Gut microbiome features and metabolites in non-alcoholic fatty liver disease among community-dwelling middle-aged and older adults.

BACKGROUND: The specific microbiota and associated metabolites linked to non-alcoholic fatty liver disease (NAFLD) are still controversial. Thus, we aimed to understand how the core gut microbiota and metabolites impact NAFLD. METHODS: The data for the discovery cohort were collected from the Guangzhou Nutrition and Health Study (GNHS) follow-up conducted between 2014 and 2018. We collected 272 metadata points from 1546 individuals. The metadata were input into four interpretable machine learning models to identify important gut microbiota associated with NAFLD. These models were subsequently applied to two validation cohorts [the internal validation cohort (n = 377), and the prospective validation cohort (n = 749)] to assess generalizability. We constructed an individual microbiome risk score (MRS) based on the identified gut microbiota and conducted animal faecal microbiome transplantation experiment using faecal samples from individuals with different levels of MRS to determine the relationship between MRS and NAFLD. Additionally, we conducted targeted metabolomic sequencing of faecal samples to analyse potential metabolites. RESULTS: Among the four machine learning models used, the lightGBM algorithm achieved the best performance. A total of 12 taxa-related features of the microbiota were selected by the lightGBM algorithm and further used to calculate the MRS. Increased MRS was positively associated with the presence of NAFLD, with odds ratio (OR) of 1.86 (1.72, 2.02) per 1-unit increase in MRS. An elevated abundance of the faecal microbiota (f__veillonellaceae) was associated with increased NAFLD risk, whereas f__rikenellaceae, f__barnesiellaceae, and s__adolescentis were associated with a decreased presence of NAFLD. Higher levels of specific gut microbiota-derived metabolites of bile acids (taurocholic acid) might be positively associated with both a higher MRS and NAFLD risk. FMT in mice further confirmed a causal association between a higher MRS and the development of NAFLD. CONCLUSIONS: We confirmed that an alteration in the composition of the core gut microbiota might be biologically relevant to NAFLD development. Our work demonstrated the role of the microbiota in the development of NAFLD.

Proteome-wide profiling reveals dysregulated molecular features and accelerated aging in osteoporosis: A 9.8-year prospective study.

The role of circulatory proteomics in osteoporosis is unclear. Proteome-wide profiling holds the potential to offer mechanistic insights into osteoporosis. Serum proteome with 413 proteins was profiled by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline, and the 2nd, and 3rd follow-ups (7704 person-tests) in the prospective Chinese cohorts with 9.8 follow-up years: discovery cohort (n = 1785) and internal validation cohort (n = 1630). Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA) at follow-ups 1 through 3 at lumbar spine (LS) and femoral neck (FN). We used the Light Gradient Boosting Machine (LightGBM) to identify the osteoporosis (OP)-related proteomic features. The relationships between serum proteins and BMD in the two cohorts were estimated by linear mixed-effects model (LMM). Meta-analysis was then performed to explore the combined associations. We identified 53 proteins associated with osteoporosis using LightGBM, and a meta-analysis showed that 22 of these proteins illuminated a significant correlation with BMD (p < 0.05). The most common proteins among them were PHLD, SAMP, PEDF, HPTR, APOA1, SHBG, CO6, A2MG, CBPN, RAIN APOD, and THBG. The identified proteins were used to generate the biological age (BA) of bone. Each 1 SD-year increase in KDM-Proage was associated with higher risk of LS-OP (hazard ratio [HR], 1.25; 95% CI, 1.14-1.36, p = 4.96 × 10-06 ), and FN-OP (HR, 1.13; 95% CI, 1.02-1.23, p = 9.71 × 10-03 ). The findings uncovered that the apolipoproteins, zymoproteins, complements, and binding proteins presented new mechanistic insights into osteoporosis. Serum proteomics could be a crucial indicator for evaluating bone aging.

The Association between Circulating 25-Hydroxyvitamin D and Carotid Intima-Media Thickness Is Mediated by Gut Microbiota and Fecal and Serum Metabolites in Adults.

