Genetically predicted blood metabolites mediate the association between circulating immune cells and pancreatic cancer: A Mendelian randomization study.

BACKGROUND: Pancreatic cancer is characterized by metabolic dysregulation and unique immunological profiles. Nevertheless, the comprehensive understanding of immune and metabolic dysregulation of pancreatic cancer remains unclear. In the present study, we aimed to investigate the causal relationship of circulating immune cells and pancreatic cancer and identify the blood metabolites as potential mediators. METHODS: The exposure and outcome genome-wide association studies (GWAS) data used in the present study were obtained from the GWAS open-access database (https://gwas.mrcieu.ac.uk). The study used 731 circulating immune cell features, 1400 types of blood metabolites and pancreatic cancer from GWAS. We then performed bidirectional Mendelian randomization (MR) analyses to explore the causal relationships between the circulating immune cells and pancreatic cancer, and two-step MR to discover potential mediating blood metabolites in this process. All statistical analyses were performed in R software. The STROBE-MR (i.e. Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization) checklist for the reporting of MR studies was also used. RESULTS: MR analysis identified seven types of circulating immune cells causally associated with pancreatic cancer. Furthermore, there was no strong evidence that genetically predicted pancreatic cancer had an effect on these seven types of circulating immune cells. Further two-step MR analysis found 10 types of blood metabolites were causally associated with pancreatic cancer and the associations between circulating CD39+CD8+ T cells and pancreatic cancer were mediated by blood orotates with proportions of 5.18% (p = 0.016). CONCLUSIONS: The present study provides evidence supporting the causal relationships between various circulating immune cells, especially CD39+CD8+ T cells, and pancreatic cancer, with a potential effect mediated by blood orotates. Further research is needed on additional risk factors as potential mediators and establish a comprehensive immunity-metabolism network in pancreatic cancer.

Human blood metabolites and risk of sepsis: A Mendelian randomization investigation.

BACKGROUND: Evidence supports the observational correlations between human blood metabolites and sepsis. However, whether these associations represent a causal relationship is unknown. In this study, we applied two-sample Mendelian randomization (MR) analyses to examine causality between genetically proxied 486 blood metabolites and sepsis risk. METHODS: We used summary data from genome-wide association studies (GWAS) on 486 metabolites involving 7824 individuals as exposure and a sepsis GWAS including 11,643 cases and 474,841 controls as the outcome. The inverse-variance weighted (IVW) was the primary method to estimate the causal relationship between exposure and outcome, with MR-Egger and weighted median serving as supplements. Sensitivity analyses were implemented with Cochrane's Q test, MR-Egger intercept, MR-PRESSO and leave-one-out analysis. In addition, we performed replication MR, meta-analysis, Steiger test, linkage disequilibrium score (LDSC) regression and multivariable MR (MVMR) to thoroughly verify the causation. RESULTS: We identified that genetically determined high levels of 1-oleoylglycerophosphoethanolamine (odds ratio (OR) = .52, 95% confidence interval (CI): .31-.87, p = .0122), alpha-glutamyltyrosine (OR = .75, 95% CI: .60-.93, p = .0102), heptanoate (7:0) (OR = .51, 95% CI: .33-.81, p = .0041) and saccharin (OR = .84, 95% CI: .74-.94, p = .0036) were causally associated with a lower risk of sepsis. MVMR analysis demonstrated the independent causal effect of these metabolites on sepsis. CONCLUSIONS: These findings indicated that four blood metabolites have a protective impact on sepsis, thus providing novel perspectives into the metabolite-mediated development mechanism of sepsis by combining genomics and metabolomics.

Causal Relationships between Gut Microbiotas, Blood Metabolites, and Neuroendocrine Tumors: A Mediated Mendelian Randomization Study.

