Strain-specific gut microbial signatures in type 2 diabetes identified in a cross-cohort analysis of 8,117 metagenomes.

The association of gut microbial features with type 2 diabetes (T2D) has been inconsistent due in part to the complexity of this disease and variation in study design. Even in cases in which individual microbial species have been associated with T2D, mechanisms have been unable to be attributed to these associations based on specific microbial strains. We conducted a comprehensive study of the T2D microbiome, analyzing 8,117 shotgun metagenomes from 10 cohorts of individuals with T2D, prediabetes, and normoglycemic status in the United States, Europe, Israel and China. Dysbiosis in 19 phylogenetically diverse species was associated with T2D (false discovery rate < 0.10), for example, enriched Clostridium bolteae and depleted Butyrivibrio crossotus. These microorganisms also contributed to community-level functional changes potentially underlying T2D pathogenesis, for example, perturbations in glucose metabolism. Our study identifies within-species phylogenetic diversity for strains of 27 species that explain inter-individual differences in T2D risk, such as Eubacterium rectale. In some cases, these were explained by strain-specific gene carriage, including loci involved in various mechanisms of horizontal gene transfer and novel biological processes underlying metabolic risk, for example, quorum sensing. In summary, our study provides robust cross-cohort microbial signatures in a strain-resolved manner and offers new mechanistic insights into T2D.

Multi-modal molecular determinants of clinically relevant osteoporosis subtypes.

Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).

Association Between Bowel Movement Pattern and Cognitive Function: Prospective Cohort Study and a Metagenomic Analysis of the Gut Microbiome.

BACKGROUND AND OBJECTIVES: Little is known regarding the association between intestinal motility patterns and cognitive function in individuals who are baseline cognitively healthy. The gut microbiome may contribute to the association. We examined the association between bowel movement (BM) pattern and cognitive function and explored the role of the gut microbiome in explaining this association. METHODS: In this prospective study, we leveraged 3 cohort studies, Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS). Participants reported BM frequency and subjective cognitive function. In a subset of NHSII participants, we assessed cognitive function using an objective neuropsychological battery. We profiled the gut microbiome in a subset of participants using whole-genome shotgun metagenomics. General linear models, Poisson regression, and logistic regression were used to quantify the association of BM frequency with different cognitive measurements. RESULTS: We followed 112,753 men and women (women: 87.6%) with a mean age of 67.2 years at baseline (NHS: 76 years, NHSII: 59 years, HPFS: 75 years) for a median follow-up of 4 years (NHSII and HPFS: 4 years, NHS: 2 years). Compared with those with BM once daily, participants with BM frequency every 3+ days had significantly worse objective cognitive function, equivalent to 3.0 (95% confidence interval [CI],1.2-4.7) years of chronological cognitive aging. We observed similar J-shape dose-response relationships of BM frequency with the odds of subjective cognitive decline and the likelihood of having more subsequent subjective cognitive complaints (both p nonlinearity < 0.001). BM frequencies of every 3+ days and ≥twice/day, compared with once daily, were associated with the odds ratios of subjective cognitive decline of 1.73 (95% CI 1.60-1.86) and 1.37 (95% CI 1.33-1.44), respectively. BM frequency and subjective cognitive decline were significantly associated with the overall gut microbiome configuration (both p < 0.005) and specific microbial species in the 515 participants with microbiome data. Butyrate-producing microbial species were depleted in those with less frequent BM and worse cognition, whereas a higher abundance of proinflammatory species was associated with BM frequency of ≥twice/day and worse cognition. DISCUSSION: Lower BM frequency was associated with worse cognitive function. The gut microbial dysbiosis may be a mechanistic link underlying the association.

Gut microbiome alterations in pulmonary hypertension in highlanders and lowlanders.

Background: Alterations in the gut microbiota have been observed in patients with pulmonary hypertension (PH), though whether the roles of the gut microbiota in PH at different altitudes are the same is unknown. This study aims to evaluate the associations of the gut microbiome with PH in highlanders and lowlanders. Methods: PH patients and controls were recruited from those who permanently live on the Tibetan plateau (highlanders) or the plains (lowlanders), and underwent transthoracic echocardiography close to their altitude of residence (at 5070 m for highlanders versus6 m for lowlanders). The gut microbiome was profiled using metagenomic shotgun sequencing. Results: In total, 13 PH patients (46% highlanders) and 88 controls (70% highlanders) were included. The overall microbial composition was different in PH patients compared to controls (p=0.003). Notably, among lowlanders, a composite microbial score of pro-atherosclerotic trimethylamine-producing species was increased in PH patients compared with that in controls (p=0.028), while among highlanders no such difference was observed (p=0.087). Another composite gut microbial score including eight species of Lactobacillus, which has shown beneficial effects on cardiovascular functions, was higher in highlanders than lowlanders (p<0.01). Furthermore, this score tended to be lower in PH patients than controls among highlanders (p=0.056) but not among lowlanders (p=0.840). In addition, the gut microbiome showed a good performance in distinguishing PH patients from controls in both lowlanders and highlanders. Conclusions: Our study reported differently altered gut microbiome profiles between highland and lowland PH patients, highlighting the distinct microbial mechanism in PH in highlanders compared with lowlanders.

