Microbiota-Derived Extracellular Vesicle as Emerging Actors in Host Interactions

Abstract

The human microbiota is an intricate micro-ecosystem comprising a diverse range of dynamic microbial populations mainly consisting of bacteria, whose interactions with hosts strongly affect several physiological and pathological processes. The gut microbiota is being increasingly recognized as a critical player in maintaining homeostasis, contributing to the main functions of the intestine and distal organs such as the brain. However, gut dysbiosis, characterized by composition and function alterations of microbiota with intestinal barrier dysfunction has been linked to the development and progression of several pathologies, including intestinal inflammatory diseases, systemic autoimmune diseases, such as rheumatic arthritis, and neurodegenerative diseases, such as Alzheimer's disease. Moreover, oral microbiota research has gained significant interest in recent years due to its potential impact on overall health. Emerging evidence on the role of microbiota-host interactions in health and disease has triggered a marked interest on the functional role of bacterial extracellular vesicles (BEVs) as mediators of inter-kingdom communication. Accumulating evidence reveals that BEVs mediate host interactions by transporting and delivering into host cells effector molecules that modulate host signaling pathways and cell processes, influencing health and disease. This review discusses the critical role of BEVs from the gut, lung, skin and oral cavity in the epithelium, immune system, and CNS interactions.

Keywords: bacterial extracellular vesicles; dysbiosis; gut-brain axis; immune-cell-response; microbiota; neuroninflammation.

Figure 1

Schematic representation of microbiota’s presence in the human body. In red is indicated the gut microbiota that represents more than 99% of the total microbial community within the body (created with BioRender.com).

Figure 2

Schematic representation of communication network in the body. The communication network in the body is a complex and interconnected system that allows for different organs and systems to work together. There are different axes in the human body that represent bidirectional or multi-directional communications among different body compartments consisting not only of anatomical connections but also of molecules derived from the immune and endocrine systems, metabolites transported through the bloodstream, and bacterial products including BEVs originating from microbiota residing in the different organs. The gut is the key place of interaction with other organs. The brain–gut axis (green) is a complex connection system between the CNS and gastrointestinal tract based on the vagus nerve, enteric nervous system, neuroendocrine system, and circulatory system, thereby affecting the gut microbiota homeostasis and brain function, including behavior. The Gut–Lung–Brain (pink) axis is an intricate network, linking the gut, lung, and brain, that consists of various components, such as vagus nerve, hypothalamus–pituitary–adrenal (HPA) axis, immune system, metabolites, and bacterial microbiota. For instance, the vagus nerve, communicating with the gastrointestinal tract and respiratory apparatus, influences the motility, immunity, permeability of gut mucosa and bronchial smooth muscle contraction, and oxygen consumption. The oral–brain–gut axis (orange) is a complex interconnection among the oral cavity, brain, and gut, and it is mostly observed by studying the role of oral microbiota in periodontitis and neurodegenerative diseases. Microbiota resident in the gut–lung epithelial mucosa are among the targets of these molecules, and, in turn, they respond by producing different mediators (such as fatty acids, gut peptides, BEVs) that impact directly and indirectly the brain functions. The brain–gut–other organ axis (blue) is mainly based on the vagus nerve’s innervation of other organs. In particular, the vagus nerve supplies parasympathetic fibers to all organs, except the adrenal glands, transmitting and receiving information feedback. (Created with BioRender.com).

Figure 3

Structure of the Gram-negative and Gram-positive cell envelope and biogenesis mechanisms of BEVs. (A) The architecture of Gram-negative cell envelope consists of two membranes: outer membrane (OM) and inner membrane (IM). The OM consists of an exterior leaflet of lipopolysaccharides (LPS) and an internal leaflet of phospholipids while IM is composed of a classic phospholipid bilayer. Between IM and OM, there is the periplasmic space, a thin layer of peptidoglycans (PG) in which Braun’s lipoproteins (Lpp) are immersed and covalently link PG to the two layers providing structural integrity to OM. The porin outer-membrane proteins (Omp) and Tol–Pal (peptidoglycan-associated lipoprotein) complex are embedded in OM and interact with OM via PG. The structure of the Gram-positive cell envelope consists of a thick layer of PG in which are present molecules of lipoteichoic acids (LTA) covalently linked to lipids of the underlying cytoplasmic membrane and wall lipoteichoic acids (WTA), conferring a negative charge to Gram-positive bacteria. The plasmatic membrane (PM) is a classic lipid bilayer in which are immerse membrane channels and functional transmembrane proteins (in orange and green colors). The periplasmic space is located between PG and PM. (B) BEV biogenesis occurs through three mechanisms: blebbing, explosive cell lysis, and nanotube formation. Gram-negative bacteria produce mainly OMVs through blebbing and EOMVs through explosive cell lysis in which OM dissociates from the PG, forming OM vesicles; OIMVs are produced by explosive cell lysis and contain both inner and outer membranes. Gram-positive bacteria produce cytoplasmic membranes (CMVs) lacking an OM through an explosive cell lysis mechanism or a non-explosive lysis (bubbling) consisting of the cell integrity loss and cell death. The formation of BEVs from nanotube, filamentous structures occurs in both Gram-positive bacteria, through a process of extrusion of the plasma membrane, and Gram-negative bacteria, from the extrusion of the OM. (Created with BioRender.com).

Figure 4

Schematic interaction between BEVs and cellular barriers in health and disease (created with BioRender.com).