INTRODUCTION: Neuroendocrine tumors (NETs) are a heterogeneous group of epithelial tumors originating from different anatomical sites, and identifying the gut microbiota and metabolic mechanisms involved in the onset of NETs may help to develop appropriate disease prevention and monitoring strategies. METHODS: We employed a mediated two-sample Mendelian randomization (MR) approach, analyzing gut microbiota from German studies and NET datasets from the 10th round of the FinnGen project. Mediation analyses were conducted using the metabolites dataset from the Canadian Longitudinal Study of Aging (CLSA) and the TwinsUK study. Instrumental variables were chosen according to established MR criteria and analyzed using the Wald ratio, inverse-variance weighted (IVW), MR-Egger, and weighted median methods. To ensure robustness, sensitivity analyses were performed using Cochrane's Q, Egger's intercept, MR-PRESSO, and leave-one-out methods. RESULTS: Causal relationships were identified between the genetic determinants of 6, 5, 2, 1, 2, 3 gut microbiotas and the risk of colorectal, lung, pancreatic, rectum, small intestine, and stomach NETs. Similarly, the genetic determinants of 4, 6, 1, 5, 10, and 7 metabolites were found to be causally related to the risk of colorectal, lung, pancreatic, rectum, small intestine, and stomach NETs, respectively. Through Wald ratio and IVW methods, we preliminarily identified 957 microbiota-metabolite pairs with significant causal associations and formed 13 mediated relationships between the impact of gut microbiotas on NETs. CONCLUSION: Our study suggests that gut microbiotas and its derived metabolites may contribute to the onset of NET, offering a novel insight into the disease's pathogenesis.

Evaluation of the causal effects of blood metabolites on irritable bowel syndrome: Mendelian randomization.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain, discomfort, and changes in bowel habits. The mechanism underlying IBS remains unclear, and little evidence exists for clarifying the causal relationship between blood metabolites and IBS. METHODS: We conducted a Mendelian randomization (MR) study using two samples. Exposure data for 7824 Europeans were extracted from a genome-wide association study (GWAS) on metabolite levels. The IBS GWAS data from the GWAS database were used for the initial analysis. The primary analysis of causal relationships was conducted using inverse-variance weighting (IVW) with MR-Egger and weighted medians as supplementary analyses. Sensitivity analyses were performed using a combination of the Cochran's Q test, MR-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier, and leave-one-out analysis. For significant associations, replication and meta-analyses were performed using additional independent IBS case GWAS data released by the FinnGen Consortium R9. To identify the metabolites, score regression, confounding analysis, and reverse MR were performed to further assess the causal relationships between the metabolites. RESULTS: After rigorous screening, we identified four known metabolites to be associated with IBS (stearate, odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.59-0.92; arginine, OR: 1.36, 95% CI: 1.07-1.74; 1-palmitoylglycerol, OR:1.49, 95% CI: 1.07-2.07; 1-palmitoylglycerophosphoinositol, OR: 0.84, 95% CI: 0.71-0.99). CONCLUSIONS: MR analysis revealed a causal relationship between the four metabolites and IBS, providing preliminary evidence for the pathogenesis of IBS. Our results provide novel insights into the potential biomarkers of IBS.

Causal effects of genetically determined blood metabolites on asthma: a bidirectional Mendelian randomization study.

OBJECTIVE: The observational association between blood metabolites and asthma has been extensively studied. However, it is still unclear whether this association is causal. In this study, we aimed to investigate the causal relationship between blood metabolites and asthma using a bidirectional Mendelian randomization (MR) analysis. Additionally, we aimed to explore the potential mechanisms underlying this relationship. METHODS: The study design involved the use of genetic instruments as instrumental variables (IVs) to fulfill the assumptions of MR analysis. The data on 1,091 metabolites and 309 metabolite ratios were obtained from the Canadian Longitudinal Study on Aging (CLSA), while the data on asthma were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project. Utilizing the inverse variance-weighted (IVW) method as the primary MR analysis approach, sensitivity tests were conducted to assess the reliability of the findings, which involved employing Cochran's Q and the MR-Egger intercept. Furthermore, Bayesian weighted MR was used to further test the robustness of the results. Additionally, pathway analysis was conducted to explore the metabolic explanations underlying asthma. RESULT: In our study, a comprehensive MR Analysis identified 10 metabolites and 6 metabolite ratios significantly associated with the development of asthma (FDR < 0.05). The metabolites included glycerophosphocholines(GPCs), glycerophosphoethanolamines(GPEs), and an unknown metabolite. Of these, 1-arachidonoyl-GPC, 1-myristoyl-2-arachidonoyl-GPC, 1-palmitoyl-2-arachidonoyl-GPC, and 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC were associated with an increased risk of asthma, whereas 1,2-dilinoleoyl-GPC, 1-palmitoyl-2-linoleoyl-GPC, 1,2-dilinoleoyl-GPE, 1 - oleoyl - 2 - linoleoyl - GPE, 1-palmitoyl-2-linoleoyl-GPE, and X-21470 were found to have a protective effect. No heterogeneity and pleiotropy were observed in the significant metabolites (p > 0.05), and each metabolite exhibited a consistent effect direction across all five methods. BWMR analysis results confirmed the significance and direction of effects across exposures, except for Cholesterol to linoleoyl-arachidonoyl-glycerol ratio(p = 0.673). Pathway analysis suggests that glycerophospholipid metabolism may potentially be a mechanism underlying the development of asthma. CONCLUSION: Our MR findings suggest that the identified metabolites and pathways can serve as biomarkers for clinical asthma screening and prevention, while also providing new insights for future mechanistic exploration and drug target selection.