Exposure to Multiple Air Pollutants and the Risk of Fractures: A Large Prospective Population-Based Study.

Atmospheric chemistry studies suggest air pollution impedes ultraviolet B photons and thus reduces cutaneous vitamin D3 synthesis. Biological evidence shows that inhaled pollutants disrupt circulating 25-hydroxyvitamin D (25[OH]D) metabolism and ultimately impact bone health. The hypothesis is that higher air pollution concentrations are associated with a higher risk of fractures, mediated by lower circulating 25(OH)D. The study included participants of the UK Biobank who were free of fracture history at enrollment (2006 to 2010) and analyzed their environmental exposure data (2007 to 2010). Air pollution measurements included the annual averages of air particulate matter (PM2.5 , PM2.5-10 , and PM10 ), nitrogen oxides (NO2 and NOx ), and a composite air pollution score. Multivariable Cox proportional hazard models were used to assess the associations of the individual pollutants and the score with fracture risks. Mediation analyses were conducted to assess the underlying role of serum 25(OH)D in such associations. Among 446,395 participants with a median of 8-year follow-up, 12,288 incident fractures were documented. Participants living in places with the highest quintile of air pollution score had a 15.3% increased risk of fractures (hazard ratio [95%CI]: 1.15[1.09,1.22]) compared to those in the lowest, and 5.49% of this association was mediated through serum 25(OH)D (pmediation < 0.05). Pollutant-specific hazard of top-to-bottom quintiles was 16% for PM2.5 , 4% for PM2.5-10 , 5% for PM10 , 20% for NO2 , and 17% for NOx , with a 4% to 6% mediation effect of serum 25(OH)D concentrations. The associations of the air pollution score with fracture risks were weaker among female participants, those who drank less alcohol, and consumed more fresh fruit than their counterparts (pinteraction < 0.05). © 2023 American Society for Bone and Mineral Research (ASBMR).

Gut microbiota and plasma metabolites associated with bone mineral density in women with or at risk of HIV infection.

OBJECTIVE: To evaluate gut microbiota (GMB) alterations and metabolite profile perturbations associated with bone mineral density (BMD) in the context of HIV infection. DESIGN: Cross-sectional studies of 58 women with chronic HIV infection receiving antiretroviral therapy and 33 women without HIV infection. METHODS: We examined associations of GMB and metabolites with BMD among 91 women. BMD was measured by dual-energy X-ray absorptiometry (DXA), and T -scores of lumbar spine or total hip less than -1 defined low BMD. GMB was measured by 16S rRNA V4 region sequencing on fecal samples, and plasma metabolites were measured by liquid chromatography-tandem mass spectrometry. Associations of GMB with plasma metabolites were assessed in a larger sample (418 women; 280 HIV+ and 138 HIV-). RESULTS: Relative abundances of five predominant bacterial genera ( Dorea , Megasphaera , unclassified Lachnospiraceae, Ruminococcus , and Mitsuokella ) were higher in women with low BMD compared with those with normal BMD (all linear discriminant analysis (LDA) scores >2.0). A distinct plasma metabolite profile was identified in women with low BMD, featuring lower levels of several metabolites belonging to amino acids, carnitines, caffeine, fatty acids, pyridines, and retinoids, compared with those with normal BMD. BMD-associated bacterial genera, especially Megasphaera , were inversely associated with several BMD-related metabolites (e.g. 4-pyridoxic acid, C4 carnitine, creatinine, and dimethylglycine). The inverse association of Megasphaera with dimethylglycine was more pronounced in women with HIV infection compared with those without HIV infection ( P for interaction = 0.016). CONCLUSION: Among women with and at risk of HIV infection, we identified altered GMB and plasma metabolite profiles associated with low BMD.

