Table 3.
Therapeutic mechanisms of microbial EVs.
| Species | Indication | Mechanism | Ref. |
|---|---|---|---|
| Akkermansia muciniphila (A. muciniphila) | Colitis | In vitro pretreatment with A. muciniphila EVs induced secretion of the proinflammatory cytokine IL-6 from colon epithelial cells. Additionally, oral application of A. muciniphila EVs protected against IBD characteristics, such as bodyweight loss, decreased colon length, and inflammatory cell infiltration of colon wall. | Kang et al.104 |
| Metabolic disease | A. muciniphila EV administration enhanced tight junction function, reduced bodyweight gain, and improved glucose tolerance in diabetic mice. Additionally, A. muciniphila EVs decreased the gut permeability of LPS-treated Caco-2 cells. The expression of occludin was increased by A. muciniphila EV treatment. | Chelakkot et al.106 | |
| Bacteroides flagilis (B. flagilis) | Colitis | PSA in B. flagilis EVs induced immunomodulatory effects and prevented experimental colitis. DCs sensed B. flagilis EV-associated PSA through TLR2, resulting in enhancement of regulatory T cells and anti-inflammatory cytokine production. DCs treated with B. flagilis EVs containing PSA prevented experimental colitis. | Shen et al.128 |
| Bifidobacterium longum (B. longum) | Food allergy | B. longum EVs bound specifically to mast cells and induced apoptosis without affecting T cell immune responses. Furthermore, injection of B. longum EVs carrying extracellular solute-binding protein into mice markedly reduced the occurrence of diarrhea in a mouse food allergy model. | Kim et al.111 |
| Bifidobacterium bifidum (B. bifidum) | Allergen-specific immunotherapy | DCs stimulated by B. bifidum EVs strongly promoted differentiation of functional CD25highFOXP3highCD127−/low Treg cells and induced the higher levels of IL-10 than of the proinflammatory cytokines IFN-γ, TNF-α and IL-17. B. bifidum EVs can be potentially used as an effective adjuvant for immunotherapy. | Lopez et al.129 |
| Bacteroides vulgatus (B. vulgatus) | Systemic disease | BMDCs stimulated by B. vulgatus EVs led to the induction of a tolerant semimature phenotype. Thereby, the MAMPs delivered by B. vulgatus EVs were crucial for the interaction and the resulting maturation of immune cells. In addition to molecules binding to host TLR4, a yet unknown ligand of TLR2 is indispensable for the conversion of immature BMDCs into a semimature state. Thus, by crossing the epithelial mucus layer and directly contacting host cells, B. vulgatus EVs mediated cross-tolerance via the transport of various Toll-like receptor antigens. | Maerz et al.130 |
| Escherichia coli (E. coli) | Cancer | Administered E. coli EVs specifically targeted and accumulated in the tumor tissue and subsequently induced the production of the antitumor cytokines CXCL10 and IFN-γ. | Kim et al.131 |
| Klebsiella pneumonia (K. pneumoniae) | Breast cancer | K. pneumoniae EVs enhanced the antihormonal effects of tamoxifen in MCF7 cells via Cyclin E2 and p-ERK. | An et al.132 |
| Lactobacillus plantarum (L. plantarum) | Atopic dermatitis | In vitro, IL-6 secretion from keratinocytes and macrophages was decreased and cell viability was restored with L. plantarum EV treatment. Additionally, in mouse AD models, L. plantarum EV administration reduced epidermal thickening and the IL-4 level. | Kim et al.107 |
| Skin inflammation | L. plantarum EVs promoted differentiation of human monocytic THP1 cells toward an anti-inflammatory M2 phenotype, specifically, the M2b phenotype, by inducing biased expression of cell surface markers and cytokines associated with M2 macrophages. Pretreatment or posttreatment with L. plantarum EVs under inflammatory M1 macrophage-favoring conditions, induced by LPS and IFN-γ, inhibited M1-associated surface marker (HLA-DRα) expression. Moreover, L. plantarum EVs treatment significantly induced IL-1β, GM-CSF and IL-10 expression in human skin organ cultures. Hence, L. plantarum EVs can trigger M2 macrophage polarization in vitro, and induce an anti-inflammatory phenomenon in human skin. | Kim et al.108 | |
