Membrane Vesicles Derived from Gut Microbiota and Probiotics: Cutting-Edge Therapeutic Approaches for Multidrug-Resistant Superbugs Linked to Neurological Anomalies

Abstract

Multidrug-resistant (MDR) superbugs can breach the blood-brain barrier (BBB), leading to a continuous barrage of pro-inflammatory modulators and induction of severe infection-related pathologies, including meningitis and brain abscess. Both broad-spectrum or species-specific antibiotics (β-lactamase inhibitors, polymyxins, vancomycin, meropenem, plazomicin, and sarecycline) and biocompatible poly (lactic-co-glycolic acid) (PLGA) nanoparticles have been used to treat these infections. However, new therapeutic platforms with a broad impact that do not exert off-target deleterious effects are needed. Membrane vesicles or extracellular vesicles (EVs) are lipid bilayer-enclosed particles with therapeutic potential owing to their ability to circumvent BBB constraints. Bacteria-derived EVs (bEVs) from gut microbiota are efficient transporters that can penetrate the central nervous system. In fact, bEVs can be remodeled via surface modification and CRISPR/Cas editing and, thus, represent a novel platform for conferring protection against infections breaching the BBB. Here, we discuss the latest scientific research related to gut microbiota- and probiotic-derived bEVs, and their therapeutic modifications, in terms of regulating neurotransmitters and inhibiting quorum sensing, for the treatment of neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases. We also emphasize the benefits of probiotic-derived bEVs to human health and propose a novel direction for the development of innovative heterologous expression systems to combat BBB-crossing pathogens.

Keywords: blood–brain barrier; extracellular vesicles; gut microbiota; membrane vesicles; meningitis; probiotics; superbugs.

Figure 1

Bottom-up approach for the transport of probiotic-derived extracellular vesicles (bEVs). The figure was created using BioRender.com (https://app.biorender.com; accessed on 2 November 2022).

Figure 2

Application of the CRISPR/Cas system for the development of biotherapeutic tools against infections crossing the BBB. (A) Lactobacillus expression host, (B) CRISPR/Cas expression vector, (C) expression of the engineered vector in Lactobacillus, (D) CRISPR/Cas-enriched Lactobacillus bEV, and (E) targeted therapy against pathogenic bacteria via surface protein receptors. The figure was created using BioRender.com (https://app.biorender.com; accessed on 2 November 2022).

Figure 3

Remodeling of probiotic-derived bEVs against BBB related anomalies. The figure was created using BioRender.com (https://app.biorender.com; accessed on 2 November 2022).