Exosomes are small (nano-sized) particles released by all cells and organisms. They are found in most physiological compartments such as saliva, breast milk, blood, urine, and faeces, and contain various bioactive cargoes including nucleic acid, lipids, and proteins that may or may not be similar to those of the parent cells, which means they can function as signal transmission vehicles, essentially carrying messages to neighbouring/distant cells and can act as autocrine, paracrine, juxtracrine, and endocrine regulators [1], often resulting in functional changes at at the various cell types where their cargo is delivered [2,3]. It is becoming clear that this intercellular regulation plays a vital role in many aspects of human health and disease, including inflammatory bowel disease (IBD)[4], central nervous system (CNS) diseases [5], diabetes [6], and cancer [7]. Accordingly, exosomes have been developed as a promising tool for therapeutic delivery in multiple disease models due to their stability, efficient exchange of cellular components, biocompatibility, and ability to cross natural barriers, and as a multicomponent diagnostic tool due to their presence in various biological fluids [8].

Figure created with BioRender.com

In the brain, exosomes can cross the blood-brain barrier (BBB) which is one of the most complex and selective barriers in the human body, and crossing it remains a major obstacle for new brain therapies [9]. Recent studies have shown that exosomes can play a dual role in brain diseases; (1) remove toxic proteins and aggregates out of the unhealthy cells; (2) deliver these toxic cargoes into healthy cells. For example, they are involved in the delivery and aggregation of α-synuclein in Parkinson’s disease (PD), and the aggregation and degradation of amyloid-beta and tau proteins in Alzheimer’s disease [5]. Hence, they are gaining relevance due to their crucial roles in intercellular communication among brain cells in addition to their involvement in neurodegenerative and neuroinflammatory diseases as well as in brain tumours [10]. Moreover, studies have suggested the use of exosomes as a biomarker for an early and non-invasive diagnosis and prognosis of brain disease, as they are able to migrate from the CNS, and their cargoes can be cell-specific and disease-specific [11].

It is now becoming clear that exosomes mediate not only cell-cell communication, but also organism-cell interaction, including between host and microbiota. The balance between host and commensal microbe is the key to maintaining gut homeostasis which appears critical to maintain a healthy human state. In one direction, exosomes released from commensal bacteria (commonly known as outer-membrane vesicles or OMVs) play a crucial role in the host-microbe communications that regulate various cellular processes such as immune signalling pathways [12]. By extension, pathogenic bacterial exosomes can alter this homeostasis in various ways contributing to disease [13]. Fascinatingly, however, exosomes originating from human cells also appear to function in the opposite direction, with evidence now showing uptake, internalisation and functional changes to species within the microbiota.

The bidirectional communication and crosstalk between the gut and the brain has been well studied, termed the ‘gut-brain axis’ [14]. Recent studies have demonstrated the key role of the gut microbiota in this bidirectional communication, leading to the development of a complex multi-organisms concept of the gut-brain-microbiome axis. It consists of: (1) the neural network including central, autonomic, and enteric nervous systems; (2) the hypothalamic-pituitary-adrenal axis; (3) neuroendocrine networks including neurotransmitters, neuropeptides, and hormones; (4) gut microbiota and their metabolic products; (5) gut immune system; (6) the intestinal and BBB [15]. In addition to their effective interkingdom modulatory function, emerging evidence implies that exosomes are a functional link in the gut-brain-microbiome axis[16]. Notably, the ability of exosomes to cross these systems and drive functional changes within the GBMAs suggests that they play a critical role in the interactions and pathologies of the microbiome-gut-brain axis. Emerging evidence links perturbation in the gut microbiome to various neurological diseases, such as PD [17] , it was shown that PD is associated with gut dysbiosis [18] and modulation of the gut microbiome may be useful in treating neurological age-related disorders [19], which points to a role for exosomes in this kind of multi-system pathology.

A key exosome cargo, microRNA (miRNA), represents a novel regulatory system for the microbiome-gut-brain axis and a potential therapeutic target to modulate microbiome-gut-brain axis function. They are small, non-coding RNA molecules that modulate gene expression at the post-transcriptional level [15] miRNAs can be delivered to various target cells, they are considered a vital component of the exosomes that have been implicated in microbiome-host communications [20]. Gut miRNAs have been associated with dysbiosis which is linked to various diseases [21], on the other hand, gut microbiota modulates gut gene expression by modulating miRNAs expression in gut cells [22]. They also modulate brain miRNAs expression [23], therefore, exosomes can be considered a novel regulatory system for bi-directional communication in the microbiome-gut-brain axis via intercellular transfer of miRNAs; fascinatingly, there is now evidence that these human regulatory RNAs can directly target bacterial RNA – providing evidence that exosomes as a miRNA delivery system may be able to regulate the microbiome towards healthy or pathogenic states [24]. Not only that, but because of their cross-system nature, brain-derived exosomes may alter the gut and the microbiota via a ‘top-down’ manner, in parallel, microbiota-derived exosomes may modulate the pathophysiological condition of the brain via a ‘bottom-up’ manner as they are capable to cross the BBB [25].

It therefore seems that exosomes could be considered a highly novel regulatory system for the complex multi-directional communications in the microbiome-gut-brain axis and should be considered as a key link in conditions that link the diverse environment of gut, brain and microbiome.


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