Gut microbiota, lipid metabolism and systemic inflammation in common variable immunodeficiency: A translational research approach

Abstract

Patients with common variable immunodeficiency (CVID) have a dysfunctional immune system leading to recurrent infections while also frequently suffering non-infectious autoimmune and inflammatory complications. These non-infectious complications are connected with higher mortality rates.

The aim of this thesis was to explore the gut microbiome and novel molecular mechanisms involved in the underlying pathogenesis of systemic inflammation in CVID in order to identify therapeutic targets to reduce autoimmune and inflammatory manifestations.

Through a randomized controlled trial, we tested if the oral antibiotic rifaximin would alter gut microbial composition and thereby modulate systemic inflammation in CVID patients. Indeed, rifaximin decreased their gut microbial diversity, but did not significantly change any markers of systemic inflammation or gut leakage.

Gut microbes also interact with the regulation of lipids and we found reduced HDL cholesterol levels in the plasma of CVID patients. Low HDL correlated with raised inflammatory markers CRP and sCD25. Important HDL functions, related to reverse cholesterol transport, were significantly impaired in CVID patients. Dietary nutrients are metabolized by gut microbes to form the organic compound TMAO. In CVID patients, we found an abundance of gut Gammaproteobacteria to be associated with raised plasma levels of TMAO, inflammatory markers TNF and IL-12 and lipopolysaccharide. This indicates a connection between gut leakage, TMAO and inflammation in CVID. Overall, gut microbial dysbiosis in CVID patients appears linked to systemic inflammation through the metabolite TMAO and altered lipid metabolism via reduced reverse cholesterol transport. Modulating the gut microbiota using a short-term course of oral antibiotic rifaximin is not sufficient to affect systemic inflammation in CVID. HDL levels and function and gut microbial composition emerge as novel therapeutic targets to reduce sterile systemic inflammation in CVID.