The causal associations of circulating amino acids with blood pressure: a Mendelian randomization study.

BACKGROUND: Circulating levels of amino acids were associated with blood pressure (BP) in observational studies. However, the causation of such associations has been hypothesized but is difficult to prove in human studies. Here, we aimed to use two-sample Mendelian randomization analyses to evaluate the potential causal associations of circulating levels of amino acids with BP and risk of hypertension. METHODS: We generated genetic instruments for circulating levels of nine amino acids by conducting meta-analyses of genome-wide association study (GWAS) in UK Biobank participants with metabolomic data (n = 98,317) and another published metabolomics GWAS (n = 24,925). Data on the associations of the genetic variants with BP and hypertension were obtained in the UK Biobank participants without metabolomic data (n = 286,390). The causal effects were estimated using inverse-variance weighted method. RESULTS: Significant evidence consistently supported the causal effects of increased branched-chain amino acids (BCAAs, i.e., leucine, isoleucine, and valine) levels on higher BP and risk of hypertension (all P < 0.006 after Bonferroni correction except for Pleucine-on-diastolicBP = 0.008). For example, per standard deviation higher of genetically predicted isoleucine levels were associated with 2.71 ± 0.78 mmHg higher systolic BP and 1.24 ± 0.34 mmHg higher diastolic BP, as well as with 7% higher risk of hypertension (odds ratio: 1.07, [95% CI: 1.04-1.10]). In addition, per standard deviation higher of genetically predicted glycine level was associated with lower systolic BP (- 0.70 ± 0.17 mmHg, P = 4.04 × 10-5) and a lower risk of hypertension (0.99 [0.98-0.99], P = 6.46 × 10-5). In the reverse direction, genetically predicted higher systolic BP was associated with lower circulating levels of glycine (- 0.025±0.008, P = 0.001). CONCLUSIONS: This study provides evidence for causal impacts of genetically predicted circulating BCAAs and glycine levels on BP. Meanwhile, genetically predicted higher BP was associated with lower glycine levels. Further investigations are warranted to clarify the underlying mechanisms.

Associations of visceral adipose tissue with bone mineral density and fracture: observational and Mendelian randomization studies.

BACKGROUND: The associations between visceral adipose tissue (VAT) and bone mineral density (BMD) or fracture have been controversial and the causality of the associations remains to be assessed. This study aimed to explore the associations of VAT^ (predicted value of VAT mass) with BMD and fracture risk in men and women, and to examine their potential causation by two-sample Mendelian randomization (MR) analyses. METHODS: UK Biobank is a large, population-based prospective cohort study that recruited more than 500,000 participants aged 40-69 in the United Kingdom from 2006 to 2010. In this study, we used a validated and reliable prediction model to estimate the VAT amount of the participants. On this basis, linear and nonlinear multivariable statistical models were used to explore the association of VAT^ with BMD and fracture risk in different groups of sex and BMI. In observational analyses, the multivariable linear regression model and Cox proportional-hazards model were used to assess VAT^ association with BMD and fracture risk, respectively. Inverse variance weighting was used as the main result of MR analysis. RESULTS: In 190,836 men, an inverted U-shaped association was observed between VAT^ and heel BMD (P for nonlinearity < 0.001), with a turning point of VAT^ = 1.25 kg. Per kg increase in VAT^ was associated with a 0.13 standard deviation (SD) increase in heel BMD (P = 1.5 × 10-16) among men with lower amounts of VAT^, and associated with a 0.05 SD decrease in heel BMD (P = 1.3 × 10-15) among men with higher amounts of VAT^. In 193,592 women, per kg increase in VAT^ was monotonically associated with a 0.16 SD increase in heel BMD (P = 1.2 × 10-136, P for VAT^-sex interaction = 8.4 × 10-51). During a median follow-up of 8.2 years, VAT^ was associated with lower risks of hip fractures in the overall men and women (P for VAT^-sex interaction = 1.9 × 10-4 for total fractures; 1.5 × 10-4 for other fractures). There were significant interactions of VAT^ and BMI on heel BMD and fracture risks in men only (P for VAT^-BMI interaction = 5.9 × 10-31 for heel BMD; 2.7 × 10-4 for total fractures; 5.7 × 10-3 for hip fractures; 6.8 × 10-3 for other fractures). In two-sample MR analyses, evidence of causality was not observed between VAT^ and DXA-derived BMD or fractures. CONCLUSIONS: These novel findings demonstrated gender-dependent associations of VAT^ with BMD and fracture risk, with the association in men being modified by adiposity. Evidence of causality was not observed, suggesting that the observational association of VAT^ with BMD and fracture risk could be the result of confounding.