The causal relationship between human blood metabolites and the risk of visceral obesity: a mendelian randomization analysis.

BACKGROUND: We aimed to explore the causal relationship between blood metabolites and the risk of visceral obesity, as measured by visceral adipose tissue (VAT). METHODS: Summary statistics for 486 blood metabolites and total, as well as sex-stratified, MRI-derived VAT measurements, adjusted for body mass index (BMI) and height, were collected from previous genome-wide association studies (GWAS). A two-sample Mendelian Randomization (MR) design was used. Comprehensive evaluation was further conducted, including sensitivity analysis, linkage disequilibrium score (LDSC) regression, Steiger test, and metabolic pathway analysis. RESULTS: After multiple testing correction, arachidonate (20:4n6) has been implicated in VAT accumulation (ß = 0.35, 95%CI:0.18-0.52, P < 0.001; FDR = 0.025). Additionally, several blood metabolites were identified as potentially having causal relationship (FDR < 0.10). Among them, lysine (ß = 0.67, 95%CI: 0.28-1.06, P < 0.001; FDR = 0.074), proline (ß = 0.30, 95%CI:0.13-0.48, P < 0.001; FDR = 0.082), valerate (ß = 0.50, 95%CI:0.23-0.78, P < 0.001, FDR = 0.091) are associated with an increased risk of VAT accumulation. On the other hand, glycine (ß=-0.21, 95%CI: -0.33-0.09), P < 0.001, FDR = 0.076) have a protective effect against VAT accumulation. Most blood metabolites showed consistent trends between different sexes. Multivariable MR analysis demonstrated the effect of genetically predicted arachidonate (20:4n6) and proline on VAT remained after accounting for BMI and glycated hemoglobin (HbA1c). There is no evidence of heterogeneity, pleiotropy, and reverse causality. CONCLUSION: Our MR findings suggest that these metabolites may serve as biomarkers, as well as for future mechanistic exploration and drug target selection of visceral obesity.

The causal relationship between blood metabolites and rosacea: A Mendelian randomization.

BACKGROUND: An increasing amount of research demonstrates that metabolic disorders are related to rosacea. However, the correlations and causal relationships among them remain unknown. METHODS: We conducted not only forward 2-sample MR (Mendelian randomization) analyses but also reverse MR analyses which showed positive results in the forward MR analysis. In the forward MR analyses, inverse-variance weighted (IVW) and MR-Egger were performed as MR analyses. Cochran's Q test and the MR-Egger Intercept were used for sensitivity analyses. Concerning reverse MR analyses, IVW, MR-Egger, weighted median, simple mode, and weighted mode were applied. Cochran's Q test, MR-Egger Intercept, and MR pleiotropy residual sum and outlier (MR-PRESSO) outlier test were applied as sensitivity analyses. RESULTS: A total of 24 metabolites and 1 metabolite ratio were shown to have a causal effect on rosacea. N-lactoyl phenylalanine (N-Lac-Phe) was estimated as statistically significant by Bonferroni correction. Interestingly, we found three metabolites that were negatively associated with rosacea, especially caffeine, which are in line with the results of a large cohort study of females. For reverse MR analysis, we revealed that rosacea could potentially decrease the generation of two metabolites: octadecenedioate (C18:1-DC) and methyl vanillate sulfate. CONCLUSION: This study identified blood metabolites that may be associated with the development of rosacea. However, the exact mechanism by which these positive metabolites influence rosacea remains uncertain due to the paucity of experimental investigations. The combination of genetics and metabolomics offers novel viewpoints on the research of underlying mechanisms of rosacea and has significant value in screening and prevention of rosacea.

