Curcumin supplementation alleviates hepatic fat content associated with modulation of gut microbiota-dependent bile acid metabolism in patients with nonalcoholic simple fatty liver disease: a randomized controlled trial.

BACKGROUND: Our previous studies showed that curcumin prevented hepatic steatosis in animal models. OBJECTIVES: This study aimed to assess the effects of curcumin on hepatic fat content, body composition, and gut microbiota-dependent bile acid (BA) metabolism in patients with nonalcoholic simple fatty liver (NASFL). METHODS: In a 24-wk double-blind randomized trial, 80 patients with NASFL received 500 mg/d curcumin or placebo. Hepatic fat content was measured using FibroTouch-based controlled attenuation parameters (CAPs). Microbial composition and BA metabolites were analyzed using 16S rRNA sequencing and metabolomics. RESULTS: Curcumin consumption significantly reduced CAP value compared with placebo (-17.5 dB/m; 95% confidence interval [CI]: -27.1, -7.8 dB/m; P < 0.001). This corresponded to reduction in weight (-2.6 kg; 95% CI: -4.4, -0.8 kg; P < 0.001) and BMI (-1.0 kg/m2; 95% CI: -2.0, -0.1 kg/m2; P = 0.032) compared with placebo group. Additionally, free fatty acid (-0.12 mmol/L; 95% CI: -0.20, -0.04 mmol/L; P = 0.004), triglycerides (-0.29 mmol/L; 95% CI: -0.41, -0.14 mmol/L; P < 0.001), fasting blood glucose (-0.06 mmol/L; 95% CI: -0.12, -0.01 mmol/L; P = 0.038), hemoglobin A1c (-0.06%; 95% CI: -0.33, -0.01%; P = 0.019), and insulin (-4.94 µU/L; 95% CI: -9.73, -0.15 µU/L; P = 0.043) showed significant reductions in the curcumin group compared with placebo group. Gut microbiota analysis indicated that curcumin significantly decreased Firmicutes to Bacteroidetes ratio and significantly increased Bacteroides abundance. Serum levels of deoxycholic acid, the most potent activator of Takeda G protein-coupled receptor 5 (TGR5), were significantly elevated after curcumin intervention (37.5 ng/mL; 95% CI: 6.7, 68.4 ng/mL; P = 0.018). Curcumin treatment also increased TGR5 expression in peripheral blood mononuclear cells and serum glucagon-like peptide-1 levels (0.73 ng/mL; 95% CI: 0.16, 1.30 ng/mL; P = 0.012). CONCLUSIONS: Improvements in gut microbiota-dependent BA metabolism and TGR5 activation after 24-wk curcumin intervention were associated with a reduction in hepatic fat content in patients with NASFL, providing evidence that curcumin is a potential nutritional therapy for NASFL. The trial was registered at www.chictr.org.cn as ChiCTR2200058052.

Association between vitamin D, depression, and sleep health in the National Health and Nutrition Examination Surveys: a mediation analysis.

OBJECTIVE: This study aimed to assess the association between vitamin D and sleep health and to investigate whether depression could mediate this relationship. METHODS: A cross-sectional analysis was performed using the 2005-2014 US National Health and Nutrition Examination Survey (NHANES) data. The logistic regression models were conducted to evaluate association of serum vitamin D concentrations with sleep health and depression. Mediation analyses were conducted to investigate the mediated effects of depression on the association of vitamin D with sleep health. RESULTS: In multivariate logistic models, vitamin D was found to be negatively associated with an increased risk of poor sleep health, with an odds ratio (OR) of vitamin D deficiency versus sufficiency was 1.256 (95% CI = 1.084-1.455). Additionally, univariate logistic models showed that vitamin D was also negatively associated with depression risk (vitamin D deficiency vs. sufficiency: OR = 1.699, 95% CI = (1.373-2.103). Further mediation analyses showed that the association of vitamin D with sleep health was mediated by depression, with the mediating effects of depression accounted for 44.56% of the total effects. CONCLUSION: Vitamin D affects sleep health directly and indirectly through depression. The results suggest that interventions increasing intake of vitamin D should be prioritized to promote sleep health of persons with or at risk of depression.

