Gut microbial genomes with paired isolates from China illustrate probiotic and cardiometabolic effects.

The gut microbiome displays genetic differences among populations, and characterization of the genomic landscape of the gut microbiome in China remains limited. Here, we present the Chinese Gut Microbial Reference (CGMR) set, comprising 101,060 high-quality metagenomic assembled genomes (MAGs) of 3,707 nonredundant species from 3,234 fecal samples across primarily rural Chinese locations, 1,376 live isolates mainly from lactic acid bacteria, and 987 novel species relative to worldwide databases. We observed region-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. Preliminary mouse experiments suggest a probiotic effect of two Faecalibacillus intestinalis isolates in alleviating constipation, cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and isolates from the genera Parabacteroides and Lactobacillus in host lipid metabolism. Our study expands the current microbial genomes with paired isolates and demonstrates potential host effects, contributing to the mechanistic understanding of host-microbe interactions.

Temporal colonization and metabolic regulation of the gut microbiome in neonatal oxen at single nucleotide resolution.

The colonization of microbes in the gut is key to establishing a healthy host-microbiome symbiosis for newborns. We longitudinally profiled the gut microbiome in a model consisting of 36 neonatal oxen from birth up to 2 months postpartum and carried out microbial transplantation to reshape their gut microbiome. Genomic reconstruction of deeply sequenced fecal samples resulted in a total of 3931 metagenomic-assembled genomes from 472 representative species, of which 184 were identified as new species when compared with existing databases of oxen. Single nucleotide level metagenomic profiling shows a rapid influx of microbes after birth, followed by dynamic shifts during the first few weeks of life. Microbial transplantation was found to reshape the genetic makeup of 33 metagenomic-assembled genomes (FDR < 0.05), mainly from Prevotella and Bacteroides species. We further linked over 20 million microbial single nucleotide variations to 736 plasma metabolites, which enabled us to characterize 24 study-wide significant associations (P < 4.4 × 10-9) that identify the potential microbial genetic regulation of host immune and neuro-related metabolites, including glutathione and L-dopa. Our integration analyses further revealed that microbial genetic variations may influence the health status and growth performance by modulating metabolites via structural regulation of their encoded proteins. For instance, we found that the albumin levels and total antioxidant capacity were correlated with L-dopa, which was determined by single nucleotide variations via structural regulations of metabolic enzymes. The current results indicate that temporal colonization and transplantation-driven strain replacement are crucial for newborn gut development, offering insights for enhancing newborn health and growth.

Early microbial intervention reshapes phenotypes of newborn Bos taurus through metabolic regulations.

BACKGROUND: The rumen of neonatal calves has limited functionality, and establishing intestinal microbiota may play a crucial role in their health and performance. Thus, we aim to explore the temporal colonization of the gut microbiome and the benefits of early microbial transplantation (MT) in newborn calves. RESULTS: We followed 36 newborn calves for 2 months and found that the composition and ecological interactions of their gut microbiomes likely reached maturity 1 month after birth. Temporal changes in the gut microbiome of newborn calves are widely associated with changes in their physiological statuses, such as growth and fiber digestion. Importantly, we observed that MT reshapes the gut microbiome of newborns by altering the abundance and interaction of Bacteroides species, as well as amino acid pathways, such as arginine biosynthesis. Two-year follow-up of those calves further showed that MT improves their later milk production. Notably, MT improves fiber digestion and antioxidant capacity of newborns while reducing diarrhea. MT also contributes to significant changes in the metabolomic landscape, and with putative causal mediation analysis, we suggest that altered gut microbial composition in newborns may influence physiological status through microbial-derived metabolites. CONCLUSIONS: Our study provides a metagenomic and metabolomic atlas of the temporal development of the gut microbiome in newborn calves. MT can alter the gut microbiome of newborns, leading to improved physiological status and later milk production. The data may help develop strategies to manipulate the gut microbiota during early life, which may be relevant to the health and production of newborn calves.

Urocortin2 attenuates diabetic coronary microvascular dysfunction by regulating macrophage extracellular vesicles.