SCOPE: Vitamin D is vital to cardiovascular health. This study examines the association between plasma 25-hydroxyvitamin D (25[OH]D) and the progression of carotid intima-media thickness (cIMT) and identifies the potential mediating biomarkers of gut microbiota and metabolites in adults. METHODS AND RESULTS: This 9-year prospective study includes 2975 subjects with plasma 25(OH)D at baseline and determined cIMT every 3 years. Higher circulating 25(OH)D is associated with decreased odds of higher (≥median) 9-year cIMT changes at the common carotid artery (hΔCCA-cIMT) (p-trend < 0.001). Multivariable-adjusted OR (95%CI) of hΔCCA-cIMT for tertiles 2 and 3 (vs. 1) of 25(OH)D is 0.87 (0.73-1.04) and 0.68 (0.57-0.82). Gut microbiome and metabolome analysis identify 18 biomarkers significantly associated with both 25(OH)D and hΔCCA-cIMT, including three microbial genera, seven fecal metabolites, eight serum metabolites, and pathway of synthesis and degradation of ketone bodies. Mediation/path analyses show the scores generated from the overlapped differential gut microbiota, fecal and serum metabolites, and serum acetoacetic acid alone could mediate the beneficial association between 25(OH)D and hΔCCA-cIMT by 10.8%, 23.1%, 59.2%, and 62.0% (all p < 0.05), respectively. CONCLUSIONS: These findings show a beneficial association between plasma 25(OH)D and the CCA-cIMT progression. The identified multi-omics biomarkers provide novel mechanistic insights for the epidemiological association.

Phenome-wide Mendelian randomization study evaluating the association of circulating vitamin D with complex diseases.

Background: Circulating vitamin D has been associated with multiple clinical diseases in observational studies, but the association was inconsistent due to the presence of confounders. We conducted a bidirectional Mendelian randomization (MR) study to explore the healthy atlas of vitamin D in many clinical traits and evaluate their causal association. Methods: Based on a large-scale genome-wide association study (GWAS), the single nucleotide polymorphism (SNPs) instruments of circulating 25-hydroxyvitamin D (25OHD) from 443,734 Europeans and the corresponding effects of 10 clinical diseases and 42 clinical traits in the European population were recruited to conduct a bidirectional two-sample Mendelian randomization study. Under the network of Mendelian randomization analysis, inverse-variance weighting (IVW), weighted median, weighted mode, and Mendelian randomization (MR)-Egger regression were performed to explore the causal effects and pleiotropy. Mendelian randomization pleiotropy RESidual Sum and Outlier (MR-PRESSO) was conducted to uncover and exclude pleiotropic SNPs. Results: The results revealed that genetically decreased vitamin D was inversely related to the estimated BMD (ß = -0.029 g/cm2, p = 0.027), TC (ß = -0.269 mmol/L, p = 0.006), TG (ß = -0.208 mmol/L, p = 0.002), and pulse pressure (ß = -0.241 mmHg, p = 0.043), while positively associated with lymphocyte count (ß = 0.037%, p = 0.015). The results did not reveal any causal association of vitamin D with clinical diseases. On the contrary, genetically protected CKD was significantly associated with increased vitamin D (ß = 0.056, p = 2.361 × 10-26). Conclusion: The putative causal effects of circulating vitamin D on estimated bone mass, plasma triglyceride, and total cholesterol were uncovered, but not on clinical diseases. Vitamin D may be linked to clinical disease by affecting health-related metabolic markers.

Comparison of fecal and blood metabolome reveals inconsistent associations of the gut microbiota with cardiometabolic diseases.

Blood metabolome is commonly used in human studies to explore the associations of gut microbiota-derived metabolites with cardiometabolic diseases. Here, in a cohort of 1007 middle-aged and elderly adults with matched fecal metagenomic (149 species and 214 pathways) and paired fecal and blood targeted metabolomics data (132 metabolites), we find disparate associations with taxonomic composition and microbial pathways when using fecal or blood metabolites. For example, we observe that fecal, but not blood butyric acid significantly associates with both gut microbiota and prevalent type 2 diabetes. These findings are replicated in an independent validation cohort involving 103 adults. Our results suggest that caution should be taken when inferring microbiome-cardiometabolic disease associations from either blood or fecal metabolome data.

Mapping the human gut mycobiome in middle-aged and elderly adults: multiomics insights and implications for host metabolic health.

OBJECTIVE: The human gut fungal community, known as the mycobiome, plays a fundamental role in the gut ecosystem and health. Here we aimed to investigate the determinants and long-term stability of gut mycobiome among middle-aged and elderly adults. We further explored the interplay between gut fungi and bacteria on metabolic health. DESIGN: The present study included 1244 participants from the Guangzhou Nutrition and Health Study. We characterised the long-term stability and determinants of the human gut mycobiome, especially long-term habitual dietary consumption. The comprehensive multiomics analyses were performed to investigate the ecological links between gut bacteria, fungi and faecal metabolome. Finally, we examined whether the interaction between gut bacteria and fungi could modulate the metabolic risk. RESULTS: The gut fungal composition was temporally stable and mainly determined by age, long-term habitual diet and host physiological states. Specifically, compared with middle-aged individuals, Blastobotrys and Agaricomycetes spp were depleted, while Malassezia was enriched in the elderly. Dairy consumption was positively associated with Saccharomyces but inversely associated with Candida. Notably, Saccharomycetales spp interacted with gut bacterial diversity to influence insulin resistance. Bidirectional mediation analyses indicated that bacterial function or faecal histidine might causally mediate an impact of Pichia on blood cholesterol. CONCLUSION: We depict the sociodemographic and dietary determinants of human gut mycobiome in middle-aged and elderly individuals, and further reveal that the gut mycobiome may be closely associated with the host metabolic health through regulating gut bacterial functions and metabolites.

