Increased levels of systemic LPS-positive bacterial extracellular vesicles in patients with intestinal barrier dysfunction

We read with interest recent papers reporting on the impact of gut microbiota on several aspects of health and disease due to altered intestinal permeability resulting in systemic immune activation by pathogen-associated molecular patterns (PAMP), a process termed microbial translocation.1–4 Common to these studies is the analysis of systemic lipopolysaccharide (LPS), the major outer membrane PAMP of Gram-negative bacteria, to quantitatively assess microbial translocation. While systemic LPS is typically regarded as a soluble product, either or not neutralised by lipoproteins and endotoxin core antibodies, LPS is also released as a membrane-associated PAMP through extracellular vesicles (EV).5–7 Bacterial EV are nanometre-sized membrane particles transporting nucleic acids, metabolites, proteins and endotoxins.8 As such, bacterial EV that enter the systemic circulation may deliver and elicit a variety of immunological and metabolic responses in different organs including the brain.9 To date, the systemic presence and activity of bacterial EV in patients with intestinal barrier dysfunction have not been investigated. Here, we fractionated plasma of 49 subjects to distinguish bacterial EV-associated LPS from other LPS products (online supplementary file 1 …