https://orcid.org/0000-0002-5587-5520
Figures & data
Figure 1. Formation of MVs from the three domains of life and factors that influence their secretion.
The three life domains are Eukarya, Archaea, and Bacteria.
Figure 2. Overview of bacterial membrane vesicles.
This overview centers on general knowledge regarding the biogenesis, composition, and functions of bacterial MVs.
Table 1. Differences between MVs produced by Gram-negative bacteria and Gram-positive bacteria.
Figure 3. Composition and functions of MVs from Gram-positive and Gram-negative bacteria.
The cargos of MVs from Gram-negative bacteria differ slightly from that of Gram-positive. Represented functions include biofilm formation, antibiotics resistance, phage neutralization, immune modulation, gene transfer, the killing of microorganisms, and gut microbiota homeostasis.
Figure 4. MVs in phage neutralization, antibiotics resistance, gene transfer, and delivery of bioactive compounds.
MVs on the surface of their parent bacteria can neutralize phages by binding to them. They can also inactivate antibiotics by the same mechanism or by releasing enzymes that confer resistance to the parent bacteria. MVs are also involved in the transfer of antibiotic-resistance genes and other virulence factors to different bacteria species. These will in turn inhibit the actions of host defense factors, preventing the elimination of the bacterial pathogens from the system. They can also mediate the transfer of bioactive molecules that can aid host defense factors in the elimination of harmful pathogens.
Figure 5. Internalization of membrane vesicles into host cells and modulation of the immune system.
MVs are internalized by epithelial cells via macropinocytosis (dependent on actin), clathrin-mediated/caveolin-mediated endocytosis, membrane fusion, and lipid-raft. MVs interact with various immune cells upon internalization to elicit an immune response. MVs of P. gingivalis containing gingipains selectively coat, activate, and consequently degranulate neutrophils to ensure the survival of the parent bacterium. MVs can activate naïve macrophages via interactions of their MAMPS with PRR present in macrophages. Interactions of MVs-derived LPS, LTA, DNAs, and flagellins, with TLRs of macrophages can polarize them to either M1 or M2 phenotype (depending on the producing bacteria, among other factors), inducing the expression of anti-/pro-inflammatory cytokines. DCs activate the expression of cytokines (TNF-α and IL-12) and specific surface molecules (CD86 and MHC-II molecules) that promote differentiation of T-cells to specific functional subsets immediately upon internalization of bacterial membrane vesicles. MAMPS – Microbe-associated molecular patterns; PRR – Pattern recognition receptors, LTA – Lipoteichoic acid, DNA – Deoxyribonucleic acid, TLRs – Toll-like receptors.
Table 2. Bacterial MVs in the pathogenesis of IBD.
Figure 6. Bacterial membrane vesicles in the pathogenesis of IBD.
Membrane vesicles (MVs) from pathogenic bacteria promote inflammation in the gut. MVs from ETEC, after internalization by intestinal epithelial cells, release their LPS, inducing the release of strong proinflammatory cytokines. MVs from E. coli BL21 promote the recruitment of caspase-5 and PIKfyve upon internalization by intestinal epithelial cells, also resulting in the release of their LPS into the cytosol, which culminates in intestinal barrier dysfunction. Fn-MVs triggered an upregulation of the proinflammatory cytokines IL-1β, IL-6, TNF-α, and iNOS and downregulation of anti-inflammatory IL-10 in vitro and in vivo. These MVs also enhanced apoptosis of intestinal epithelial cells by inducing the pro-inflammatory M1 phenotype, resulting in intestinal barrier dysfunction via FADD-RIPK1-caspase 3 signaling. They significantly reduced the levels of tight junction proteins ZO-1, claudin-1, and occludin, as well as MUC-1 and −2, dysregulating the epithelial barrier integrity. MVs from E. coli and Ruminococcus gnavus have been found to increase biofilm formation in the gut, limiting the efficacy of host defense factors and antibiotics against the parent bacterium.
Table 3. Application of MVs in IBD therapy.
Figure 7. Bacterial membrane vesicles (MVs) repair the intestinal epithelial integrity and restore gut microbiota homeostasis.
(a) MVs from a variety of probiotics (L. kefirgranum PRCC-1301, F. prausnitzii, C. butyricum, A. muciniphila) have been implicated in the repair of damaged intestinal epithelial barrier resulting from colitis. They upregulate tight junction proteins occludin, claudin-1, ZO-1, and mucin 1, 2, 3, and 4. Exposure of MVs from fecal fermentation to miR-200b-3p also upregulated the intestinal epithelial mucins and claudin-3. (b) MVs from A. muciniphila selectively promoted the proliferation of beneficial bacteria B. acidifaciens, B. thetaiotaomicron, and B. fragilis by fusion but did not fuse with pathogenic B. vulgatus thereby inhibiting its growth. MVs from L. plantarum Q7, L. rhamnosus GG, and fucoxanthin-loaded MVs (FX-MVs) from L. plantarum re-modeled DSS-damaged gut microbiota promoting microbial diversity present and richness, grossly reducing the population of harmful bacteria and promoting the proliferation of probiotics and commensals. Increased short-chain fatty acids (SCFAs), were observed in FX-MVs re-modeled gut.
Figure 8. Bacterial membrane vesicles modulate the immune system under IBD conditions to enhance intestinal immune barrier function.
C. butyricum-MVs restored the expression miR-199a-3p, which targets map3k4, suppressing proinflammatory MAPK and NF-κB signaling pathways. These MVs also polarized macrophages to M2 phenotype and significantly reduced the levels of plasma LPS, IL-6, and TNF-α. F. prausnitzii-MVs increased the ratio of T-reg cells, downregulating the expression of proinflammatory cytokines and upregulating the anti-inflammatory cytokines. A. muciniphila-MVs elicited mucosal immunoglobulin A response by translocating into Peyer’s patches and then activating DCs and B-cells preventing invasion by pathogens. Interaction of DCs with capsular polysaccharide A-containing MVs of B. fragilis via Growth Arrest and DNA-Damage Inducible protein (Gadd45α) prevented colitis by suppression of TNF-α and IL-17 and increased secretion of IL-10. These MVs also stimulated increased production of IL-10 from T-reg cells. P. pentosaceus-derived MVs promoted M2-like macrophage polarization and myeloid-derived suppressor cell differentiation, eliciting increased expressions of IL-10 and arginase-1 from the differentiated cells.
