Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation

Abstract

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.

CVID enteropathy is characterized by exceeding low mucosal IgA levels and interferon-driven inflammation possibly related to the presence of a pathobiont

“…Studies conducted by Malamut et al [7], showed that intraepithelial lymphocytes (IELs) in celiac disease differed from those in CVID enteropathy with regard to some natural killer cell markers and the TCRγ/δ phenotype characteristic of that in celiac disease was generally not present in CVID. These differences between CVID and celiac disease were corroborated by recent work showing that the two diseases are also quite distinct in gene profiling studies [8]. Finally, studies of the immunologic features of CVID enteropathy conducted by Mannon et al[9] revealed that lamina propria T cells extracted from patients with this disease produce increased amounts of IL-12 and IFN-γ but little if any IL-17.…”

“…In another study [8], it was found that the fecal microbiome of CVID patients exhibited a “dysbiosis” characterized by multiple alterations in the composition of the microbial community including both increases and decreases of several taxa compared to those in control individuals. In general, however, these changes in fecal microbiome did not differentiate patients with enteropathy from those without enteropathy and did not identify a specific organism as a cause of the enteropathy.…”

Loss of Circulating Mucosal-Associated Invariant T Cells in Common Variable Immunodeficiency Is Associated with Immune Activation and Loss of Eomes and PLZF

“…We have recently reported that similar perturbations in gd T cells also occur in CVID (32), and in the current study we observed a trend toward an association between the levels of sCD14, an indirect marker of microbial translocation, and MAIT cell loss in CVID. Two studies have reported elevated levels of LPS in CVID (30,31) and elevated LPS levels were associated with CD4 + T cell exhaustion. This suggests that microbial translocation may underlie several perturbations in CVID and possibly explain some of the similarities in T cell anomalies between CVID and HIV infection (11).…”

“…Microbial translocation is now recognized to have a major role in HIV immuno-pathogenesis, and recent evidence suggests that microbial translocation could be responsible for CD4 + T cell exhaustion in CVID patients (30). Elevated levels of LPS in CVID are also associated with dysbiosis of the gut microbiota (31). This present study aimed to investigate if MAIT cell frequency, phenotype, and function are affected in CVID patients.…”

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

“…While microbiome perturbations in IBD can have a complex etiology, dysbiosis in patients with VEO‐IBD or IEI is driven primarily by the gene defects. A study of the gut microbiome in CVID patients showed significant differences in bacterial composition with dysbiosis and low alpha diversity characteristic of the patients with IBD . Interestingly, while elevated dysbiosis index was a characteristic of patients “with infections only” and “with complications” subgroups, the latter had also reduced alpha diversity of the gut microbiota.…”