Diabetic patients develop coronary microvascular dysfunction (CMD) and exhibit high mortality of coronary artery disease. Methylglyoxal (MGO) largely accumulates in the circulation due to diabetes. We addressed whether macrophages exposed to MGO exhibited damaging effect on the coronary artery and whether urocortin2 (UCN2) serve as protecting factors against such diabetes-associated complication. Type 2 diabetes was induced by high-fat diet and a single low-dose streptozotocin in mice. Small extracellular vesicles (sEV) derived from MGO-treated macrophages (MGO-sEV) were used to produce diabetes-like CMD. UCN2 was examined for a protective role against CMD. The involvement of arginase1 and IL-33 was tested by pharmacological inhibitor and IL-33-/- mice. MGO-sEV was capable of causing coronary artery endothelial dysfunction similar to that by diabetes. Immunocytochemistry studies of diabetic coronary arteries supported the transfer of arginase1 from macrophages to endothelial cells. Mechanism studies revealed arginase1 contributed to the impaired endothelium-dependent relaxation of coronary arteries in diabetic and MGO-sEV-treated mice. UCN2 significantly improved coronary artery endothelial function, and prevented MGO elevation in diabetic mice or enrichment of arginase1 in MGO-sEV. Diabetes caused a reduction of IL-33, which was also reversed by UCN2. IL-33-/- mice showed impaired endothelium-dependent relaxation of coronary arteries, which can be mitigated by arginase1 inhibition but can't be improved by UCN2 anymore, indicating the importance of restoring IL-33 for the protection against diabetic CMD by UCN2. Our data suggest that MGO-sEV induces CMD via shuttling arginase1 to coronary arteries. UCN2 is able to protect against diabetic CMD via modulating MGO-altered macrophage sEV cargoes.

The RAISE Trial: A Novel Device and First-in-Man Trial.

BACKGROUND: Currently, standard medical therapies have limited effects on heart failure with preserved ejection fraction (HFpEF), which impacts on the life quality and survival of patients. This study aimed to evaluate the safety and efficacy of the percutaneous radiofrequency ablation-based interatrial shunting for HFpEF with a novel atrial septostomy device. METHODS: A preclinical study in 11 normal domestic pigs and the first-in-man study in 10 patients with HFpEF were performed. The major safety events and interatrial shunt performance were evaluated at baseline, 1 month, 3 months, and 6 months post-procedure in both animals and human patients. The clinical functional status was also assessed in the first-in-man study. RESULTS: Percutaneous radiofrequency ablation-based interatrial shunting therapy was performed successfully both in animals and patients. In the animal study, a left-to-right interatrial shunt was created with a mean defect size of 5.5±2.2 mm without procedure-related safety events. Seven pigs showed the continuous shunting with a mean defect size of 4.1±1.5 mm at 6 months. In the first-in-man study, a median interatrial defect diameter of 5.0 (4.0-6.0) mm was measured immediately. No major safety events including death and thromboembolism were observed. The continuous shunting with the defect size of 4.0 (3.0-4.0) mm could still be observed in 7 patients at 6 months. The clinical status was significantly improved with NT-proBNP (N-terminal pro-B-type natriuretic peptide) reduced by 2149 pg/mL ([95% CI, 204-3301] P=0.028), with 6-minute walk distance increased by 88 m ([95% CI, 50-249] P=0.008) and with New York Heart Association class improved in 8 patients at 6 months. CONCLUSIONS: The present results showed that percutaneous radiofrequency ablation-based interatrial shunting was a safe and potentially effective therapy for HFpEF, providing a nonpharmacological and nonimplanted option for HFpEF management. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1900027664.

Monocyte-to-high-density lipoprotein-cholesterol ratio (MHR) and the risk of all-cause and cardiovascular mortality: a nationwide cohort study in the United States.