Curcumin protects against bisphenol A-induced hepatic steatosis by inhibiting cholesterol absorption and synthesis in CD-1 mice.

Curcumin is a polyphenol extracted from the rhizome of turmeric, and our previous research showed that curcumin inhibited cholesterol absorption and had cholesterol-lowering effect. Bisphenol A (BPA), a common plasticizer, is widely used in the manufacture of food packaging and is associated with non-alcoholic fatty liver disease (NAFLD). We hypothesized that curcumin could protect against BPA-induced hepatic steatosis by inhibiting cholesterol absorption and synthesis. Male CD-1 mice fed BPA-contaminated diet with or without curcumin for 24 weeks were used to test our hypothesis. We found that chronic low-dose BPA exposure significantly increased the levels of serum triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol and the contents of liver TG and TC, resulting in liver fat accumulation and hepatic steatosis while curcumin supplementation could alleviate BPA-induced dyslipidemia and hepatic steatosis. Moreover, the anti-steatosis and cholesterol-lowering effects of curcumin against BPA coincided with a significant reduction in intestinal cholesterol absorption and liver cholesterol synthesis, which was modulated by suppressing the expression of sterol regulatory element-binding protein-2 (SREBP-2), Niemann-Pick C1-like 1 (NPC1L1), and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in the small intestine and liver. In addition, the expression levels of liver lipogenic genes such as liver X receptor alpha (LXRα), SREBP-1c, acetyl-CoA carboxylase 1 (ACC1), and ACC2 were also markedly down-regulated by curcumin. Overall, our findings indicated that curcumin inhibited BPA-induced intestinal cholesterol absorption and liver cholesterol synthesis by suppressing SREBP-2, NPC1L1, and HMGCR expression, subsequently reducing liver cholesterol accumulation and fat synthesis, thereby preventing hepatic steatosis and NAFLD.

Association between Di-2-ethylhexyl phthalate and nonalcoholic fatty liver disease among US adults: Mediation analysis of body mass index and waist circumference in the NHANES.

Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used plasticizer and is ubiquitous in the environment and food. As a result, diet is the most significant source of exposure to DEHP in the general population. However, there is little research about the impact of DEHP on the risk of nonalcoholic fatty liver disease (NAFLD) or significant fibrosis in human beings. A cross-sectional analysis was performed using the National Health and Nutrition Examination Survey (NHANES) 2017-2018 data. Controlled attenuation parameter (CAP) and median liver stiffness measurement (LSM) were acquired by vibration-controlled transient elastography for diagnosis of NAFLD and significant fibrosis. The concentration of DEHP (∑DEHP) was calculated by each metabolite and split into quartiles for analysis. Results of logistic regression models showed that the risk of NAFLD was increased in those with higher concentration of urinary DEHP [ΣDEHP (OR = 1.22, 95%CI = 1.09-1.36)]. However, no significant association was found between urinary DEHP and significant fibrosis in the fully adjusted model. Mediation analyses suggested that the total effect of urinary DEHP on NAFLD risk mediated by BMI was 46.28% and by WC was 65.89%.

Bisphenol A induced hepatic steatosis by disturbing bile acid metabolism and FXR/TGR5 signaling pathways via remodeling the gut microbiota in CD-1 mice.

Dysregulation of gut microbiota-mediated bile acid (BA) metabolism plays an important role in the pathogenesis of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). Our previous studies found that bisphenol A (BPA) exposure induced hepatic steatosis and gut microbiota dysbiosis. However, whether the gut microbiota-dependent BA metabolism alterations were involved in BPA-induced hepatic steatosis remains unclear. Therefore, we explored the gut microbiota-related metabolic mechanisms of hepatic steatosis induced by BPA. Male CD-1 mice were exposed to low-dose BPA (50 µg/kg/day) for 6 months. Fecal microbiota transplantation (FMT) and broad-spectrum antibiotic cocktail (ABX) treatment were further adopted to test the role of gut microbiota in the adverse effects of BPA. We found that BPA induced hepatic steatosis in mice. Additionally, 16S rRNA gene sequencing showed that BPA reduced the relative abundance of Bacteroides, Parabacteroides and Akkermansia, which are associated with BA metabolism. Metabolomic analyses demonstrated that BPA significantly altered the ratio of conjugated to unconjugated BAs and increased the total level of taurine-α/ß-muricholic acid while decreasing the level of chenodeoxycholic acid, thus inhibiting the activation of special receptors, including farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), in the ileum and liver. The inhibition of FXR reduced short heterodimer partner and subsequently induced cholesterol 7α-hydroxylase and sterol regulatory element-binding protein-1c expression, which is related to hepatic BA synthesis and lipogenesis, eventually leading to liver cholestasis and steatosis. Furthermore, we found that mice that received FMT from BPA-exposed mice developed hepatic steatosis, and the influences of BPA on hepatic steatosis and FXR/TGR5 signaling pathways could be eliminated by ABX treatment, confirming the role of gut microbiota in BPA effects. Collectively, our study illustrates that suppressed microbiota-BA-FXR/TGR signaling pathways may be a potential mechanism for hepatic steatosis induced by BPA, providing a new target for the prevention of BPA-induced NAFLD.

