Circadian Rhythm Disruption Influenced Hepatic Lipid Metabolism, Gut Microbiota and Promoted Cholesterol Gallstone Formation in Mice.

Background: Hepatic lipid metabolism regulates biliary composition and influences the formation of cholesterol gallstones. The genes Hmgcr and Cyp7a1, which encode key liver enzymes, are regulated by circadian rhythm-related transcription factors. We aimed to investigate the effect of circadian rhythm disruption on hepatic cholesterol and bile acid metabolism and the incidence of cholesterol stone formation. Methods: Adult male C57BL/6J mice were fed either a lithogenic diet (LD) only during the sleep phase (time-restricted lithogenic diet feeding, TRF) or an LD ad libitum (non-time-restricted lithogenic diet feeding, nTRF) for 4 weeks. Food consumption, body mass gain, and the incidence of gallstones were assessed. Circulating metabolic parameters, lipid accumulation in the liver, the circadian expression of hepatic clock and metabolic genes, and the gut microbiota were analyzed. Results: TRF caused a dysregulation of the circadian rhythm in the mice, characterized by significant differences in the circadian expression patterns of clock-related genes. In TRF mice, the circadian rhythms in the expression of genes involved in bile acid and cholesterol metabolism were disrupted, as was the circadian rhythm of the gut microbiota. These changes were associated with high biliary cholesterol content, which promoted gallstone formation in the TRF mice. Conclusion: Disordered circadian rhythm is associated with abnormal hepatic bile acid and cholesterol metabolism in mice, which promotes gallstone formation.

Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells.

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.

Omics Analyses of Gut Microbiota in a Circadian Rhythm Disorder Mouse Model Fed with Oolong Tea Polyphenols.

Microbiome has been revealed as a key element involved in maintaining the circadian rhythms. Oolong tea polyphenols (OTP) has been shown to have potential prebiotic activity. Therefore, this study focused on the regulation mechanisms of OTP on host circadian rhythms. After 8 weeks of OTP administration, a large expansion in the relative abundance of Bacteroidetes with a decrease in Firmicutes was observed, which reflected the positive modulatory effect of OTP on gut flora. In addition, Kyoto Encyclopedia of Genes and Genomes pathways of ATP-binding cassette transporters, two-component system, and the biosynthesis of amino acids enriched the most differentially expressed genes after OTP treatment. Of the differentially expressed proteins identified, most were related to metabolism, genetic information processing, and environmental information processing. It underscores the ability of OTP to regulate circadian rhythm by enhancing beneficial intestinal microbiota and affecting metabolic pathways, contributing to the improvement of host microecology.