Sleep quality mediates the relationship between systemic inflammation and neurocognitive performance.

Background: Systemic inflammation is a significant mechanism underpinning adverse cognitive changes. Sleep quality is a crucial factor associated with systemic inflammation and neurocognitive health. Elevated levels of pro-inflammatory cytokines in the periphery help mark inflammation. With this background, we examined the relationship between systemic inflammation, subjective sleep quality, and neurocognitive performance in adults. Method & Results: In 252 healthy adults, we measured the systemic inflammation reflected by serum levels of IL-6, IL-12, IL-18, TNF-α and IFN-γ, subjective sleep quality reflected by the global scores of the Pittsburgh Sleep Quality Index, and their neurocognitive performance measured by the Hong Kong Montreal Cognitive Assessment. We observed that neurocognitive performance was negatively related to IL-18 (p = 0.046) and positively related to sleep quality (p = 0.006). We did not observe significant associations between other cytokines and neurocognitive performance. Furthermore, we found that sleep quality as a mediator explained the relationship between IL-18 and neurocognitive performance depending on the levels of IL-12 (index of moderated mediation: 95% CI = [0.0047, 0.0664]). Better subjective sleep quality buffered the negative effect of IL-18 on neurocognitive performance when IL-12 was low (bootstrapping 95% CI: [- 0.0824, - 0.0018]). On the contrary, poor subjective sleep quality mediated the association between higher IL-18 and poorer neurocognitive performance when IL-12 was elevated (bootstrapping 95% CI: [0.0004, 0.0608]). Conclusion & Implications: Our findings indicate that systemic inflammation was negatively associated with neurocognitive performance. Sleep quality regulated by IL-18/IL-12 axis activation could be a potential mechanism underpinning neurocognitive changes. Our results illustrate the intricate relationships between immune functioning, sleep quality and neurocognitive performance. These insights are essential to understand the potential mechanisms underpinning neurocognitive changes, paving the way for the development of preventive interventions for the risk of cognitive impairment.

Sex Differences in Association Between Gut Microbiome and Essential Hypertension Based on Ambulatory Blood Pressure Monitoring.

BACKGROUND: Sex differences in the pathogenesis of hypertension exist. While gut microbiota (GM) has been associated with hypertension, it is unclear whether there are sex-linked differences in the association between GM and hypertension. METHODS: We conducted a cross-sectional study to investigate the sex differences in associations between GM characterized by shotgun sequencing, GM-derived short-chain fatty acids, and 24-hour ambulatory blood pressure in 241 Hong Kong Chinese (113 men and 128 women; mean age, 54±6 years). RESULTS: The hypertensive group was associated with GM alterations; however, significant differences in ß-diversity and GM composition in hypertensive versus normotensive groups were only observed in women and not in men under various statistical models adjusting for the following covariates: age, sex, body mass index, sodium intake estimated by spot urine analysis, blood glucose, triglycerides, low- and high-density lipoprotein cholesterol, smoking, menopause, and fatty liver status. Specifically, Ruminococcus gnavus, Clostridium bolteae, and Bacteroides ovatus were significantly more abundant in the hypertensive women, whereas Dorea formicigenerans was more abundant in the normotensive women. No bacterial species were found to be significantly associated with hypertension in men. Furthermore, total plasma short-chain fatty acids and propionic acid were independent predictors of systolic and diastolic blood pressure in women but not men. CONCLUSIONS: GM dysregulation was strongly associated with 24-hour ambulatory blood pressure in women but not men, which may be mediated through propionic acid. Our work suggests that sex differences may be an important consideration while assessing the role of GM in the development and treatment of hypertension.

Deficiency of exchange protein directly activated by cAMP (EPAC)-1 in mice augments glucose intolerance, inflammation, and gut dysbiosis associated with Western diet.

BACKGROUND: Gut microbiota (GM) dysregulation, known as dysbiosis, has been proposed as a crucial driver of obesity associated with "Western" diet (WD) consumption. Gut dysbiosis is associated with increased gut permeability, inflammation, and insulin resistance. However, host metabolic pathways implicated in the pathophysiology of gut dysbiosis are still elusive. Exchange protein directly activated by cAMP (Epac) plays a critical role in cell-cell junction formation and insulin secretion. Here, we used homozygous Epac1-knockout (Epac1-/-), Epac2-knockout (Epac2-/-), and wild-type (WT) mice to investigate the role of Epac proteins in mediating gut dysbiosis, gut permeability, and inflammation after WD feeding. RESULTS: The 16S rRNA gene sequencing of fecal DNA showed that the baseline GM of Epac2-/-, but not Epac1-/-, mice was represented by a significantly higher Firmicutes to Bacteroidetes ratio and significant alterations in several taxa compared to WT mice, suggesting that Epac2-/- mice had gut dysbiosis under physiological conditions. However, an 8-week WD led to a similar gut microbiome imbalance in mice regardless of genotype. While Epac1 deficiency modestly exacerbated the WD-induced GM dysbiosis, the WD-fed Epac2-/- mice had a more significant increase in gut permeability than corresponding WT mice. After WD feeding, Epac1-/-, but not Epac2-/-, mice had significantly higher mRNA levels of tumor necrosis factor-alpha (TNF-α) and F4/80 in the epididymal white adipose tissue (EWAT), increased circulating lipocalin-2 protein and more severe glucose intolerance, suggesting greater inflammation and insulin resistance in WD-fed Epac1-/- mice than corresponding WT mice. Consistently, Epac1 protein expression was significantly reduced in the EWAT of WD-fed WT and Epac2-/- mice. CONCLUSION: Despite significantly dysregulated baseline GM and a more pronounced increase in gut permeability upon WD feeding, WD-fed Epac2-/- mice did not exhibit more severe inflammation and glucose intolerance than corresponding WT mice. These findings suggest that the role of gut dysbiosis in mediating WD-associated obesity may be context-dependent. On the contrary, we demonstrate that deficiency of host signaling protein, Epac1, drives inflammation and glucose intolerance which are the hallmarks of WD-induced obesity. Video abstract.