Gut microbiome alterations and gut barrier dysfunction are associated with host immune homeostasis in COVID-19 patients.

BACKGROUND: COVID-19 is an infectious disease characterized by multiple respiratory and extrapulmonary manifestations, including gastrointestinal symptoms. Although recent studies have linked gut microbiota to infectious diseases such as influenza, little is known about the role of the gut microbiota in COVID-19 pathophysiology. METHODS: To better understand the host-gut microbiota interactions in COVID-19, we characterized the gut microbial community and gut barrier function using metagenomic and metaproteomic approaches in 63 COVID-19 patients and 8 non-infected controls. Both immunohematological parameters and transcriptional profiles were measured to reflect the immune response in COVID-19 patients. RESULTS: Altered gut microbial composition was observed in COVID-19 patients, which was characterized by decreased commensal species and increased opportunistic pathogenic species. Severe illness was associated with higher abundance of four microbial species (i.e., Burkholderia contaminans, Bacteroides nordii, Bifidobacterium longum, and Blautia sp. CAG 257), six microbial pathways (e.g., glycolysis and fermentation), and 10 virulence genes. These severity-related microbial features were further associated with host immune response. For example, the abundance of Bu. contaminans was associated with higher levels of inflammation biomarkers and lower levels of immune cells. Furthermore, human-origin proteins identified from both blood and fecal samples suggested gut barrier dysfunction in COVID-19 patients. The circulating levels of lipopolysaccharide-binding protein increased in patients with severe illness and were associated with circulating inflammation biomarkers and immune cells. Besides, proteins of disease-related bacteria (e.g., B. longum) were detectable in blood samples from patients. CONCLUSIONS: Our results suggest that the dysbiosis of the gut microbiome and the dysfunction of the gut barrier might play a role in the pathophysiology of COVID-19 by affecting host immune homeostasis.

The gut microbiome and microbial metabolites in acute myocardial infarction.

Emerging evidence has highlighted the role of gut microbiome in human health. However, the integrative role of gut microbiome and microbial metabolites in acute myocardial infarction (AMI) remains unclear. The current study profiles the microbial community through 16S rRNA gene sequencing and shotgun metagenomic sequencing and measures fecal short-chain fatty acids and circulating choline pathway metabolites among 117 new-onset AMI cases and 78 controls. Significant microbial alternations are observed in AMI patients compared with controls (P = 0.001). The abundances of nine species (e.g., Streptococcus salivarius and Klebsiella pneumoniae) are positively associated, and one species (Roseburia hominis) is inversely associated with AMI status and severity. A gut microbial score at disease onset is associated with the risk of major adverse cardiovascular events in 3.2 years (hazard ratio [95% CI]: 2.01 [1.04-4.24]) in AMI patients. The molar proportions of fecal acetate and butyrate are higher, and the circulating levels of choline and carnitine are lower in AMI patients than in controls. In addition, disease classifiers show that AMI cases and controls have a more distinct pattern in taxonomical composition than in pathways or metabolites. Our findings suggest that microbial composition and functional potentials are associated with AMI status and severity.

A Predictive Model Based on a New CI-AKI Definition to Predict Contrast Induced Nephropathy in Patients With Coronary Artery Disease With Relatively Normal Renal Function.

Background: Contrast induced nephropathy (CIN) is a common complication in patients receiving intravascular contrast media. In 2020, the American College of Radiology and the National Kidney Foundation issued a new contrast induced acute kidney injury (CI-AKI) criteria. Therefore, we aimed to explore the potential risk factors for CIN under the new criteria, and develop a predictive model for patients with coronary artery disease (CAD) with relatively normal renal function (NRF). Methods: Patients undergoing coronary angiography or percutaneous coronary intervention at Zhongshan Hospital, Fudan University between May 2019 and April 2020 were consecutively enrolled. Eligible candidates were selected for statistical analysis. Univariate and multivariate logistic regression analyses were used to identify the predictive factors. A stepwise method and a machine learning (ML) method were used to construct a model based on the Akaike information criterion. The performance of our model was evaluated using the area under the receiver operating characteristic curves (AUC) and calibration curves. The model was further simplified into a risk score. Results: A total of 2,009 patients with complete information were included in the final statistical analysis. The results showed that the incidence of CIN was 3.2 and 1.2% under the old and new criteria, respectively. Three independent predictors were identified: baseline uric acid level, creatine kinase-MB level, and log (N-terminal pro-brain natriuretic peptide) level. Our stepwise model had an AUC of 0.816, which was higher than that of the ML model (AUC = 0.668, P = 0.09). The model also achieved accurate predictions regarding calibration. A risk score was then developed, and patients were divided into two risk groups: low risk (total score < 10) and high risk (total score ≥ 10). Conclusions: In this study, we first identified important predictors of CIN in patients with CAD with NRF. We then developed the first CI-AKI model on the basis of the new criteria, which exhibited accurate predictive performance. The simplified risk score may be useful in clinical practice to identify high-risk patients.