Association of low diastolic blood pressure with all-cause death among US adults with normal systolic blood pressure.

Although the effect of intensive systolic blood pressure lowering is widely recognized, treatment-related low diastolic blood pressure still worrisome. This was a prospective cohort study based on the National Health and Nutrition Examination Survey. Adults (≥20 years old) with guideline-recommended blood pressure were included and pregnant women were excluded. Survey-weighted logistic regression and cox models were used for analysis. A total of 25 858 participants were included in this study. After weighted, the overall mean age of the participants was 43.17 (16.03) years, including 53.7% women and 68.1% non-Hispanic white. Numerous factors were associated with low DBP (<60 mmHg), including advanced age, heart failure, myocardial infarction, and diabetes. The use of antihypertensive drugs was also associated with lower DBP (OR, 1.52; 95% CI, 1.26-1.83). DBP of less than 60 mmHg were associated with a higher risk of all-cause death (HR, 1.30; 95% CI, 1.12-1.51) and cardiovascular death (HR, 1.34; 95% CI, 1.00-1.79) compared to those with DBP between 70 and 80 mmHg. After regrouping, DBP <60 mmHg (no antihypertensive drugs) was associated with a higher risk of all-cause death (HR, 1.46; 95% CI, 1.21-1.75). DBP <60 mmHg after taking antihypertensive drugs was not associated with a higher risk of all-cause death (HR, 0.99; 95% CI, 0.73-1.36). Antihypertensive drug is an important factor contributing to DBP below 60 mmHg. But the pre-existing risk does not increase further with an additional reduction of DBP after antihypertensive drugs treatment.

Curcumin Supplementation Ameliorates Bile Cholesterol Supersaturation in Hamsters by Modulating Gut Microbiota and Cholesterol Absorption.

Curcumin is a polyphenol that has been shown to have prebiotic and cholesterol-lowering properties. This study aimed to investigate the impact of curcumin on bile cholesterol supersaturation and the potential mechanistic role of intestinal microbiota and cholesterol absorption. Male hamsters (n = 8) were fed a high-fat diet (HFD) supplemented with or without curcumin for 12 weeks. Results showed that curcumin significantly decreased cholesterol levels in the serum (from 5.10 to 4.10 mmol/L) and liver (from 64.60 to 47.72 nmol/mg protein) in HFD-fed hamsters and reduced the bile cholesterol saturation index (CSI) from 1.64 to 1.08 due to the beneficial modifications in the concentration of total bile acids (BAs), phospholipids and cholesterol (p < 0.05). Gut microbiota analysis via 16S rRNA sequencing revealed that curcumin modulated gut microbiota, predominantly increasing microbiota associated with BA metabolism and short-chain fatty acid production, which subsequently up-regulated the expression of hepatic cholesterol 7-alpha hydroxylase and increased the synthesis of bile acids (p < 0.05). Furthermore, curcumin significantly down-regulated the expression of intestinal Niemann−Pick C1-like protein 1(NPC1L1) in hamsters and reduced cholesterol absorption in Caco-2 cells (p < 0.05). Our results demonstrate that dietary curcumin has the potential to prevent bile cholesterol supersaturation through modulating the gut microbiota and inhibiting intestinal cholesterol absorption.