Role of Microbiota-Derived Extracellular Vesicles in Gut-Brain Communication

Abstract

Human intestinal microbiota comprise of a dynamic population of bacterial species and other microorganisms with the capacity to interact with the rest of the organism and strongly influence the host during homeostasis and disease. Commensal and pathogenic bacteria coexist in homeostasis with the intestinal epithelium and the gastrointestinal tract's immune system, or GALT (gut-associated lymphoid tissue), of the host. However, a disruption to this homeostasis or dysbiosis by different factors (e.g., stress, diet, use of antibiotics, age, inflammatory processes) can cause brain dysfunction given the communication between the gut and brain. Recently, extracellular vesicles (EVs) derived from bacteria have emerged as possible carriers in gut-brain communication through the interaction of their vesicle components with immune receptors, which lead to neuroinflammatory immune response activation. This review discusses the critical role of bacterial EVs from the gut in the neuropathology of brain dysfunctions by modulating the immune response. These vesicles, which contain harmful bacterial EV contents such as lipopolysaccharide (LPS), peptidoglycans, toxins and nucleic acids, are capable of crossing tissue barriers including the blood-brain barrier and interacting with the immune receptors of glial cells (e.g., Toll-like receptors) to lead to the production of cytokines and inflammatory mediators, which can cause brain impairment and behavioral dysfunctions.

Keywords: bacteria; brain; extracellular vesicles; microbiota; neuropathology.

Figure 1

Architecture and composition of eukaryotic and bacterial extracellular vesicles. (A) Eukaryotic microvesicle, lipid bilayer-enclosed structures formed by the outward budding and fission of the plasma membrane with characteristic components such as flotillin-2, selectins, integrins, metalloproteinases and a high level of phosphatidylserine on the envelope. (B) Bacteria Gram-positive vesicles are comprised of the cytoplasmic membrane and also lipid bilayer-enclosed spheres and the cargo comes from the cytoplasm. (C) The outer membrane vesicles (OMVs) from Gram-negative bacteria are produced through outer membrane blebbing, whose cargo comes from the periplasm and contains peptidoglycan and periplasmic proteins and lipopolysaccharide (LPS) on their surface. (D) Outer-inner membrane vesicles (O-IMVs) are produced by Gram-negative bacteria under extreme stress or explosive cell lysis and contain a double bilayer showing inner membrane proteins and cytoplasmic proteins.

Figure 2

Scheme of the three possible mechanisms used by bacterial vesicles to penetrate the BBB. EVs can cross the BBB by themselves, in infected immune cells or through bacteria in different disorders. Once bacterial EVs are inside the brain, membrane components and the cargo of vesicles act as ligands of innate immune receptors (e.g., TLRs, NALP3 inflammasome) and activate the inflammatory immune response.

Figure 3

Bacterial EVs released during dysbiosis are able to cause brain disorders. In dysbiosis, the abundance of pathogenic bacterial species and harmful molecules such as LPS, peptidoglycans and toxins increase in the gastrointestinal tract and the intestinal epithelium is damaged by both bacterial activity and the inflammatory immune response, which increases the permeability and the transfer of EV components (e.g., LPS, RNA, DNA, proteins) from the intestinal lumen to the bloodstream. EVs might use paracellular and/or transcellular pathways to cross the intestinal barrier or be released by the bacteria already in blood vessels. If these vesicles reach the CNS, they activate immune cells (e.g., astrocytes and microglia) through the immune receptors of TLRs by triggering pro-inflammatory cytokines and causing neuronal damage.