Severity-associated markers and assessment model for predicting the severity of COVID-19: a retrospective study in Hangzhou, China.

BACKGROUND: The severity of COVID-19 associates with the clinical decision making and the prognosis of COVID-19 patients, therefore, early identification of patients who are likely to develop severe or critical COVID-19 is critical in clinical practice. The aim of this study was to screen severity-associated markers and construct an assessment model for predicting the severity of COVID-19. METHODS: 172 confirmed COVID-19 patients were enrolled from two designated hospitals in Hangzhou, China. Ordinal logistic regression was used to screen severity-associated markers. Least Absolute Shrinkage and Selection Operator (LASSO) regression was performed for further feature selection. Assessment models were constructed using logistic regression, ridge regression, support vector machine and random forest. The area under the receiver operator characteristic curve (AUROC) was used to evaluate the performance of different models. Internal validation was performed by using bootstrap with 500 re-sampling in the training set, and external validation was performed in the validation set for the four models, respectively. RESULTS: Age, comorbidity, fever, and 18 laboratory markers were associated with the severity of COVID-19 (all P values < 0.05). By LASSO regression, eight markers were included for the assessment model construction. The ridge regression model had the best performance with AUROCs of 0.930 (95% CI, 0.914-0.943) and 0.827 (95% CI, 0.716-0.921) in the internal and external validations, respectively. A risk score, established based on the ridge regression model, had good discrimination in all patients with an AUROC of 0.897 (95% CI 0.845-0.940), and a well-fitted calibration curve. Using the optimal cutoff value of 71, the sensitivity and specificity were 87.1% and 78.1%, respectively. A web-based assessment system was developed based on the risk score. CONCLUSIONS: Eight clinical markers of lactate dehydrogenase, C-reactive protein, albumin, comorbidity, electrolyte disturbance, coagulation function, eosinophil and lymphocyte counts were associated with the severity of COVID-19. An assessment model constructed with these eight markers would help the clinician to evaluate the likelihood of developing severity of COVID-19 at admission and early take measures on clinical treatment.

Cohort profile: the Westlake BioBank for Chinese (WBBC) pilot project.

PURPOSE: The Westlake BioBank for Chinese (WBBC) pilot cohort is a population-based prospective study with its major purpose to better understand the effect of genetic and environmental factors on growth and development from adolescents to adults. PARTICIPANTS: A total of 14 726 participants (4751 males and 9975 females) aged 14-25 years were recruited and the baseline survey was carried out from 2017 to 2019. The pilot cohort contains rich range of information regarding of demographics and anthropometric measurements, lifestyle and sleep patterns, clinical and health outcomes. Visit the WBBC website for more information (https://wbbc.westlake.edu.cn/index.html). FINDINGS TO DATE: The mean age of the study samples were 18.6 years for males and 18.5 years for females, respectively. The mean height and weight were 172.9 cm and 65.81 kg for males, and 160.1 cm and 52.85 kg for females. Results indicated that the prevalence of underweight in female was much higher than male, but the prevalence of overweight and obesity in female was lower than male. The mean serum 25(OH)D level in the 14 726 young participants was 22.4±5.3 ng/mL, and male had a higher level of serum 25(OH)D than female, overall, 33.5% of the participants had vitamin D deficiency and even more participants suffered from vitamin D insufficiency (58.2%). The proportion of deficiency in females was much higher than that in males (41.8 vs 16.4%). The issue of underweight and vitamin D deficiency in young people should be paid attention, especially in females. These results reflected the fact that thinness and paler skin are preferred in modern aesthetics of Chinese culture. FUTURE PLANS: WBBC pilot is designed as a prospective cohort study and provides a unique and rich data set analysing health trajectories from adolescents to young adults. WBBC will continue to collect samples with old age.

Body roundness index is a superior indicator to associate with the cardio-metabolic risk: evidence from a cross-sectional study with 17,000 Eastern-China adults.