Comparison of Fecal Collection Methods on Variation in Gut Metagenomics and Untargeted Metabolomics.

Integrative analysis of high-quality metagenomics and metabolomics data from fecal samples provides novel clues for the mechanism underpinning gut microbe-human interactions. However, data regarding the influence of fecal collection methods on both metagenomics and metabolomics are sparse. Six fecal collection methods (the gold standard [GS] [i.e., immediate freezing at -80°C with no solution], 95% ethanol, RNAlater, OMNIgene Gut, fecal occult blood test [FOBT] cards, and Microlution) were used to collect 88 fecal samples from eight healthy volunteers for whole-genome shotgun sequencing (WGSS) and untargeted metabolomic profiling. Metrics assessed included the abundances of predominant phyla and α- and ß-diversity at the species, gene, and pathway levels. Intraclass correlation coefficients (ICCs) were calculated for microbes and metabolites to estimate (i) stability (day 4 versus day 0 within each method), (ii) concordance (day 0 for each method versus the GS), and (iii) reliability (day 4 for each method versus the GS). For the top 4 phyla and microbial diversity metrics at the species, gene, and pathway levels, generally high stability and reliability were observed for most methods except for 95% ethanol; similar concordances were seen for different methods. For metabolomics data, 95% ethanol showed the highest stability, concordance, and reliability (median ICCs = 0.71, 0.71, and 0.65, respectively). Taken together, OMNIgene Gut, FOBT cards, RNAlater, and Microlution, but not 95% ethanol, were reliable collection methods for gut metagenomic studies. However, 95% ethanol was the best for preserving fecal metabolite profiles. We recommend using separate collecting methods for gut metagenomic sequencing and fecal metabolomic profiling in large population studies. IMPORTANCE The choice of fecal collection method is essential for studying gut microbe-human interactions in large-scale population-based research. In this study, we examined the effects of fecal collection methods and storage time at ambient temperature on variations in the gut microbiome community composition; microbial diversity metrics at the species, gene, and pathway levels; antibiotic resistance genes; and metabolome profiling. Our findings suggest using different fecal sample collection methods for different data generation purposes. OMNIgene Gut, FOBT cards, RNAlater, and Microlution, but not 95% ethanol, were reliable collection methods for gut metagenomic studies. However, 95% ethanol was the best for preserving fecal metabolite profiles.

Sexual Dysfunction and the Impact of Beta-Blockers in Young Males With Coronary Artery Disease.

Objective: We aimed to assess the association of erectile dysfunction (ED) with the extent of coronary atherosclerosis, and to examine whether revascularization and medication use have an impact on ED status in patients with early onset of coronary artery disease (EOCAD). Methods: International Index of Erectile Function (IIEF-5) was used to evaluate sexual function in 296 male patients with EOCAD (age, 39.9 ± 4.8 years), and 354 male controls (age, 40.6 ± 4.4 years). The extent of coronary atherosclerosis was measured by Gensini score. Endothelial function was evaluated by two vasomotor indexes including endothelin-1 (ET-1) and nitric oxide (NO) by ELISA. Results: ED was more frequent (57.8 vs. 31.1%, P < 0.001) and serious (IIEF-5 score:17.7 ± 6.0 vs. 21.6 ± 5.0, P < 0.001) among EOCAD patients than that among controls. IIEF-5 score was negatively correlated with Gensini score (r = -0.383, P < 0.001). The adjusted odds ratio (OR) for the presence of ED (EOCAD vs. controls) was 1.88 [95% confidential interval (CI), 1.12-3.18]. However, ET-1 and NO attenuated the association between ED and EOCAD (adjusted OR: 1.54, 95% CI: 0.84-2.80). IIEF-5 score increased after coronary revascularization in patients not on beta-blockers (18.71 ± 4.84 vs. 17.59 ± 6.05, P < 0.001) as compared with baseline, while stayed unchanged in the subgroup using beta-blockers (17.82 ± 5.12 vs. 17.70 ± 5.98, P = 0.09). Conclusions: ED was common in patients with EOCAD, and associated with the severity of coronary atherosclerosis. Endothelial dysfunction may be a pathophysiologic mechanism underlying both ED and EOCAD. Coronary revascularization confers a benefit in ED amelioration, while this effect did not appear in patients using beta-blocker.

