Gut Microbiome and Circadian Interactions with Platelets Across Human Diseases, including Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, and Cancer

Abstract

Platelets have traditionally been investigated for their role in clot formation in the course of cardiovascular diseases and strokes. However, recent work indicates platelets to be an integral aspect of wider systemic processes, with relevance to the pathophysiology of a host of diverse medical conditions, including neurodegenerative disorders and cancer. This article reviews platelet function and interactions with the gut microbiome and circadian systems, highlighting the role of the platelet mitochondrial melatonergic pathway in determining platelet activation, fluxes and plasticity. This provides a number of novel conceptualizations of platelet function and mode of interaction with other cell types, including the pathoetiology and pathophysiology of diverse medical conditions, such as cancer, Alzheimer’s disease, and amyotrophic lateral sclerosis. It is proposed that a platelet-gut axis allows platelets to contribute to many of the pathophysiological processes linked to gut dysbiosis and gut permeability. This is at least partly via platelet sphingosine- 1-phosphate release, which regulates enteric glial cells and lymphocyte chemotaxis, indicating an etiological role for platelets in a wide array of medical conditions linked to alterations in the gut microbiome. Platelets are also an important regulator of the various microenvironments that underpin most human medical conditions, including the tumor microenvironment, neurodegenerative diseases, and autoimmune disorders. Platelet serotonin release regulates the availability of the mitochondrial melatonergic pathway systemically, thereby being an important determinant of the dynamic metabolic interactions occurring across cell types that underpin the pathoetiology of many medical conditions. In addition, a number of novel and diverse future research directions and treatment implications are proposed.

Role of the Night-Time Systemic Processes and the Astrocyte Tryptophan-Melatonin Pathway in the Regulation of α-Synuclein and Wider Parkinson’s Disease Pathophysiology

“…Many PD prodromal symptoms, including REM sleep behavioral disorder and sleep/circadian dysregulation, are evident at night, indicative of alterations in night-time processes in PD pathoetiology [104,105]. As highlighted recently in other medical conditions, alterations in the nighttime interactions of melatonin, butyrate and BAG-1 with GR activation in the course of CAR and stress-linked HPA axis activity may be important to the pathoetiology of diverse medical disorders, including cancer, Alzheimer's disease and amyotrophic lateral sclerosis [30]. A growing body of data indicates the role of stress/trauma in the pathoetiology of REM sleep behavior disorder [106], with most REM sleep behavior disorder patients being diagnosed within 10 years with an αsynucleinopathy [107].…”

“…Both erythrocytes and platelets are significant producers of α-synuclein, with erythrocyte α-synuclein proposed to seed the increase in gut α-synuclein in PD [28], thereby initiating alterations in the gut microbiome and gut permeability, whilst also providing α-synuclein to be retrogradely transported via the vagal nerve to the CNS [1]. There is a growing appreciation of the role of platelets in neurodegenerative disorders and other medical conditions, including cancer [30]. Importantly, like SNpc dopamine neurons, platelets are regulated by systemic processes, including circadian melatonin and gut microbiomederived butyrate and lipopolysaccharide (LPS), with platelet-derived serotonin being an important serotonin source for the initiation of the melatonergic pathway across body and CNS microenvironments [30].…”

“…There is a growing appreciation of the role of platelets in neurodegenerative disorders and other medical conditions, including cancer [30]. Importantly, like SNpc dopamine neurons, platelets are regulated by systemic processes, including circadian melatonin and gut microbiomederived butyrate and lipopolysaccharide (LPS), with platelet-derived serotonin being an important serotonin source for the initiation of the melatonergic pathway across body and CNS microenvironments [30]. Platelet function may therefore be synchronized with wider changes in PD via regulation by systemic processes as well as genetic factors and epigenetic processes.…”

“…Platelet function may therefore be synchronized with wider changes in PD via regulation by systemic processes as well as genetic factors and epigenetic processes. Platelets are also a significant source of sphingosine-1-phosphate (S1P), which regulates enteric glial cell function and lymphocyte chemotaxis to the gut [30], as well as attenuating SNpc dopamine neuron loss [31]. The enteric nervous system [32], and especially enteric glial cells may be crucial regulators of the interface of the gut, immunity and vagal nerve in PD, as in other gut-linked medical conditions [9].…”

“…Is late or midsleep feeding relevant to PD pathoetiology? Given that melatonin increases gut butyrate, seals the gut barrier and suppresses circulating LPS [123], is the production of butyrate at night intimately linked to variations in pineal melatonin production and therefore to the dramatic decrease in pineal melatonin over aging [30]?…”