| Depression | L. plantarum EVs could have a role in regulating neuronal function and stress-induced depressive-like behaviors. HT22 cells treated with the stress hormone glucocorticoid had reduced expression of BDNF and Sirt1, whereas L. plantarum EVs treatment reversed glucocorticoid-induced decreases in the expression of BDNF and Sirt1. siRNA-mediated knockdown of Sirt1 in HT22 cells decreased BDNF4, a splicing variant of BDNF, and Creb expression, suggesting that Sirt1 plays a role in the L. plantarum EV-induced increase in BDNF and Creb expression. L. plantarum EV treatment in mice rescued the reduced expression of BDNF, and blocked stress-induced depressive-like behaviors. Furthermore, L. plantarum EV injection inhibited the reduced expression of BDNF and Nt4/5 and stress-induced depressive-like behaviors. These results suggest that L. plantarum EVs can change the expression of neurotropic factors in the hippocampus and induce antidepressant-like effects in mice with stress-induced depression. | Choi et al.117 | |
| Lactobacillus paracasei (L. paracasei) | Inflammatory bowel disease |
In in vitro experiments, L. paracasei EVs reduced the expression of the LPS-induced pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, and TNF-α), LPS-induced inflammation in HT29 cells, and the activation of inflammation-associated proteins (COX-2, iNOS, NF-κB, and NO) but increased the expression of the anti-inflammatory cytokines IL-10 and TGF-β. In in vivo mouse experiments, oral administration of L. paracasei EVs also protected against DSS-induced colitis by reducing weight loss, maintaining colon length, and decreasing the disease activity index. In addition, L. paracasei EVs induced the expression of endoplasmic reticulum stress-associated proteins, while the inhibition of these proteins blocked the anti-inflammatory effects of L. paracasei EVs in LPS-treated HT29 cells, restoring the pro-inflammatory effects of LPS. L. paracasei EVs attenuated LPS-induced inflammation in the intestine through endoplasmic reticulum stress activation. |
Choi et al.105 |
| Lactobacillus kefir (L. kefir), Lactobacillus kefiranofaciens (L. kefiranofaciens), Lactobacillus kefirgranum (L. kefirgranum) | Inflammatory bowel disease | Treatment of TNF-α-stimulated Caco-2 cells with each kefir-derived Lactobacillus EV type (L. kefir, L. kefiranofaciens, and L. kefirgranum) reduced both mRNA expression and the IL-8 level in association with inhibition of TNF-α signaling by reducing the phosphorylation of p65, a subunit of NF-κB. Subsequent administration of kefir-derived Lactobacillus EVs into IBD mice alleviated bodyweight loss and rectal bleeding and enhanced stool consistency. Histological examination showed that kefir-derived Lactobacillus EVs substantially reduced the infiltration of transmural leukocytes and loss of goblet cells within the colon, and the serum level of myeloperoxidase was significantly lower in the EV-treated group than control group. | Seo et al.109 |
| Lactobacillus sakei (L. sakei) | Immune system disease | IgA production in Peyer’s patch cells was enhanced by L. sakei EVs. In addition, stimulation of BMDCs with L. sakei EVs increased gene expression of inducible NO synthase, retinaldehyde dehydrogenase 2, and several inflammatory cytokines via TLR2. | Miyoshi et al.110 |
| Lactobacillus rhamnosus (L. rhamnosus) | Enteric nervous system disease | Ingested labeled L. rhamnosus EVs were detected in murine Peyer’s patch DCs within 18 h. After 3 days, Peyer’s patch and mesenteric lymph node DCs assumed a regulatory phenotype and increased functional regulatory CD4+25+Foxp3+ T cells. L. rhamnosus EVs similarly induced phenotypic changes in cocultured DCs via multiple pathways including C-type lectin receptors specific intercellular adhesion molecule-3 grabbing nonintegrin-related 1 and Dectin-1, as well as TLR-2 and TLR-9. L. rhamnosus EVs also decreased the amplitude of neuronally dependent MMCs in an ex vivo model of peristalsis. Gut epithelial application of L. rhamnosus EVs caused an increase in the number of action potentials recorded in adjacent patch-clamped sensory neurons. | AI-Nedawi et al.133 |
PSA polysaccharide A, DC dendritic cell, BMDC bone marrow-derived dendritic cell, ERK extracellular signal-regulated kinase, MAMP microbe-associated molecular pattern.