BACKGROUND: To investigate the ability of body shape index (ABSI), body roundness index (BRI), waist circumference (WC), body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and body adiposity index (BAI) for predicting non-adipose cardio-metabolic risk. METHODS: A total of 17,360 Chinese subjects aged 18-95 years old who escaped cardiovascular disease (CVD) or diabetes were recruited in the cross-sectional study. Anthropometric and biochemical parameters were assessed. Receiver operating characteristic curve (ROC) and multinomial logistic regression were conducted to examine the association of anthropometric indicators with cardio-metabolic risk factors. RESULTS: The mean age of subjects were 53.7(13.1) years, 41.6 % were males. The areas under the curve (AUC) demonstrated that WC, BMI, WHR, WHtR and BRI were able to predict high cardio-metabolic risk (AUC > 0.70). Meanwhile, multinomial logistic regression showed BRI was significantly associated with high cardio-metabolic risk (OR 3.27, 95% CI 3.01-3.55). The optimal cut-off values of BRI for high cardio-metabolic risk were (< 60 y: 3.49 vs. ≥60 y: 3.46) in males and (< 60 y: 3.47 vs. ≥60 y: 3.60) in females. CONCLUSIONS: WC, BMI WHR, and WHtR were potential obesity indicators in discriminating high cardio-metabolic risk, while BAI or ABSI was not. Moreover, BRI revealed superior predictive capacity and significant association with accumulated cardio-metabolic risk factors.

Effect of mannose-binding lectin gene polymorphisms on the risk of rheumatoid arthritis: Evidence from a meta-analysis.

BACKGROUND: The effect of mannose-binding lectin (MBL) gene polymorphisms on susceptibility of rheumatoid arthritis (RA) were evaluated in ethnically different populations, whereas the results were always inconsistent. MATERIALS AND METHODS: Fourteen articles involving 36 datasets were recruited to evaluate the association between MBL gene polymorphisms and rheumatoid arthritis in a meta-analysis. The random or fixed effect models were used to evaluate the pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). RESULTS: Stratified analysis by ethnicities was conducted and the result revealed that rs1800450 (T vs C, OR = 1.32, 95% CI: 1.04-1.67, P < .05) and MBL-A/O (T vs C, OR = 1.20, 95% CI: 1.08-1.34, P < .001) were strongly associated with RA in Brazilian populations. In addition, the significant relationship between rs11003125 (T vs C, OR = 1.16, 95% CI: 1.06-1.26, P < .05) with RA were also observed in East Asian populations. Meanwhile, the inverse associations between rs5030737 with RA in East Asians and rs1800450 with RA in Indians were acquired. However, no association between any MBL polymorphism with RA susceptibility was confirmed in Caucasians. CONCLUSIONS: The structural polymorphisms in exon 1 of MBL gene may significantly contribute to susceptibility and development of RA in Brazilian and Indian populations, whereas the functional polymorphisms in the promoter region were more likely to associate with RA in East Asians.

Effect of CD14 polymorphisms on the risk of cardiovascular disease: evidence from a meta-analysis.

BACKGROUND: CD14 polymorphisms are associated with an increased risk of cardiovascular events. So far, many studies have been conducted, whereas the results were not always consistent. MATERIALS AND METHODS: Twenty-six articles involving thirty-seven datasets were recruited to evaluate the association between rs2569190 (9413 patients and 7337 controls), C-159T (4813 patients and 2852 controls) polymorphisms and cardiovascular diseases in a meta-analysis. The random or fixed effect models were used to evaluate the pooled odds ratios (ORs) and their corresponding 95% confidence intervals. RESULTS: The strongest association was observed between rs2569190 and CVD in overall population (T vs. C, OR = 1.169, 95% CI: 1.087-1.257, p = 2.44 × 10- 5). Analysis after stratification by ethnicity indicated that rs2569190 was related to CVD in East Asian population (T vs. C, OR = 1.370, 95% CI; 1.226-1.531, p = 2.86 × 10- 8) and a potential relationship in European (T vs. C, OR = 1.100, 95% CI: 1.019-1.189, p = 0.015). In the stratification of endpoints, the associations were found in CHD subgroup (T vs. C, OR = 1.357, 95% CI: 1.157-1.592, p = 2.47 × 10- 7) and in AMI subgroup (T vs. C, OR = 1.152, 95% CI: 1.036-1.281, p = 0.009). However, we did not find any association between C-159T polymorphism with cardiovascular disease under any model. CONCLUSIONS: The SNP rs2569190 significantly contribute to susceptibility and development of cardiovascular disease, particularly in the East Asian population and in the subtype CHD group, in addition, a potential association was observed in the AMI group, T allele acts as a risk factor for cardiovascular disease.