BACKGROUND: Elevated monocyte-to-high-density lipoprotein-cholesterol ratio (MHR) is relevant to higher all-cause and cardiovascular mortality in patients with coronary artery disease and other comorbidities. However, the predictive values of MHR for mortality in the general population have been underutilized. This study investigated the association of MHR with all-cause and cardiovascular mortality in the adult population of the United States. METHODS: This study included 34,335 participants (≥20 years) from the National Health and Nutrition Examination Survey 1999-2014 that were grouped according to MHR tertiles. Kaplan-Meier plots and long-rank tests were employed to investigate differences in survival among the groups. Moreover, the relationship of MHR with all-cause and cardiovascular mortality was further explored using multivariate Cox regression and restricted cubic spline analysis. RESULTS: During the average follow-up of 93.5 ± 56 months, 4310 (12.6%) participants died, with 754 (2.2%) deaths attributed to cardiovascular diseases. Kaplan-Meier analysis revealed statistically obvious differences in all-cause and cardiovascular mortality among the MHR tertiles (log-rank test: all P < 0.001). In multi-adjusted models, participants in the highest tertile of MHR had an increased risk of all-cause (hazard ratio [HR] = 1.19, 95% confidence interval [CI] 1.10-1.29) and cardiovascular mortality (HR = 1.44, 95% CI 1.17-1.77), compared to those in the lowest tertile. Furthermore, the restricted cubic spline curve indicated that MHR had a non-linear association with all-cause mortality (P < 0.001), and the inflection point of MHR was 0.006. Each 2-fold change in MHR exhibited a 32% decrease (HR = 0.68, 95%CI 0.58-0.82) and a 20% increase (HR = 1.20, 95%CI 1.13-1.27) in the risk of all-cause mortality on the left and right flanks of the inflection point, respectively. Additionally, the risk of cardiovascular mortality increased by 21% per 2-fold change in MHR (HR = 1.21, 95%CI 1.07-1.36) in a linear manner. CONCLUSIONS: MHR was significantly related to all-cause and cardiovascular mortality in the general population independent of established risk factors.

Prognostic Role of Neutrophil to High-Density Lipoprotein Cholesterol Ratio for All-Cause and Cardiovascular Mortality in the General Population.

BACKGROUND: Neutrophil counts to high-density lipoprotein cholesterol ratio (NHR), a composite marker of inflammation and lipid metabolism, has been considered as a predictor of clinical outcomes in patients with acute ischemic stroke and acute myocardial infarction. However, the predictive value of NHR for all-cause and cardiovascular mortality in the general population remains unclear. METHODS: Our study population comprised 34,335 adults in the United States obtained from the National Health and Nutrition Examination Survey (NHANES) (1999-2014) and were grouped in accordance with tertiles of NHR. Kaplan-Meier curves and log-rank test were used to investigate the differences of survival among groups. Multivariate Cox regression, restricted cubic spline analysis, and subgroup analysis were applied to explore the relationship of NHR with all-cause and cardiovascular mortality. RESULTS: The mean age of the study cohort was 49.6 ± 18.2 years and 48.4% were men. During a median follow-up of 82 months, 4,310 (12.6%) all-cause deaths and 754 (2.2%) cardiovascular deaths occurred. In a fully-adjusted Cox regression model, participants in the highest tertile had 29% higher hazard of all-cause mortality than those in the lowest tertile [hazard ratio (HR) = 1.29, 95% CI: 1.19-1.41]. For cardiovascular mortality, the continuously increased HR with 95% CIs among participants in the middle and highest tertile were 1.30 (1.06-1.59) and 1.44 (1.17-1.78), respectively. The restricted cubic spline curve indicated that NHR had a non-linear association with all-cause mortality (p for non-linearity < 0.001) and a linear association with cardiovascular mortality (p for non-linearity = 0.553). CONCLUSION: Increased NHR was a strong and independent predictor of all-cause and cardiovascular mortality in the general population.

Decoding microbial genomes to understand their functional roles in human complex diseases.

Complex diseases such as cardiovascular disease (CVD), obesity, inflammatory bowel disease (IBD), kidney disease, type 2 diabetes (T2D), and cancer have become a major burden to public health and affect more than 20% of the population worldwide. The etiology of complex diseases is not yet clear, but they are traditionally thought to be caused by genetics and environmental factors (e.g., dietary habits), and by their interactions. Besides this, increasing pieces of evidence now highlight that the intestinal microbiota may contribute substantially to the health and disease of the human host via their metabolic molecules. Therefore, decoding the microbial genomes has been an important strategy to shed light on their functional potential. In this review, we summarize the roles of the gut microbiome in complex diseases from its functional perspective. We further introduce artificial tools in decoding microbial genomes to profile their functionalities. Finally, state-of-the-art techniques have been highlighted which may contribute to a mechanistic understanding of the gut microbiome in human complex diseases and promote the development of the gut microbiome-based personalized medicine.

Association Between Waist Circumference and the Prevalence of (Pre) Hypertension Among 27,894 US Adults.

