Abstract
A substantial proportion of patients with common variable immunodeficiency (CVID) have inflammatory and autoimmune complications of unknown etiology. We have previously shown that systemic inflammation in CVID correlates with their gut microbial dysbiosis. The gut microbiota dependent metabolite trimethylamine N-oxide (TMAO) has been linked to several metabolic and inflammatory disorders, but has hitherto not been investigated in relation to CVID. We hypothesized that TMAO is involved in systemic inflammation in CVID. To explore this, we measured plasma concentrations of TMAO, inflammatory markers, and lipopolysaccharide (LPS) in 104 CVID patients and 30 controls. Gut microbiota profiles and the bacterial genes CutC and CntA, which encode enzymes that can convert dietary metabolites to trimethylamine in the colon, were examined in fecal samples from 40 CVID patients and 86 controls. Furthermore, a food frequency questionnaire and the effect of oral antibiotic rifaximin on plasma TMAO concentrations were explored in these 40 patients. We found CVID patients to have higher plasma concentrations of TMAO than controls (TMAO 5.0 [2.9–8.6] vs. 3.2 [2.2–6.3], p = 0.022, median with IQR). The TMAO concentration correlated positively with tumor necrosis factor (p = 0.008, rho = 0.26), interleukin-12 (p = 0.012, rho = 0.25) and LPS (p = 0.034, rho = 0.21). Dietary intake of meat (p = 0.678), fish (p = 0.715), egg (p = 0.138), dairy products (p = 0.284), and fiber (p = 0.767) did not significantly impact on the TMAO concentrations in plasma, nor did a 2-week course of the oral antibiotic rifaximin (p = 0.975). However, plasma TMAO concentrations correlated positively with gut microbial abundance of Gammaproteobacteria (p = 0.021, rho = 0.36). Bacterial gene CntA was present in significantly more CVID samples (75%) than controls (53%), p = 0.020, potentially related to the increased abundance of Gammaproteobacteria in these samples. The current study demonstrates that elevated TMAO concentrations are associated with systemic inflammation and increased gut microbial abundance of Gammaproteobacteria in CVID patients, suggesting that TMAO could be a link between gut microbial dysbiosis and systemic inflammation. Gut microbiota composition could thus be a potential therapeutic target to reduce systemic inflammation in CVID.
Highlights
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency among adults with an estimated prevalence of between 1:25,000 and 1:50,000 [1], comprising a clinically and immunologically heterogeneous group
The main findings of this study were: (i) CVID patients had persistently elevated plasma concentrations of trimethylamine N-oxide (TMAO) and its precursors carnitine, choline, betaine as well as its intermediate metabolite yBB compared to healthy controls; (ii) TMAO concentrations were positively correlated with TNFα and IL-12, representing prototypical inflammatory markers in CVID; (iii) The abundance of Gammaproteobacteria in stool and LPS in plasma were associated with increased concentrations of TMAO in CVID, bacterial genes carnitine oxygenase (CntA) and cholineTMA lyase (CutC) encoding TMA producing enzymes were more abundant in the gut microbiota of CVID patients than in controls
Our findings suggest that TMAO could be a link between disturbed gut microbiota and systemic inflammation in CVID
Summary
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency among adults with an estimated prevalence of between 1:25,000 and 1:50,000 [1], comprising a clinically and immunologically heterogeneous group. ∼70% of CVID patients have autoimmune and inflammatory complications [2, 3], associated with persistent systemic inflammation and immune activation, reflecting abnormalities in other immune cells such as monocytes/macrophages and T-cells [4]. The mechanisms leading to systemic sterile inflammation and autoimmunity in CVID are not fully understood. We have previously shown that gut microbial composition is related to systemic inflammation and autoimmunity in CVID. The relative abundance of certain key groups of bacteria, which included increased levels of Gammaproteobacteria, were associated with systemic immune activation in CVID [8]. The mechanisms by which an altered gut microbiota may translate into systemic inflammation in these patients are not clear
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