Habitual use of fish oil supplements, genetic predisposition, and risk of fractures: a large population-based study.

BACKGROUND: Epidemiologic studies have suggested an inverse association between circulating concentrations of long-chain ω-3 PUFAs and fracture risk. However, whether supplementation of long-chain ω-3 PUFA (i.e. fish oil) is associated with fracture risk, and whether the association is modified by genetic predisposition to fracture risk remain unclear. OBJECTIVES: To evaluate the associations of habitual fish oil supplement use with fracture risk, and to explore the potential effect modification by genetic predisposition. METHODS: This study included 492,713 participants from the UK Biobank who completed a questionnaire on habitual fish oil supplement use between 2006 and 2010. HRs and 95% CIs for fractures were estimated from multivariable Cox proportional hazards models. A weighted fracture-genetic risk score (GRS) was derived from 14 validated single nucleotide polymorphisms. RESULTS: During a median follow-up of 8.1 y, 12,070 incident fractures occurred among participants free of fracture at baseline (n = 441,756). Compared with nonuse, habitual use of fish oil supplements was associated with a lower risk of total fractures (HR = 0.93; 95% CI: 0.89, 0.97), hip fractures (HR = 0.83; 95% CI: 0.75, 0.92), and vertebrae fractures (HR = 0.85; 95% CI: 0.72, 0.99). The inverse association for total fractures was more pronounced among participants having a higher fracture-GRS than among those with a lower fracture-GRS (P-interaction <0.001). Among participants with a history of fracture at baseline (n = 50,957), fish oil use was associated with a lower risk of total recurrent fractures (HR = 0.88; 95% CI: 0.82, 0.96) and vertebrae recurrent fractures (HR = 0.64; 95% CI: 0.46, 0.88) but not with hip fracture recurrence. CONCLUSIONS: Our findings suggest that habitual fish oil supplement use is associated with lower risks of both incident and recurrent fractures. The inverse associations of fish oil use with total fractures appeared to be more pronounced among individuals at higher genetic risk of fractures than those with lower genetic risk.

Dietary factors, gut microbiota, and serum trimethylamine-N-oxide associated with cardiovascular disease in the Hispanic Community Health Study/Study of Latinos.

BACKGROUND: Trimethylamine-N-oxide (TMAO), a diet-derived and gut microbiota-related metabolite, is associated with cardiovascular disease (CVD). However, major dietary determinants and specific gut bacterial taxa related to TMAO remain to be identified in humans. OBJECTIVES: We aimed to identify dietary and gut microbial factors associated with circulating TMAO. METHODS: This cross-sectional study included 3972 participants (57.3% women) aged 18-74 y from the Hispanic Community Health Study/Study of Latinos in the United States. Dietary information was collected by 24-h dietary recalls at baseline interview (2008-2011), and baseline serum TMAO and its precursors were measured by an untargeted approach. Gut microbiome was profiled by shotgun metagenomic sequencing in a subset of participants (n = 626) during a follow-up visit (2016-2018). Logistic and linear regression were used to examine associations of inverse-normalized metabolites with prevalent CVD, dietary intake, and bacterial species, respectively, after adjustment for sociodemographic, behavioral, and clinical factors. RESULTS: TMAO was positively associated with prevalent CVD (case number = 279; OR = 1.34; 95% CI: 1.17, 1.54, per 1-SD). Fish (P = 1.26 × 10-17), red meat (P = 3.33 × 10-16), and egg (P = 3.89 × 10-5) intakes were top dietary factors positively associated with TMAO. We identified 9 gut bacterial species significantly associated with TMAO (false discovery rate <0.05). All 4 species positively associated with TMAO belong to the order Clostridiales, of which 3 might have homologous genes encoding carnitine monooxygenase, an enzyme converting carnitine to trimethylamine (TMA). The red meat-TMAO association was more pronounced in participants with higher abundances of these 4 species compared with those with lower abundance (Pinteraction = 0.013), but such microbial modification was not observed for fish-TMAO or egg-TMAO associations. CONCLUSION: In US Hispanics/Latinos, fish, red meat, and egg intakes are major dietary factors associated with serum TMAO. The identified potential TMA-producing gut microbiota and microbial modification on the red meat-TMAO association support microbial TMA production from dietary carnitine, whereas the fish-TMAO association is independent of gut microbiota.