The gut-facial aging axis: A two-sample Mendelian randomization and mediation analysis of gut microbiota, gut microbiota metabolic pathways, and blood metabolites.

BACKGROUND: Facial aging (FA) is a complex process influenced by both genetic and environmental factors. Gut microbiota (GM), gut microbiota metabolic pathways (GMMPs), and blood metabolites (BMs) have been implicated in the regulation of FA, but the causal and mediating effects of these factors remain unclear. METHODS: We used summary-level data from genome-wide association studies (GWAS) of 16S rRNA gene sequencing data for GM (n = 18 340), GWAS of GMMPs (n = 7738), BMs (n = 24 925), and GWAS of FA (n = 423 999). We applied Mendelian randomization (MR) methods to estimate the causal effects of GM, GMMPs, and BMs on FA. We performed mediation analysis to quantify the proportion of the effects mediated by blood metabolites. RESULTS: We identified nine genus, two phylum, two families of GM, nine GM metabolic pathways, and 73 BMs that showed potential causal effects on FA. After Bonferroni correction, three BMs remained causally associated with FA, including average number of methylene groups per double bond (ß, -0.023; 95% CI, -0.032∼-0.014; p = 3.120×10-7) and average number of methylene groups in a fatty acid chain (ß, -0.031; 95% CI, -0.045∼-0.016; p = 2.062×10-5), which had strong negative causal effects on FA, and ratio of bisallylic groups to total fatty acids (ß, 0.023; 95% CI, 0.017∼-0.029; p = 8.441×10-15), which had a strong positive causal effect on FA. Mediation analysis revealed that histidine, average number of methylene groups in a fatty acid chain, and triglycerides in chylomicrons and largest VLDL particles mediated the effects of anaerofilum and/ or superpathway of Laspartate and Lasparagine biosynthesis on FA. CONCLUSION: Our study provides novel insights into the causal and mediating effects of GM, GMMPs, and BMs on FA. These findings may have implications for the development of new strategies for preventing or delaying FA.

Genetic causality and metabolite pathway identifying the relationship of blood metabolites and psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory disease that causes significant disability. However, little is known about the underlying metabolic mechanisms of psoriasis. Our study aims to investigate the causality of 975 blood metabolites with the risk of psoriasis. MATERIALS AND METHODS: We mainly applied genetic analysis to explore the possible associations between 975 blood metabolites and psoriasis. The inverse variance weighted (IVW) method was used as the primary analysis to assess the possible association of blood metabolites with psoriasis. Moreover, generalized summary-data-based Mendelian randomization (GSMR) was used as a supplementary analysis. In addition, linkage disequilibrium score regression (LDSC) was used to investigate their genetic correction further. Metabolic pathway analysis of the most suggested metabolites was also performed using MetaboAnalyst 5.0. RESULTS: In our primary analysis, 17 metabolites, including unsaturated fatty acids, phospholipids, and triglycerides traits, were selected as potential factors in psoriasis, with odd ratios (OR) ranging from 0.986 to 1.01. The GSMR method confirmed the above results (ß = 0.001, p < 0.05). LDSC analysis mainly suggested the genetic correlation of psoriasis with genetic correlations (rg) from 0.088 to 0.155. Based on the selected metabolites, metabolic pathway analysis suggested seven metabolic pathways including ketone body that may be prominent pathways for metabolites in psoriasis. CONCLUSION: Our study supports the causal role of unsaturated fatty acid properties and lipid traits with psoriasis. These properties may be regulated by the ketone body metabolic pathway.

Postprandial kinetics of digestive function in rainbow trout (Oncorhynchus mykiss): genes expression, enzymatic activity and blood biochemistry as a practical tool for nutritional studies.

