Altered Microbiota, Impaired Quality of Life, Malabsorption, Infection, and Inflammation in CVID Patients With Diarrhoea

Abstract

Background: Diarrhoea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). Objective: The aim of this study was to describe the prevalence and clinical presentation of chronic and recurrent diarrhoea in the Royal-Free-Hospital (RFH) London CVID cohort, including symptoms, infections, level of inflammation, and microbial diversity. Methods: A cross-sectional study of adult CVID patients (139 out of 172 diagnosed with CVID completed the screening questionnaire). Those with diarrhoea ≥6 days/month had stool and blood samples analysed and completed the short Inflammatory Bowel Disease Questionnaire (sIBDQ). BMI, spleen-size, lymphocytes and gut-microbial diversity were compared. Due to logistical and clinical restraints, not all patients could be analysed on all measures. Results: 46/139 (33.1%) patients had current significant diarrhoea. In patients with past or present diarrhoea, BMI was lower (median 23.7 vs. 26, p = 0.005), malabsorption more common (57.97 vs. 35.71%, p = 0.011). CD4+ lymphocytes were higher in patients with diarrhoea (p = 0.028; n = 138), but CD4+ naïve lymphocytes were significantly higher in non-diarrhoea patients (p = 0.009, N = 28). Nine patients had confirmed or probable current gastrointestinal infections. Calprotectin was >60 µg/g in 13/29 with significant diarrhoea including 9 without infection. SIBDQ revealed a low median score of 4.74. Microbial alpha diversity was significantly lower in CVID patients compared to healthy household controls. There was no significant difference in alpha diversity in relation to antibiotic intake during the 6 weeks prior to providing samples. Conclusion: Patients with CVID and significant diarrhoea had infections, raised calprotectin, malabsorption, a lower BMI, an impaired quality of life (comparable van Schewick et al. Longstanding Diarrhoea in CVID to active IBD), and they differed from non-diarrhoea patients in their lymphocyte phenotyping. Furthermore, microbial diversity was altered. These findings strongly imply that there may be an inflammatory nature and a systemic predisposition to diarrhoea in CVID, which necessitates further investigation.

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

“…The limited size of samples is a result of the relatively low prevalence and underdiagnosis of CVID in the population and also of the study inclusion and exclusion criteria, however, size of the cohort is comparable to other CVID microbiome studies. Since previous studies showed that the microbiome of CVID patients is affected by the disease diagnosis, disease severity (11,13), and also by sharing the same household (13,14), we have selected paired samples that could minimize the effect of environment and diet, together with selection of CVID patients without gastroenterological symptomatology for minimization of the impact of CVID complications and treatment regiments.…”

“…However, in our study, the effect of diagnosis on bacterial composition was lower than the effect of the environment and nutrition suggesting that the microbial composition is impacted by several additional factors and highlighting the importance of picking the closest control possible. Recently, two studies used matched housemates as controls for CVID and both observed significant effect of household (13,14).…”

“…Since IgA is the dominant mucosal immunoglobulin maintaining intestinal homeostasis (10), CVID is expected to impact the gut microbiome. Indeed, several studies showed changes in bacterial composition of the gut associated with CVID and with severity of the disease (11)(12)(13)(14)(15). While previous studies analyzed CVID microbiome using sequencing of 16S rRNA gene, we performed metagenome deep-sequencing for identification of differences among bacterial species and genetic functions.…”

The relationship between mucosal microbiota, colitis and systemic inflammation in Chronic Granulomatous Disorder

“…Our findings also support the concept that there is not a single universal healthy gut microbiota composition. Host lifestyle factors, genetic background, health or specific diseases, the environment as well as aging drive microbiota composition and may result in several shifts and alterations over time [49][50][51]. For example, we discovered a modest but significant impact of age and genetic type of CGD (X-linked versus autosomal recessive) on beta diversity in our cohort.…”

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

“…The molecular pathways by which gut microbiota contribute to systemic inflammation in patients with CVID are of great importance but remain poorly understood. CVID patients may have increased intestinal permeability caused by a variety of direct and indirect microbial and immunological mechanisms associated to CVID-related enteropathy ( 44 , 48 , 63 ). This condition provides an impairment of the gut barrier, predominantly caused by disruption of intercellular tight junctions.…”