We conducted a Mendelian randomization analysis to examine the causal relationships between the gut microbiome and heart failure and the mediating role of blood lipids. Six gut microbial taxa were identified as having potentially causal effects on heart failure, with Bacteroides dorei being the most significant one. Apolipoprotein B was found to be the primary lipid determinant of heart failure among five common lipids and mediated 10.1% of the causal effect of Bacteroides dorei on heart failure.

Context Observational studies indicated obesity and glutamatergic dysfunction as potential risk factors of depression, and reported disturbance of glutamine metabolism in obese state. However, it remains unclear whether the interrelationships between obesity, glutamine, and depression are causal. Objective We conducted 2-sample bidirectional mendelian randomization (MR) analyses to explore the causalities between circulating glutamine levels, specific depressive symptoms, major depressive disorder (MDD), and body mass index (BMI). Methods Univariable MR, multivariable MR (MVMR), and linkage disequilibrium score regression (LDSR) analyses were performed. Results Genetic downregulation of glutamine was causally associated with MDD, anhedonia, tiredness, and depressed mood at the false discovery rate (FDR)-controlled significance level (estimate, −0.036 ∼ −0.013; P = .005 to P = .050). Elevated BMI was causally linked to lower glutamine level (estimate, –0.103; P = .037), as well as more severe depressed mood, tiredness, and anhedonia (estimate, 0.017 ∼ 0.050; P < .001 to P = .040). In MVMR analysis, BMI was causally related to depressed mood dependently of glutamine levels. Conversely, it showed limited evidence supporting causal effects of depression on glutamine levels or BMI, except a causal association of tiredness with elevated BMI (estimate, 0.309; P = .003). LDSR estimates were directionally consistent with MR results. Conclusion The present study reported that higher BMI was causally associated with lower glutamine levels. Both obesity and downregulation of glutamine were causally linked to depression.

Little is known about the complex associations of socioeconomic status (SES) and healthy lifestyle with cognitive dysfunction. Using data from the Health and Retirement Study (HRS) [2008-2020] and the English Longitudinal Study of Ageing (ELSA) [2004-2018], SES was constructed by latent class analysis using education level, total household income and wealth. Overall healthy lifestyle was derived using information on never smoking, low to moderate alcohol consumption (drinks/day: (0, 1] for women and (0, 2] for men), top tertile of physical activity, and active social contact. A total of 12,437 and 6565 participants from the HRS and ELSA were included (40.8% and 46.0% men and mean age 69.3 years and 65.1 years, respectively). Compared with participants of high SES, those of low SES had higher risk of incident dementia (hazard ratio 3.17, 95% confidence interval 2.72-3.69 in the HRS; 1.43, 1.09-1.86 in the ELSA), and the proportions mediated by overall lifestyle were 10.4% (7.3%-14.6%) and 2.7% (0.5%-14.0%), respectively. Compared with participants of high SES and favorable lifestyle, those with low SES and unfavorable lifestyle had a higher risk of incident dementia (4.27, 3.40-5.38 in the HRS; 2.02, 1.25-3.27 in the ELSA) and accelerated rate of global cognitive decline (β = -0.058 SD/year; 95% CI: -0.073, -0.043 in the HRS; β = -0.049 SD/year; 95% CI: -0.063, -0.035 in the ELSA). Unhealthy lifestyle only mediated a small proportion of the socioeconomic inequality in dementia risk in both US and UK older adults. This work was supported by grants from the National Natural Science Foundation of China (82088102 and 82370819), the National Key R&D Program of China (2023YFC2506700), the Shanghai Municipal Government (22Y31900300), the Shanghai Clinical Research Center for Metabolic Diseases (19MC1910100), the Innovative Research Team of High-Level Local Universities in Shanghai, the Special Project for Clinical Research in Health Industry of Shanghai Municipal Health Commission (202340084), and Ruijin Hospital Youth Incubation Project (KY20240805). Y.X. is supported by the National Top Young Talents program.

OBJECTIVE: We aimed to examine the effects of a 5:2 diet (2 days per week of energy restriction by formula diet) or an exercise (2 days per week of high-intensity interval training and resistance training) intervention compared with routine lifestyle education (control) on glycemic control and cardiometabolic health among adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: This two-center, open-label, three-arm, parallel-group, randomized controlled trial recruited 326 participants with overweight/obesity and type 2 diabetes and randomized them into 12 weeks of diet intervention (n = 109), exercise intervention (n = 108), or lifestyle education (control) (n = 109). The primary outcome was the change of glycemic control measured as glycated hemoglobin (HbA1c) between the diet or exercise intervention groups and the control group after the 12-week intervention. RESULTS: The diet intervention significantly reduced HbA1c level (%) after the 12-week intervention (−0.72, 95% CI −0.95 to −0.48) compared with the control group (−0.37, 95% CI −0.60 to −0.15) (diet vs. control −0.34, 95% CI −0.58 to −0.11, P = 0.007). The reduction in HbA1c level in the exercise intervention group (−0.46, 95% CI −0.70 to −0.23) did not significantly differ from the control group (exercise vs. control −0.09, 95% CI −0.32 to 0.15, P = 0.47). The exercise intervention group was superior in maintaining lean body mass. Both diet and exercise interventions induced improvements in adiposity and hepatic steatosis. CONCLUSIONS: These findings suggest that the medically supervised 5:2 energy-restricted diet could provide an alternative strategy for improving glycemic control and that the exercise regimen could improve body composition, although it inadequately improved glycemic control.