Fantastic voyage: the journey of intestinal microbiota-derived microvesicles through the body

Abstract

As part of their life cycle, Gram-negative bacteria produce and release microvesicles (outer membrane vesicles, OMVs) consisting of spherical protrusions of the outer membrane that encapsulate periplasmic contents. OMVs produced by commensal bacteria in the gastrointestinal (GI) tract of animals are dispersed within the gut lumen with their cargo and enzymes being distributed across and throughout the GI tract. Their ultimate destination and fate is unclear although they can interact with and cross the intestinal epithelium using different entry pathways and access underlying immune cells in the lamina propria. OMVs have also been found in the bloodstream from which they can access various tissues and possibly the brain. The nanosize and non-replicative status of OMVs together with their resistance to enzyme degradation and low pH, alongside their ability to interact with the host, make them ideal candidates for delivering biologics to mucosal sites, such as the GI and the respiratory tract. In this mini-review, we discuss the fate of OMVs produced in the GI tract of animals with a focus on vesicles released by Bacteroides species and the use of OMVs as vaccine delivery vehicles and other potential applications.

Answers to naysayers regarding microbial extracellular vesicles

“…The potential of EVs as vaccines is sufficient to warrant detailed studies of EVs. (There is some confusion with the clinically approved OMV vaccines, which are extracts from the outer membrane of Neisseria meningitidis, further processed into a vesicular/liposomal form [15,16]. These are not EVs since they do not derive from secretion from bacterial cell.)…”

“…While EVs from C. neoformans and B. anthracis lyze when exposed to serum albumin [58], EVs from C. gattii serve as a relatively long-range communication when interacting with mammalian macrophages [59]. In certain conditions, microbial EVs have remarkably long stability: EVs from gut bacteria were found in the bloodstream of their hosts [16], and EVs can be isolated from seawater [22]. Though these observations may seem contradictory, they may be explained by cargo and composition differences that will have to be clarified in the future.…”

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

“…Bacterial OMVs have been shown to interact with many different mammalian cell types including IECs (Parker et al, 2010;Bielaszewska et al, 2013;Stentz et al, 2014;O'Donoghue et al, 2017), lung epithelial cells (Bauman and Kuehn, 2009), endothelial cells (Kim et al, 2013), and immune cells (Vidakovics et al, 2010;Yoon et al, 2011;Hickey et al, 2015;Vanaja et al, 2016;Deo et al, 2018). Bacterial DNA of potential OMV origin has also been detected in human blood and urine (Yoo et al, 2016;Lee et al, 2017;Park et al, 2017) as well as in body compartments previously thought to be sterile, such as the heart (Svennerholm et al, 2017), suggesting OMVs can reach distant sites from their site of origin and production, including the lumen of the GI-tract (Stentz et al, 2018).…”

Gut microbiota: a new player in regulating immune- and chemo-therapy efficacy

“…EVs produced by the commensal bacteria can cross the intestinal epithelium, where they can regulate the underlying immune cells. Furthermore, bacterial EVs carrying nucleic acids (DNA and RNA) can be secreted into the circulation [40][41][42][43] , detected in human bodily fluids [44,45] , and possibly be delivered to various tissues [ Figure 1] after crossing intestinal epithelium [46] . Therefore, bacteria can potentially regulate the biological functions of host cells through the delivery of their EVs [34,[46][47][48][49] .…”

“…Furthermore, bacterial EVs carrying nucleic acids (DNA and RNA) can be secreted into the circulation [40][41][42][43] , detected in human bodily fluids [44,45] , and possibly be delivered to various tissues [ Figure 1] after crossing intestinal epithelium [46] . Therefore, bacteria can potentially regulate the biological functions of host cells through the delivery of their EVs [34,[46][47][48][49] . Indeed, bacterial EVs can be taken up by eukaryotic host cells and modulate the gene expression of recipient cells [34,45,[50][51][52][53] .…”