Aims: This study aimed to investigate the association between waist circumference and the prevalence of (pre) hypertension. Methods: Cross-sectional data from the 2007-2018 National Health and Nutrition Examination Survey were analyzed. The historical trend of abdominal obesity was assessed by the Cochran-Armitage trend test. After preprocessed by the multiple imputation strategy, we used generalized additive models to assess the association of waist circumference with systolic/diastolic blood pressure and performed correlation analysis by the Spearman correlation coefficient. Moreover, we used multivariable logistic regression (non-adjusted, minimally adjusted, and fully adjusted models), restricted cubic spline, and sensitivity analysis to investigate the association between waist circumference and (pre) hypertension. Results: A total of 27,894 participants were included in this study. In the fully adjusted model, waist circumference was positively associated with (pre) hypertension with odds ratios (95% confidence intervals) of 1.28 (1.18-1.40) in the young group and 1.23 (1.15-1.33) in the old group. Restricted cubic spline showed a higher prevalence of (pre) hypertension with the increase of waist circumference. In the subgroup analysis, waist circumference showed a robust trend across all BMI categories with odds ratios (95% confidence intervals) of 3.33 (1.29-8.85), 1.35 (1.17-1.57), 1.27 (1.13-1.41), and 1.09 (1.01-1.17) in underweight, normal weight, overweight, and obese individuals, respectively. Conclusion: This study highlighted waist circumference as a significant biomarker to evaluate the risk of (pre) hypertension. Our results supported the measure of waist circumference regardless of BMI when evaluating the cardiometabolic risk related to fat distribution.

A novel parametric method-based nomogram of left ventricular internal diameters in normal Chinese adults.

BACKGROUND: Current echocardiographic normal reference values and nomograms in healthy adults are commonly normalized by body surface area (BSA) with simple linear or isometric corrections. However, various lines of evidence suggest this method might be flawed. In this study, we established the normative data of left ventricular internal diameter (LViD) by BSA-correlated regression equations with the calculation of Z-scores in healthy Han Chinese adults. METHODS: A total of 577 healthy Han Chinese adults were enrolled (age 44.4±13.0 years, 43% male and 57% female). LViD was acquired from two-dimensional-guided M-mode echocardiography on all participants from the parasternal long-axis view. Linear and nonlinear regression models were built to correlate LViD with BSA in different sexes and age groups. The best-fit models and nomograms are presented with the Z-scores calculated by the models. Residual analysis and reproducibility were evaluated in each best-fit model for reliability. RESULTS: Body surface area showed polynomial (quadric) correlations with left ventricular end-diastolic diameter (LVDd, R2=0.615, P<0.001) and left ventricular end-systolic diameter (LVDs, R2=0.540, P<0.001). Corresponding regression equations and nomograms for computing the Z-scores of the overall LViD and BSA/sex-specific and BSA/age-specific reference values are presented. Reproducibility, residual distribution, autocorrelation and heteroscedasticity were confirmed in each model. CONCLUSIONS: This study proposes a comprehensive approach for normal reference values of left ventricular internal diameters with echocardiographic nomograms in healthy Han Chinese adults, which may offer a more precise way to diagnose cardiovascular disease in clinical practice.

Correlation between Serum Calcineurin Activity and Left Ventricular Hypertrophy in Hypertensive Patients and Its Clinical Significance.

OBJECTIVE: The aim of this study is to investigate the correlation between calcineurin (CaN) and hypertension with left ventricular hypertrophy (HLVH) and to evaluate its potential clinical significance. DESIGN: The study involved 160 patients diagnosed with hypertension and 42 controls. Based on the exclusion criteria, 42 were not eligible for this study. The remaining 118 hypertensive patients were categorized into 2 subgroups based on left ventricular mass index and relative ventricular wall thickness: a normal model subgroup with hypertension (HNM) and an HLVH subgroup. Serum CaN levels were determined by enzyme-linked immunosorbent assay, while serum CaN activity was determined by malachite green colorimetric assay. RESULTS: Among the HNM and HLVH subgroups, a positive correlation was demonstrated between serum CaN activity, but not serum CaN level, and HLVH. Moreover, the HLVH subgroup displayed a remarkable increase in the levels of brain natriuretic peptide, cystatin C, urinary albumin/creatinine ratio, and left atrium diameter compared to the HNM subgroup and controls. CONCLUSION: There was a positive correlation between serum CaN activity and LVH in hypertensive patients. Activated CaN could play an important role in the pathophysiologic mechanism of HLVH. Serum CaN activity could be a clinically useful diagnostic and prognostic biomarker for LVH.