Administration of Exogenous Melatonin Improves the Diurnal Rhythms of the Gut Microbiota in Mice Fed a High-Fat Diet

Abstract

Melatonin, a circadian hormone, has been reported to improve host lipid metabolism by reprogramming the gut microbiota, which also exhibits rhythmicity in a light/dark cycle. However, the effect of the administration of exogenous melatonin on the diurnal variation in the gut microbiota in mice fed a high-fat diet (HFD) is unclear. Here, we further confirmed the antiobesogenic effect of melatonin on mice fed an HFD for 2 weeks. Samples were collected every 4 h within a 24-h period, and diurnal rhythms of clock gene expression (Clock, Cry1, Cry2, Per1, and Per2) and serum lipid indexes varied with diurnal time. Notably, Clock and triglycerides (TG) showed a marked rhythm in the control in melatonin-treated mice but not in the HFD-fed mice. The rhythmicity of these parameters was similar between the control and melatonin-treated HFD-fed mice compared with that in the HFD group, indicating an improvement caused by melatonin in the diurnal clock of host metabolism in HFD-fed mice. Moreover, 16S rRNA gene sequencing showed that most microbes exhibited daily rhythmicity, and the trends were different for different groups and at different time points. We also identified several specific microbes that correlated with the circadian clock genes and serum lipid indexes, which might indicate the potential mechanism of action of melatonin in HFD-fed mice. In addition, effects of melatonin exposure during daytime or nighttime were compared, but a nonsignificant difference was noticed in response to HFD-induced lipid dysmetabolism. Interestingly, the responses of microbiota-transplanted mice to HFD feeding also varied at different transplantation times (8:00 and 16:00) and with different microbiota donors. In summary, the daily oscillations in the expression of circadian clock genes, serum lipid indexes, and the gut microbiota appeared to be driven by short-term feeding of an HFD, while administration of exogenous melatonin improved the composition and diurnal rhythmicity of some specific gut microbiota in HFD-fed mice. IMPORTANCE The gut microbiota is strongly shaped by a high-fat diet, and obese humans and animals are characterized by low gut microbial diversity and impaired gut microbiota compositions. Comprehensive data on mammalian gut metagenomes shows gut microbiota exhibit circadian rhythms, which is disturbed by a high-fat diet. On the other hand, melatonin is a natural and ubiquitous molecule showing multiple mechanisms of regulating the circadian clock and lipid metabolism, while the role of melatonin in the regulation of the diurnal patterns of gut microbial structure and function in obese animals is not yet known. This study delineates an intricate picture of melatonin-gut microbiota circadian rhythms and may provide insight for obesity intervention.

Circadian rhythms and obesity: Timekeeping governs lipid metabolism

“…In a high-fat diet-fed mouse model, administration of exogenous melatonin has a protective role in lipid metabolic disorders by reprogramming gut microbiota compositions and rhythm. 47,51 In addition, the daily oscillations in the expression of circadian clock genes in the liver, serum lipid indexes, and the gut microbiota appear to be driven by short-term feeding of a high-fat diet, 52 while exogenous melatonin treatment improves the diurnal rhythmicity of some specific gut microbiota. 52 Additionally, melatonin supplementation induces the conversion of inguinal white adipose tissue into brown fat in both Zucker diabetic fatty and control lean rats, 53 which further confirms the role of melatonin in lipid metabolism.…”

“…86 Meanwhile, 29 genera (58% of top 50) are identified to be markedly correlated to clock gene in the liver and these correlations are mostly positive with Clock, Cry1, and Per2 mRNA and negative with Cry2 and Per1 expressions. 52 In addition, a diet rich in fat and sugar exacerbates the circadian disruption of gut microbiota, with a drastic reduction in microbial diversity and the Firmicutes/Bacteroidetes ratio, 93 and further affects host lipid metabolism and obesity development. 85 Similarly, most of the microbiota exhibits daily variation and the diurnal network of some gut microbiota is affected by high-fat diet and reversed, at least in part, by administration of exogenous melatonin.…”

“…85 Similarly, most of the microbiota exhibits daily variation and the diurnal network of some gut microbiota is affected by high-fat diet and reversed, at least in part, by administration of exogenous melatonin. 52 The underlying mechanism may be associated with the circadian transcription factor NFIL3, which can be activated by gut microbiota and regulates lipid absorption and export in intestinal epithelial cells. 91 In addition, the microbiota also affect circulating signals, enteric neurons, and vagal afferents that convey hunger and satiety cues to the brain and thus are involved in the circadian regulation of food intake and feeding rhythms to mediate lipid metabolism.…”

miRNA-10a-5p Alleviates Insulin Resistance and Maintains Diurnal Patterns of Triglycerides and Gut Microbiota in High-Fat Diet-Fed Mice

“…Recently, the gut microbiome, a vital mediator for dietary composition entrainment, was found to be involved in the maintenance of circadian rhythm [ 6 ]. Importantly, the gut microbiome exhibits diurnal rhythm and produces oscillations in its metabolites, and these diurnal variations can be disrupted by HFD intake [ 6 , 7 ].…”

Editorial: Diets, Gut Microbiota, and Host Metabolism

“…Microbial density and diversity are established very rapidly in the gut of the newborn and drive stabilization of the normal commensal microbiota. However, the gut microbiota diversity and compositions are affected by genetic background, but most importantly by diets and environment ( 1 – 3 ). Wang et al explored the relationships among diet supplements, gut microbiota, host genetics and metabolic status, leading to the conclusion that diets more intensively disturbed the structure of gut microbiota in excess of genetic change, particularly under leptin deficient conditions.…”