Idiopathic CD4+ Lymphocytopenia Is Associated with Alterations of the Gut Microbiome

Background Idiopathic CD4 lymphocytopenia (ICL) is a rare immunodeficiency disorder characterized by low circulating CD4+ T cells (<300 cells/μl) in the absence of HIV or any other immunosuppressive condition or therapy. Patients with ICL have high risk of serious opportunistic infections and malignancies. Gut microbiota dysbiosis has previously been associated with immune deficiencies and altered responses to immune therapies. We hypothesized that patients with ICL would exhibit unique gut microbiome communities compared with healthy household contacts (HC). Methods Shotgun metagenomic sequencing was performed to measure gut microbiome diversity in rectal swabs from patients with ICL (n = 55, median CD4 88 cells/μl) ICL and HC (n = 19). Taxonomic annotations of short reads were performed against the NCBI reference genomic database (RefSeq), and abundance was estimated via read counts. Viral content was estimated from quality assessed full-length viral sequences contained within de novo assembled contigs. Permutational analysis of variance (PERMANOVA) tests were performed based on the Bray–Curtis distance matrix to assess microbial contrasts between groups. Results ICL group was further stratified to no (n = 30), single (n = 13), or multi (n = 12) antimicrobial use. Gut microbiomes of ICL were significantly different from HC with respect to bacterial (p = 0.042) and eukaryotic (p = 0.011) composition. Bacterial variability within ICL communities tended to be higher than intragroup variability of HC (p = 0.002), especially with respect to Clostridia and Bacteroidia classes. ICL patients on multiple antimicrobial medications were found to have distinct bacterial communities from ICL patients on single or no antimicrobial medications (p = 0.027 and 0.018, respectively) with relative depletion of Gammaproteobacteria. ICL had a significantly higher relative abundance of bacterial pathogens than HC, even after controlling for antibiotic use. ICL viral communities did not differ significantly from HC; however, the presence of human papillomavirus (HPV) diseases, a common ICL comorbidity, was a significant contributor to variation in both bacterial (p = 0.026) and viral community composition (p = 0.004), especially in more severe HPV cases refractory to surgical/medical management. Conclusions People with ICL have alterations in gut microbiota composition, diversity, and community stability regardless of antimicrobial use. Further investigation of metabolomic signatures may provide additional context for the potential role of microbiome changes in ICL comorbidities. Figure. PCoA with bay distances for ICL status and antibiotic use for bacterial diversity.