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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.

Diabetic foot ulcer (DFU) is a major complication of diabetes mellitus, major observations of DFU cases have reported on amputation of foot region, and microbial bioburden during DFU is a major cause that affects healing of the wound regions. Pathogenic microbes are routinely isolated from these wound regions, especially Staphylococcus, Pseudomonas, Klebsiella, and Escherichia coli have been reported, whereas higher prevalence of Pseudomonas species during chronic condition in the deeper part of the wound, when left untreated, leads to gangrene. Multiple drug-resistant Pseudomonas strains are a new threat because of their biofilm-forming ability, making it more potent and incurable. Acyl homoserine lactones (AHL) are a group of signaling molecules that can regulate biofilm growth, and Las and Rhl operon generally work in tandem to initiate biofilm formation by Pseudomonas species. These signaling molecules also initiate virulence factors that correlates upregulation of inflammatory responses, and AHL can be a therapeutic target in order to prevent the efficacy of multiple drug-resistant strains that form biofilm and also can be an alternative solution against control of multiple drug-resistant strains.

Diabetic foot ulcers (DFUs) are characterized by a lack of angiogenesis and distal limb diabetic neuropathy. This makes it possible for opportunistic pathogens to protect the biofilm-encased micro-communities, causing a delay in wound healing. The acute and chronic phases of DFU-associated infections are distinguished by the differential expression of innate proinflammatory cytokines and tumor necrosis factors (TNF-α and -β). Efforts are being made to reduce the microbial bioburden of wounds by using therapies such as debridement, hyperbaric oxygen therapy, shock wave therapy, and empirical antibiotic treatment. However, the constant evolution of pathogens limits the effectiveness of these therapies. In the wound-healing process, continuous homeostasis and remodeling processes by commensal microbes undoubtedly provide a protective barrier against diverse pathogens. Among commensal microbes, probiotics are beneficial microbes that should be administered orally or topically to regulate gut–skin interaction and to activate inflammation and proinflammatory cytokine production. The goal of this review is to bridge the gap between the role of probiotics in managing the innate immune response and the function of proinflammatory mediators in diabetic wound healing. We also highlight probiotic encapsulation or nanoformulations with prebiotics and extracellular vesicles (EVs) as innovative ways to tackle target DFUs.

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