Anderson, George

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.

There is currently an urgent need for a viable, cheap, and readily available treatment for the Ebola virus outbreak in West Africa. Here, it is proposed that melatonin may have significant utility in helping the management of this outbreak. Optimizing natural killer (NK) cell responses seems crucial to surviving Ebola virus infection. Melatonin increases NK cell cytotoxicity significantly, suggesting efficacy in managing the Ebola virus. Under conditions of challenge, melatonin increases heme oxygenase‐1 (HO‐1), which inhibits Ebola virus replication. Melatonin also has protective effects in cases of septic shock, which, although bacterial, has similar end‐point presentations involving blood vessel leakage. Melatonin's effects on haemorrhage are mediated primarily by a decrease in pro‐inflammatory cytokines. By optimizing the appropriate immune response, melatonin is likely to afford protection to those at high risk of Ebola viral infection, as well as having direct impacts on the course of infection per se. Although no direct data pertain to the utility of melatonin in the management of the Ebola virus, convergent bodies of data suggest its utility, which is reviewed in this article. J. Med. Virol. 87:537–543, 2015. © 2015 Wiley Periodicals, Inc.