The Endocannabinoid System: A Bridge between Alzheimer’s Disease and Gut Microbiota

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that progresses from mild cognitive impairment to severe dementia over time. The main clinical hallmarks of the disease (e.g., beta-amyloid plaques and neurofibrillary tangles) begin during preclinical AD when cognitive deficits are not yet apparent. Hence, a more profound understanding of AD pathogenesis is needed to develop new therapeutic strategies. In this context, the endocannabinoid (eCB) system and the gut microbiome are increasingly emerging as important players in maintaining the general homeostasis and the health status of the host. However, their interaction has come to light just recently with gut microbiota regulating the eCB tone at both receptor and enzyme levels in intestinal and adipose tissues. Importantly, eCB system and gut microbiome, have been suggested to play a role in AD in both animal and human studies. Therefore, the microbiome gut-brain axis and the eCB system are potential common denominators in the AD physiopathology. Hence, the aim of this review is to provide a general overview on the role of both the eCB system and the microbiome gut-brain axis in AD and to suggest possible mechanisms that underlie the potential interplay of these two systems.

Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles

“…An intercommunication system has been found to exist between the gut microbiota and the endocannabinoid system [285,298,[397][398][399][400][401][402]. The gut microbiota, representing more than 100 trillion microorganisms, including at least 1000 distinct species, lives in symbiosis with the host and assists in controlling the metabolic health of the host by degrading nutrients that the host is unable to digest and by providing a whole battery of small signaling molecules, metabolites, and nutrients beneficial for the host physiology [298,403].…”

Impact of bioactive lipids on gut microbiota

“…Importantly, butyrate was shown to upregulate these proteins, thereby restoring the BBB permeability in mice (Melbye et al, 2019). In fact, SCFAs' gastrointestinal levels are associated with CNS disorders, namely AD, suggesting their important role on gut-brain communication (Bisogno et al, 2021). Moreover, in inflammatory diseases, such as IBD and obesity, SCFAs develop an important role since they can also act as signaling molecules to activate GPR receptors -GPR41 and GPR43 -activating signaling cascades that control immune functions (Parada Venegas et al, 2019;Tseng & Wu, 2019).…”

“…Although further members of the endocannabinoid family have been identified and other AA derivatives have been shown to interact with endocannabinoid receptors, AEA and 2-AG are the most studied. AEA and 2-AG are synthesized from AA through enzymatic activation by multiple pathways in the membrane of different cell types such as neurons, adipocytes, and skeletal muscle cells, in response to increased intracellular Ca 2+ concentration, membrane depolarization, and/or receptor stimulation (Bisogno et al, 2021). These bioactive lipids comprise the endocannabinoid system.…”

Mutual Links between the Endocannabinoidome and the Gut Microbiome, with Special Reference to Companion Animals: A Nutritional Viewpoint

“…Several lines of evidence are recently suggesting that the altered eCBome tone featuring obesity and diabetes is correlated with gut dysbiosis [127]. Likewise, eCBome is increasingly being considered an important link between the gut microbiome and certain neuroinflammatory disorders [160]. A summary overview is given in Figure 2 and the available evidence is summarized below.…”