Abstract
Nano-sized extracellular vesicles (EVs), including exosomes, microvesicles, and other types of vesicles, are released by most mammalian cells and bacteria. We here ask whether feces contain EVs of mammalian and/or bacterial origin, and whether these EVs induce systemic inflammation. Fecal extracellular vesicles (fEVs) were isolated from mice and humans. The presence of EVs from Gram-negative and Gram-positive bacteria was detected by enzyme-linked immunosorbent assay using anti-lipid A and anti-lipoteichoic acid antibodies, whereas Western blot using anti-beta-actin antibody was employed to detect host-derived EVs in the fEVs. Further, fEVs were administered into mice by intraperitoneal injection, and inflammatory responses were investigated in the peritoneum, blood, and lungs. The role of TLR2 and TLR4 were studied using knockout mice. Significant quantities of EVs were present in feces from mice as well as humans, and derived from Gram-negative and Gram-positive bacteria, as well as the host. Bacteria-free fEVs introduced into the peritoneum induced local and systemic inflammation (including in the lungs), but fEVs from germ-free animals had weaker effects. This pronounced local and systemic inflammatory responses seemed to be induced by EVs from both Gram-negative and Gram-positive bacteria, and was attenuated in mice lacking TLR2 or TLR4. Our findings show that fEVs cause sepsis-like systemic inflammation, when introduced intraperitoneally, a process regulated by TLR2 and TLR4.
Highlights
The intestinal tract contains vast quantities of bacteria, and is exposed continuously to environmental antigens and commensal microbes that normally live in a symbiotic and mutually beneficial relationship with their hosts (O’Hara and Shanahan, 2006; Artis, 2008; Hodges and Hecht, 2012)
This study shows that feces contain significant amounts of Fecal extracellular vesicles (fEVs), which are derived from both Gram-negative and Grampositive bacteria, as well as from the host itself
We further show that fEVs have the capacity to induce local inflammation, as well as systemic and pulmonary inflammation, when introduced in a sterile way into the peritoneum
Summary
The intestinal tract contains vast quantities of bacteria, and is exposed continuously to environmental antigens and commensal microbes that normally live in a symbiotic and mutually beneficial relationship with their hosts (O’Hara and Shanahan, 2006; Artis, 2008; Hodges and Hecht, 2012). It has recently been shown that nano-sized extracellular vesicles (EVs) derived from Gram-negative bacteria, such as Escherichia coli, can provoke severe immune responses and signs of septic shock, without the presence of living bacteria (Park et al, 2010; Shah et al, 2012). This effect is substantially more potent than that of bacterial endotoxin lipopolysaccharide (LPS) alone, suggesting that the presence of other bacterial components strongly enhances the induced inflammation. It is known that membrane components derived from Gram-positive bacteria can over-activate the immune responses by binding to pattern-recognition receptors (Moreillon and Majcherczyk, 2003; Hanson and Neely, 2012), and recently we reported that Gram-positive bacteria, such as Staphylococcus aureus, can release EVs (Lee et al, 2009; Hong et al, 2011)
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