Abstract
Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate.
Highlights
The role of circadian dysregulation in multiple sclerosis (MS) is indicated by the modulation of its course by circadian gene alleles [1], and the increased risk associated with single nucleotide polymorphisms (SNPs) in the circadian genes Aryl Hydrocarbon Receptor Nuclear Translocator Like (ARNTL) and Circadian Locomotor Output Cycles Kaput (CLOCK) [2]
We review wider bodies of data on MS pathophysiology, before integrating these into a model that highlights the circadian regulation of mitochondrial function, via the mitochondrial melatonergic pathway and how this may be intimately linked to alterations in the gut microbiome
Low vitamin D and increased body mass index (BMI) can heighten the risk of pediatric MS [14]. Both low vitamin D and increased obesity/high BMI are associated with gut dysbiosis and raised levels of gut permeability [15], with gut dysbiosis linked to circadian dysregulation [16]
Summary
The role of circadian dysregulation in multiple sclerosis (MS) is indicated by the modulation of its course by circadian gene alleles [1], and the increased risk associated with single nucleotide polymorphisms (SNPs) in the circadian genes Aryl Hydrocarbon Receptor Nuclear Translocator Like (ARNTL) and Circadian Locomotor Output Cycles Kaput (CLOCK) [2]. Gut dysregulation modulates MS pathophysiology via a number of routes: (1) LPS activates ceramide, which increases apoptotic susceptibility via detrimental impact on mitochondrial function; (2) ceramide and associated inflammatory cytokines suppress the wake promoting and sleep promoting effects of orexin and melatonin, respectively; (3) the suppression of orexin and melatonin disrupts the circadian rhythm, including from the loss of the mitochondria optimizing effects of orexin and melatonin; (4) the attenuation of gut butyrate production contributes to suboptimal mitochondrial function, which increases apoptotic susceptibility, as well as the reactivity of immune cells, glia, and platelets, contributing to a wider pro-inflammatory milieu Such a model links the wide array of diverse bodies of data pertaining to MS, including data on stress, obesity, melatonin, orexin, the kynurenine pathway, oxidative stress, depression, inflammation, gut dysregulation, mitochondria dysfunction, platelet activation, thrombin, and increased myocardial infarction risk. We review wider bodies of data on MS pathophysiology, before integrating these into a model that highlights the circadian regulation of mitochondrial function, via the mitochondrial melatonergic pathway and how this may be intimately linked to alterations in the gut microbiome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