Association of Oily and Nonoily Fish Consumption and Fish Oil Supplements With Incident Type 2 Diabetes: A Large Population-Based Prospective Study.

OBJECTIVE: To evaluate associations of oily and nonoily fish consumption and fish oil supplements with incident type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We included 392,287 middle-aged and older participants (55.0% women) in the UK Biobank who were free of diabetes, major cardiovascular disease, and cancer and had information on habitual intake of major food groups and use of fish oil supplements at baseline (2006-2010). Of these, 163,706 participated in one to five rounds of 24-h dietary recalls during 2009-2012. RESULTS: During a median 10.1 years of follow-up, 7,262 incident cases of T2D were identified. Compared with participants who reported never consumption of oily fish, the multivariable-adjusted hazard ratios of T2D were 0.84 (95% CI 0.78-0.91), 0.78 (0.72-0.85), and 0.78 (0.71-0.86) for those who reported <1 serving/week, weekly, and ≥2 servings/week of oily fish consumption, respectively (P-trend < 0.001). Consumption of nonoily fish was not associated with risk of T2D (P-trend = 0.45). Participants who reported regular fish oil use at baseline had a 9% (95% CI 4-14%) lower risk of T2D compared with nonusers. Baseline regular users of fish oil who also reported fish oil use during at least one of the 24-h dietary recalls had an 18% (8-27%) lower risk of T2D compared with constant nonusers. CONCLUSIONS: Our findings suggest that consumption of oily fish but not nonoily fish was associated with a lower risk of T2D. Use of fish oil supplements, especially constant use over time, was also associated with a lower risk of T2D.

Association between the metabolome and bone mineral density in a Chinese population.

BACKGROUND: Osteoporosis is a common metabolic bone disease, which always leads to osteoporotic fractures. Biomarkers of bone mineral density (BMD) are helpful for prevention and early diagnosis of osteoporosis. This study aims to identify metabolomic biomarkers of low BMD. METHODS: We included 701 participants who had BMD measures by dual-energy X-ray absorptiometry scans and donated fasting plasma samples from three clinical centres as a discovery set and another 278 participants from the fourth centre as an independent replication set. We used a liquid chromatography-mass spectrometry-based metabolomics approach to profile the global metabolites of fasting plasma. FINDINGS: Among the 265 named metabolites identified in our study, six were associated with low BMD (FDR-adjusted P<0.05) in the discovery set and were successfully validated in the independent replication set. The circulating levels of five metabolites, i.e., inosine, hypoxanthine, PC (O-18:0/22:6), SM (d18:1/21:0) and isoleucyl-proline were associated with decreased odds of low BMD, and PC (16:0/18:3) level was associated with increased odds of low BMD. Per 1-SD increase in a composite metabolite score of these six metabolites was associated with about half decreased odds of low BMD (odds ratio 0.59, 95% confidence interval: 0.52-0.68). Furthermore, introduction of a panel of metabolites selected by elastic net regression to a prediction model of classical risk factors and plasma biomarker of bone resorption substantially improved the prediction performance for low BMD (AUCs: 0.782 vs. 0.698, P=0.002). INTERPRETATION: Metabolomics profiling may help identify novel biomarkers of low BMD and be helpful for early diagnosis of osteoporosis beyond the current clinical index. FUNDING: This study was supported by the National Key R&D Program of China [2018YFC2001500 to J.S.], Shanghai Municipal Science and Technology Major Project [2017SHZDZX01], the National Natural Science Foundation of China [Key Program, 91749204 to J.S.], the National Natural Science Foundation of China [General Program, 81771491 to J.S.], the Project of Shanghai Subject Chief Scientist [2017BR011 to J.S.], Grants from the TCM Supported Project [18431902300 to J.S.] from the Science and Technology Commission of Shanghai Municipality, and the National Natural Science Foundation of China [General Program, 81972089 to Z.X.]. Y.Z. was supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, and the National Natural Science Foundation of China [81973032].

Myocardial injury and COVID-19: Serum hs-cTnI level in risk stratification and the prediction of 30-day fatality in COVID-19 patients with no prior cardiovascular disease.

