Reviewing the Contributions of Circadian Rhythm Dysfunction and Dysbiosis to Blood-Brain Barrier Leakage

The blood-brain barrier is a layer of specialized cells wrapping blood vessels that pass through the brain. Only certain molecules and cells are admitted. The metabolism of the brain is thus isolated from that of the rest of the body. In particular, the immune system of the brain is quite different from that of the rest of the body. Unfortunately, this isolation is a vulnerability when, like all biological systems, the blood-brain barrier begins to break down and leak. The leakage of inappropriate molecules and cells into the brain provokes inflammation and dysfunction, and this is likely a contributing factor in the development of neurodegenerative conditions.

What are the mechanisms leading to blood-brain barrier dysfunction? Researchers here focus on two specific topics, first the disruption of circadian rhythm observed to occur with aging, and secondly age-related changes to the gut microbiome. Circadian rhythm is a regulatory process in cell behavior and signaling that has many aspects, and that is becomes less well orchestrated with age is a whole topic in and of itself. The connections between this and any given dysfunction of aging are usually subtle. The gut microbiome is a little more straightforward, in that pro-inflammatory microbes increase with number, while those microbes producing useful metabolites are diminished in number. Chronic, unresolved inflammation is disruptive to tissues throughout the body, and likely contributes to blood-brain barrier dysfunction.

Targeting the blood-brain barrier to delay aging-accompanied neurological diseases by modulating gut microbiota, circadian rhythms, and their interplays

Aging is an uncontrolled biological process that poses challenges to human health and becomes a social problem that can't be ignored. Aging is regarded as a common risk factor for various human diseases and by reducing sensory, motor, circadian rhythms, and cognitive functions, aging affects the brain morphologically and functionally, resulting in neurological diseases. Importantly, circadian rhythms disruption, characterized by phase shifts and reduced expression of many genes and proteins involved in circadian rhythms greatly impacts aging and longevity in many ways. Disturbances in the circadian rhythms induce disorders of cognitive function, metabolism, mental function, motor control, alertness, blood-brain barrier (BBB) damage, and sleep/wake cycles.

A prospective cohort study of 72,242 participants further supported that disturbances of circadian rhythm are a risk factor for the development of common neurodegenerative and psychiatric disorders. Interestingly, the amount and function of different microbial species fluctuate over time during aging, leading to gut microbiota dysbiosis. The gut microbiota continuously exchanges nutrients, genetic material, and metabolites with the host throughout its life cycle which regulates the homeostasis in the host, including brain function and blood-brain barrier (BBB) integrity. In individuals with neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and multiple sclerosis (MS), circadian rhythm disturbances and gut microbiota dysbiosis are common symptoms. Accumulating data suggest that either circadian rhythms or gut dysbiosis contribute to aging-accompanied neurological diseases (AAND). Notably, the disruption of the circadian system can alter microbiome communities and perturb host metabolism, energy homeostasis, and inflammatory pathways, and gut microbiota can regulate host circadian rhythms and metabolism as a transducer of dietary cues. Genetic defects of a biological clock, timing or restriction of food availability, and light/dark phase changes can significantly affect microbial oscillations, leading to a reduction in microbial abundance and species. In addition, gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs) and bile acids (BA), can alter circadian rhythms, indicating that circadian rhythms and gut microbiota can affect each other, and their interplays can induce subsequent effects.

The BBB provides nutrients to the central nervous system (CNS), maintains homeostasis, and regulates its communication with the periphery, forming a protective barrier for the CNS. The changes and destruction of the structure and functional components of the BBB could occur naturally with the aging process. Aging itself may worsen the disruption of different components of the BBB, thus accelerating the progression of brain damage and an ever-increasing global aging population has stimulated the exploration of the relationship between AAND and BBB, to prevent or delay the prevalence of AAND.

Therefore, there is an urgent need to further investigate the role of the BBB in AAND and the underlying mechanisms of BBB damage induced by aging-accompanied circadian rhythms disruption and dysbiosis of gut microbiota which play important roles in regulating BBB integrity. Further elucidation of the interplay of gut microbiota with circadian rhythms could also shed light on the systemic regulatory mechanisms of aging and the BBB. Here, in this review, we first describe how BBB, circadian rhythms, and gut microbiota are altered during the aging process and how these alterations are exacerbated in AAND. We then discuss the effect of the interplay between circadian rhythms disruption and dysbiosis of gut microbiota on BBB integrity. We then discuss and propose potential mechanisms underlying BBB damage induced by dysregulated circadian rhythms and gut microbiota, which could serve as the basis for developing potential interventions to protect the BBB in the aging population through targeting the BBB by exploiting its links with gut microbiota and circadian rhythms for treating AAND.

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