Postprandial kinetics of genes expression of gastric (chitinase, pepsinogen) and intestinal (alkaline phosphatase, maltase) digestive enzymes and nutrient transporters (peptide transporter 1, sodium-glucose transporter 1), Brush Border Membrane (BBM) enzymes activity (alkaline phosphatase, leucine aminopeptidase, maltase, saccharase) and blood biochemistry (triglycerides, cholesterol, protein, albumin, glucose, amino acids) through NMR spectroscopy, were investigated in rainbow trout (Oncorhynchus mykiss) fed a commercial aquafeed. For this purpose, fish were starved 72 h and digestive tract and blood were sampled before the meal and at 1.5, 3, 6, 9, 12, and 24 h after feeding (T0, T1.5, T3, T6, T9, T12 and T24). The postprandial kinetic showed that the expression of the genes involved in digestion and nutrient transport, the activity of BBM enzymes, and the presence of metabolites in blood were stimulated in different ways by the presence of feed in the digestive tract. The expression of most genes peaked 3 h after meal except gastric pepsinogen and maltase in distal intestine that peaked at T9 and T12, respectively. The activity of BBM enzymes were stimulated differently based on the intestine tract. The plasma proteins level increased from T1.5 until T9, while the other blood parameters unvariated during the postprandial period. This study supplied useful information about the physiological effects a single meal as a potential tool for planning nutritional studies involving the digestive functions.

Observational study on the associations between milk yield, composition, and coagulation properties with blood biomarkers of health in Holstein cows.

The considerable increase in the production capacity of individual cows owing to both selective breeding and innovations in the dairy sector has posed challenges to management practices in terms of maintaining the nutritional and metabolic health status of dairy cows. In this observational study, we investigated the associations between milk yield, composition, and technological traits and a set of 21 blood biomarkers related to energy metabolism, liver function or hepatic damage, oxidative stress, and inflammation or innate immunity in a population of 1,369 high-yielding Holstein-Friesian dairy cows. The milk traits investigated in this study included 4 production traits (milk yield, fat yield, protein yield, daily milk energy output), 5 traits related to milk composition (fat, protein, casein, and lactose percentages and urea), 11 milk technological traits (5 milk coagulation properties and 6 curd-firming traits). All milk traits (i.e., production, composition, and technological traits) were analyzed according to a linear mixed model that included the days in milk, the parity order, and the blood metabolites (tested one at a time) as fixed effects and the herd and date of sampling as random effects. Our findings revealed that milk yield and daily milk energy output were positively and linearly associated with total cholesterol, nonesterified fatty acids, urea, aspartate aminotransferase, γ-glutamyl transferase, total bilirubin, albumin, and ferric-reducing antioxidant power, whereas they were negatively associated with glucose, creatinine, alkaline phosphatase, total reactive oxygen metabolites, and proinflammatory proteins (ceruloplasmin, haptoglobin, and myeloperoxidase). Regarding composition traits, the protein percentage was negatively associated with nonesterified fatty acids and ß-hydroxybutyrate (BHB), while the fat percentage was positively associated with BHB, and negatively associated with paraoxonase. Moreover, we found that the lactose percentage increased with increasing cholesterol and albumin and decreased with increasing ceruloplasmin, haptoglobin, and myeloperoxidase. Milk urea increased with an increase in cholesterol, blood urea, nonesterified fatty acids, and BHB, and decreased with an increase in proinflammatory proteins. Finally, no association was found between the blood metabolites and milk coagulation properties and curd-firming traits. In conclusion, this study showed that variations in blood metabolites had strong associations with milk productivity traits, the lactose percentage, and milk urea, but no relationships with technological traits of milk. Specifically, increasing levels of proinflammatory and oxidative stress metabolites, such as ceruloplasmin, haptoglobin, myeloperoxidase, and total reactive oxygen metabolites, were shown to be associated with reductions in milk yield, daily milk energy output, lactose percentage, and milk urea. These results highlight the close connection between the metabolic and innate immunity status and production performance. This connection is not limited to specific clinical diseases or to the transition phase but manifests throughout the entire lactation. These outcomes emphasize the importance of identifying cows with subacute inflammatory and oxidative stress as a means of reducing metabolic impairments and avoiding milk fluctuations.

Interaction of blood calcium with milk yield, energy metabolites, subclinical mastitis, and reproductive performance in crossbred dairy cows.

