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.


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.