sean Conlan; Poorani Subramanian; Mariam Quinones; Caroline Grou; Virginie Calderon; Clayton Deming; Jennifer W Leiding; Danielle E Arnold; Brent R Logan; Linda M Griffith; Aleksandra Petrovic; Talal I Mousallem; Neena Kapoor; Jennifer R Heimall; Jessie L Barnum; Malika Kapadia; Nicola Wright; Ahmad Rayes; Sharat Chandra; Larisa A Broglie; Deepak Chellapandian; Christin L Deal; Eyal Grunebaum; Stephanie Si Lim; Kanwaldeep Mallhi; Rebecca A Marsh; Luis Murguia-Favela; Suhag Parikh; Fabien Touzot; Morton J Cowan; Christopher C Dvorak; Elie Haddad; Donald B Kohn; Luigi Notarangelo; Sung-Yun Pai; Jennifer M Puck; Michael A Pulsipher; Troy R Torgerson; Elizabeth M Kang; Harry L Malech; Julia A Segre; Clare E Bryant; Steven M Holland; Emilia Liana Falcone

doi:10.1016/j.jaci.2023.07.022

Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease

J Allergy Clin Immunol. 2023 Aug 31;S0091-6749(23)01101-6. doi: 10.1016/j.jaci.2023.07.022. Online ahead of print.

Authors

Prabha Chandrasekaran¹, Yu Han², Christa S Zerbe³, Theo Heller⁴, Suk See DeRavin³, Samantha A Kreuzberg³, Beatriz E Marciano³, Yik Siu⁵, Drew R Jones⁵, Roshini S Abraham⁶, Michael C Stephens⁷, Amy M Tsou⁸, Scott Snapper⁹, Sean Conlan¹⁰, Poorani Subramanian¹¹, Mariam Quinones¹¹, Caroline Grou¹², Virginie Calderon¹², Clayton Deming¹⁰, Jennifer W Leiding¹³, Danielle E Arnold¹⁴, Brent R Logan¹⁵, Linda M Griffith¹⁶, Aleksandra Petrovic¹⁷, Talal I Mousallem¹⁸, Neena Kapoor¹⁹, Jennifer R Heimall²⁰, Jessie L Barnum²¹, Malika Kapadia²², Nicola Wright²³, Ahmad Rayes²⁴, Sharat Chandra²⁵, Larisa A Broglie²⁶, Deepak Chellapandian²⁷, Christin L Deal²⁸, Eyal Grunebaum²⁹, Stephanie Si Lim³⁰, Kanwaldeep Mallhi³¹, Rebecca A Marsh³², Luis Murguia-Favela²³, Suhag Parikh³³, Fabien Touzot³⁴, Morton J Cowan³⁵, Christopher C Dvorak³⁵, Elie Haddad³⁴, Donald B Kohn³⁶, Luigi Notarangelo³, Sung-Yun Pai¹⁴, Jennifer M Puck³⁵, Michael A Pulsipher³⁷, Troy R Torgerson³⁸, Elizabeth M Kang³, Harry L Malech³, Julia A Segre¹⁰, Clare E Bryant³⁹, Steven M Holland³, Emilia Liana Falcone⁴⁰

Affiliations

¹ Laboratory of Clinical Investigations, National Institutes of Aging (NIA), Baltimore, MD, USA.
² Division of Molecular Genetics and Pathology, Center for Devices and Radiological Health, Food and Drug Administration (FDA), Silver Spring, MD, USA; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
³ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
⁴ Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA.
⁵ Metabolomics Laboratory, New York University Langone, New York, NY, USA.
⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
⁷ Department of Pediatric Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA.
⁸ Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, New York, NY, USA.
⁹ Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
¹⁰ National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD, USA.
¹¹ Bioinformatics and Computational Biosciences Branch (BCBB), Office of Cyber Infrastructure and Computational Biology (OCICB), NIAID, NIH, Bethesda, MD, USA.
¹² Bioinformatics Core, Montreal Clinical Research Institute (IRCM), Montreal, QC, Canada.
¹³ Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Immune Deficiency - Cellular Therapy Program, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, MD, USA.
¹⁵ Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁶ Division of Allergy, Immunology and Transplantation, NIAID, NIH, Bethesda, MD, USA.
¹⁷ Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Hospital and Research Center, Seattle, WA, USA.
¹⁸ Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
¹⁹ Division of Hematology, Oncology and Blood and Marrow Transplant, Children's Hospital, Los Angeles, CA, USA.
²⁰ Division of Allergy and Immunology, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA.
²¹ Division of Blood and Marrow Transplantation and Cellular Therapies, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
²² Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA, USA.
²³ Section of Hematology/Immunology, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.
²⁴ Intermountain Primary Children's Hospital, University of Utah, Salt Lake City, UT, USA.
²⁵ Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
²⁶ Division of Pediatric Hematology-Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
²⁷ Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
²⁸ Division of Allergy and Immunology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
²⁹ Division of Immunology and Allergy, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
³⁰ Department of Pediatrics, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI, USA; University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, Honolulu, HI, USA.
³¹ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³² Cincinnati Children's Hospital Medical Center, and University of Cincinnati, Cincinnati, OH, USA.
³³ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
³⁴ Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, QC, Canada; Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, QC, Canada.
³⁵ University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA.
³⁶ Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, USA.
³⁷ Division of Pediatric Hematology and Oncology, Intermountain Primary Children's Hospital, Huntsman Cancer Institute at the University of Utah Spencer Fox Eccles School of Medicine, Salt Lake City, UT, USA.
³⁸ Allen Institute for Immunology, Seattle, WA, USA.
³⁹ Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
⁴⁰ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA; Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, QC, Canada; Center for Inflammation, Immunity and Infectious Diseases, Montreal Clinical Research Institute (IRCM), Montreal, QC, Canada; Department of Medicine, Université de Montréal, Montreal, QC, Canada. Electronic address: emilia.falcone@ircm.qc.ca.

PMID: 37659505
DOI: 10.1016/j.jaci.2023.07.022

Abstract

Background: CGD is caused by defects in any of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived ROS production. Almost 50% of patients with chronic granulomatous disease (CGD) have IBD (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments.

Objective: To identify microbiome and metabolome signatures that can distinguish patients with CGD and CGD-IBD.

Methods: We conducted a cross-sectional, observational study of 79 patients with CGD, 8 pathogenic variant carriers and 19 healthy controls followed at the National Institutes of Health Clinical Center (NIH CC). We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 CGD patients recruited through the Primary Immune Deficiency Treatment Consortium (PIDTC).

Results: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp., Sellimonas spp. and Lachnoclostridium spp. in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the NIH CC and PIDTC cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD.

Conclusion: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets.

Keywords: CGD; Chronic granulomatous disease; IBD; NADPH oxidase; dysbiosis; inborn errors of immunity; inflammatory bowel disease; intestinal inflammation; metabolome; microbiome; primary immune deficiency.