Introduction: To explore the involvement of the cardiovascular system in coronavirus disease 2019 (COVID-19), we investigated whether myocardial injury occurred in COVID-19 patients and assessed the performance of serum high-sensitivity cardiac Troponin I (hs-cTnI) levels in predicting disease severity and 30-day in-hospital fatality. Methods: We included 244 COVID-19 patients, who were admitted to Renmin Hospital of Wuhan University with no preexisting cardiovascular disease or renal dysfunction. We analyzed the data including patients' clinical characteristics, cardiac biomarkers, severity of medical conditions, and 30-day in-hospital fatality. We performed multivariable Cox regressions and the receiver operating characteristic analysis to assess the association of cardiac biomarkers on admission with disease severity and prognosis. Results: In this retrospective observational study, 11% of COVID-19 patients had increased hs-cTnI levels (>40 ng/L) on admission. Of note, serum hs-cTnI levels were positively associated with the severity of medical conditions (median [interquartile range (IQR)]: 6.00 [6.00-6.00] ng/L in 91 patients with moderate conditions, 6.00 [6.00-18.00] ng/L in 107 patients with severe conditions, and 11.00 [6.00-56.75] ng/L in 46 patients with critical conditions, P for trend=0.001). Moreover, compared with those with normal cTnI levels, patients with increased hs-cTnI levels had higher in-hospital fatality (adjusted hazard ratio [95% CI]: 4.79 [1.46-15.69]). The receiver-operating characteristic curve analysis suggested that the inclusion of hs-cTnI levels into a panel of empirical prognostic factors substantially improved the prediction performance for severe or critical conditions (area under the curve (AUC): 0.71 (95% CI: 0.65-0.78) vs. 0.65 (0.58-0.72), P=0.01), as well as for 30-day fatality (AUC: 0.91 (0.85-0.96) vs. 0.77 (0.62-0.91), P=0.04). A cutoff value of 20 ng/L of hs-cTnI level led to the best prediction to 30-day fatality. Conclusions: In COVID-19 patients with no preexisting cardiovascular disease, 11% had increased hs-cTnI levels. Besides empirical prognostic factors, serum hs-cTnI levels upon admission provided independent prediction to both the severity of the medical condition and 30-day in-hospital fatality. These findings may shed important light on the clinical management of COVID-19.

Circulating metabolites from the choline pathway and acute coronary syndromes in a Chinese case-control study.

BACKGROUND: Accumulating evidence shows that circulating levels of trimethylamine N-oxide, which is generated from the metabolism of dietary choline, may predict cardiovascular disease among Caucasians. Acute coronary syndrome (ACS), one common presentation of cardiovascular disease, is a spectrum of signs and symptoms due to acute decreased blood flow in the coronary arteries. The relationship between the metabolites from choline pathway and ACS remains unclear. We aimed to assess the associations of circulating metabolites from the choline pathway with ACS among a Chinese population, who consume a different dietary pattern than their Western counterparts. METHODS: We recruited 501 participants who were admitted to the Department of Cardiology, Zhongshan Hospital,Shanghai China between March 2017 and June 2018, including 254 ACS cases and 247 controls. Liquid chromatography-tandem mass spectrometry was used to measure circulating concentrations of metabolites in the choline pathway, including betaine, choline, trimethylamine, and trimethylamine N-oxide. A composite metabolite score using a weighted sum of these four metabolites, and the betaine/choline ratio were calculated. Multivariable logistic regressions were applied to estimate the association of metabolites with ACS, with adjustment of age, sex, body mass index, smoking index, history of diseases, and kidney function. RESULTS: After adjusting for traditional risk factors, per 1-standard deviation (SD) increment in choline was positively associated with the odds of ACS [odds ratio (OR), 95% confidence interval (CI), 1.77(1.44-2.18)], and the other metabolites were not associated with ACS at a statistical significance level. Compared with participants in the lowest quartile of the metabolite score, those in the highest quartile had higher odds of ACS [OR (95% CI), 3.18(1.85-5.54), p < 0.001 for trend]. Per 1-SD increment in metabolite score was positively associated with higher odds of ACS [OR (95% CI), 1.80 (1.37-2.40)], and per 1-SD increment in the betaine/choline ratio was inversely associated with the odds of ACS [OR (95% CI), 0.49 (0.39-0.60)]. CONCLUSIONS: Among our Chinese participants, trimethylamine N-oxide was not associated with ACS, while a composite metabolite score of metabolites from the choline pathway was associated with increased odds of ACS. The choline pathway metabolites may be related to the pathophysiology of ACS among Chinese.