Sepsis-Like Systemic Inflammation Induced by Nano-Sized Extracellular Vesicles From Feces

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.

The Uptake, Trafficking, and Biodistribution of Bacteroides thetaiotaomicron Generated Outer Membrane Vesicles

“…We have shown that within 8 h of oral administration small numbers of labeled OMVs are evident in several organs and most notably the liver. In contrast to the parenteral administration of OMVs described in previous studies (Jang et al, 2015;Wiklander et al, 2015;Kim et al, 2017;Park et al, 2018), oral administration of Bt OMVs facilitates their interaction with the host GI-tract that is analogous to that of endogenously produced OMVs (Sonnenburg et al, 2005;Porter et al, 2017). The finding that the vast majority of Bt OMVs remain in the lumen of the GI-tract suggests that the general fate of OMVs generated in vivo is excretion.…”

“…Following our observation that Bt OMVs transmigrate across the intestinal epithelium, we sought to determine if after oral administration Bt OMVs could reach systemic tissues. Using an in vivo model adapted from those previously described (Park et al, 2010(Park et al, , 2018Jang et al, 2015;Wiklander et al, 2015;Kim et al, 2017), far-red fluorescent DiD-labeled Bt OMVs were orally administered to mice for 8 h prior to organ excision and imaging using a Bruker in vivo Xtreme imaging system. This time-point of tissue collection was optimal to observe the early stages of Bt OMV biodistribution to tissues via the blood stream.…”

The extracellular vesicle of gut microbial Paenalcaligenes hominis is a risk factor for vagus nerve-mediated cognitive impairment

“…Paenalcaligenes hominis LPS was purified as described previously (Supplement Methods) [26]. FITC (F7250 Sigma, Aldrich)-conjugated EVs (FITC to protein ratio, 0.01) and LPS (FITC to LPS ratio, 0.1) were prepared as described by Park et al [48].…”

Current State of Precision Medicine in Primary Systemic Vasculitides

“…EVs are responsible for immune regulation, cell-to-cell interaction, and signal transmission by transporting bioactive molecules including proteins and lipids, DNA, and various RNAs, such as mRNAs, small-interfering RNAs (siRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) and other molecules produced by cells (132,(137)(138)(139). EVs can be detected in many organs, tissues, and all body fluids, such as urine, blood, and synovial fluid at low levels in physiological conditions (140,141). The increased levels of EVs are noted in cardiovascular disease, cancer, and pathological conditions that are associated with vasculitis: inflammation, autoimmunity, endothelial damage, angiogenesis, procoagulation, and intimal hyperplasia (131-133, 136, 140-142).…”