Patients With Common Variable Immunodeficiency (CVID) Show Higher Gut Bacterial Diversity and Levels of Low-Abundance Genes Than the Healthy Housemates

Abstract

Common variable immunodeficiency (CVID) is a clinically and genetically heterogeneous disorder with inadequate antibody responses and low levels of immunoglobulins including IgA that is involved in the maintenance of the intestinal homeostasis. In this study, we analyzed the taxonomical and functional metagenome of the fecal microbiota and stool metabolome in a cohort of six CVID patients without gastroenterological symptomatology and their healthy housemates. The fecal microbiome of CVID patients contained higher numbers of bacterial species and altered abundance of thirty-four species. Hungatella hathewayi was frequent in CVID microbiome and absent in controls. Moreover, the CVID metagenome was enriched for low-abundance genes likely encoding nonessential functions, such as bacterial motility and metabolism of aromatic compounds. Metabolomics revealed dysregulation in several metabolic pathways, mostly associated with decreased levels of adenosine in CVID patients. Identified features have been consistently associated with CVID diagnosis across the patients with various immunological characteristics, length of treatment, and age. Taken together, this initial study revealed expansion of bacterial diversity in the host immunodeficient conditions and suggested several bacterial species and metabolites, which have potential to be diagnostic and/or prognostic CVID markers in the future.

Systematic Feature Filtering in Exploratory Metabolomics: Application toward Biomarker Discovery

“…We compared experimental MS/MS spectra with a database to find at minimum one matching fragment ion for structure validation. We confirmed the structure of 15 metabolites discriminatory between CVID and control samples . Exemplary MS/MS spectra of indole-3-propionic (IPA) acid are shown in Figure S3.…”

“…We confirmed the structure of 15 metabolites discriminatory between CVID and control samples. 47 Exemplary MS/MS spectra of indole-3propionic (IPA) acid are shown in Figure S3. IPA is a wellestablished marker of gut microbiota-mediated tryptophan metabolism in fecal samples.…”

Gut Microbiome and Common Variable Immunodeficiency: Few Certainties and Many Outstanding Questions

“…In conclusion, there is evidence that the composition of the gut microbiota in patients with CVID is significantly different from healthy individuals (22,55,56,63,68). Whether changes in the intestinal microbiota observed in CVID are cause or effect of disease still needs to be determined.…”

“…Interestingly, the authors did not find any significant taxonomic differences of fungal microbiota between patients and controls, suggesting that gut mycobiota may not affect the CVID phenotype. More recently, the same group characterized the fecal microbiota and stool metabolome in a cohort of 6 CVID patients without gastroenterological symptoms and their healthy housemates ( 56 ). CVID fecal microbiome showed increased bacterial diversity and differences in several bacterial species compared to controls.…”

“…In the last decade, few studies have started to investigate the gut microbiota profile in CVID patients. Gut microbial imbalance of patients with CVID mainly includes changes in microbial diversity, decrease in symbiotic beneficial bacteria, and increase in pathobionts (22,(54)(55)(56). The term alpha diversity was introduced to describe the mean microbial species diversity in the gut (43).…”