Limited literature is available on the consequences of postpartum low blood calcium (Ca) concentration in crossbred cows. The research aimed to investigate the correlation between postpartum serum Ca levels and various parameters, including milk yield, serum energy metabolites, milk somatic cell count, and reproductive factors in crossbred cows. Following parturition, a total of 45 potential high-yielding F2 (HF × Sahiwal; Genotype: 75:25) dairy cows were enrolled . These cows were categorized based on plasma calcium concentrations into three groups: a low calcium group (Ca-L) with a calcium concentration of <5 mg/dL, a medium calcium group (Ca-M) with a calcium concentration ranging from 5 to 8.5 mg/dL, and a high calcium group (Ca-H) with a calcium concentration exceeding 8.5 mg/dL. The study parameters were measured over an 8-week period. The results indicated that overall milk yield and blood glucose were significantly higher in the Ca-H group compared to Ca-M and Ca-L (p < .01). Blood cholesterol was significantly higher in Ca-M (p < .01), while blood triglyceride was significantly lower in both Ca-M and Ca-H. Overall, blood cortisol did not show a significant change between these groups (p < .01); however, progesterone levels were higher (p < .01) in Ca-M and Ca-H cows. Furthermore, somatic cell count (SCC) significantly (p < .01) decreased in cows with Ca-H compared to Ca-L. Additionally, postpartum oestrous interval and interestrus interval decreased significantly (p < .01) in Ca-M and Ca-H compared to Ca-L. These findings suggest that cows with blood calcium levels exceeding 8.5 mg/dL exhibited significantly higher milk yield, blood metabolite levels, a lower likelihood of subclinical mastitis, and earlier reproductive activity after calving.

Exploration of plant metabolomics variation and absorption characteristics of water-extracted Rheum tanguticum and ethanol-extracted Rheum tanguticum by UHPLC-Q-TOF-MS/MS.

BACKGROUND AND OBJECTIVE: The herb Rheum tanguticum (RT), a member of the Polygonaceae family, is listed in the Chinese Pharmacopoeia and has been widely used to treat cardiovascular and gastrointestinal disease. The research aimed to identify the different substances from two kinds of RT extraction methods and the in vivo biotransformation of RT components. METHODS: In this study, by using ultrahigh-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS), we have investigated the metabolomic variation and the in vivo metabolism of RT. A post-acquisition data processing software, PeakView, was applied to an accurate qualitative analysis of the chemical components in RT. RESULTS: Through plant metabolomics analysis, 24 related, differentially expressed metabolites of RT water extract and alcohol extract were obtained. Combined with novel identification strategies and systematic in vivo metabolism analysis, a total of 101 compounds were discovered or tentatively identified in rat serum (including 15 prototype compounds and 86 metabolites). CONCLUSION: In this study, a combination of extraction methods, liquid chromatography-mass spectrometry (LC-MS) technology, and in vivo animal metabolism studies have been established for the screening, identification, and research of chemical active components of natural medicines. LC-MS analysis combined with plant metabolomics was used to study the differential metabolites between different extraction methods of RT. Based on UHPLC-Q-TOF-MS/MS technology, the composition and metabolism of rat plasma before and after RT administration were analysed in vivo, and 15 prototype components and 86 metabolites were detected.

Cutaneous Melanoma and 486 Human Blood Metabolites: A Mendelian Randomization Study.

BACKGROUND: Cutaneous melanoma (CM) has long been recognized as a lethal form of cancer. Despite persistent research endeavors, the precise underlying pathological mechanisms remain largely unclear, and the optimal treatment for this patient population remains undetermined. OBJECTIVES: This study aims to examine the causal associations between CM and 486 metabolites. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted to ascertain the causal relationship between blood metabolites and CM. The causality analysis involved the inverse variance weighted (IVW) method, followed by the MR-Egger and weighted median (WM) methods. To increase the robustness of our findings, several sensitivity analyses, including the MR-Egger intercept, Cochran's Q test, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were performed. The robustness of our results was further validated in independent outcome samples followed by a meta-analysis. Additionally, a metabolic pathway analysis was carried out. RESULTS: The two-sample MR analysis yielded a total of 27 metabolites as potential causal metabolites. After incorporating the outcomes of the sensitivity analyses, seven causal metabolites remained. Palmitoylcarnitine (OR 0.9903 95% CI 0.9848-0.9958, p = 0.0005) emerged as the sole metabolite with a significant causality after Bonferroni correction. Furthermore, the reverse MR analysis provided no evidence of reverse causality from CM to the identified metabolites. CONCLUSIONS: This study suggested a causal relationship between seven human blood metabolites and the development of CM, thereby offering novel insights into the underlying mechanisms involved. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Feasible feeding strategies for sustainable management of serve heat stress conditions: Effect of Milk Thistle extract on growth performance and health status of newly weaned rabbits.

The trail aimed to explore the effect of dietary supplementation of Milk Thistle (MT) extract on growth performance and health status of growing rabbits exposed to serve heat stress condition, considering the economic efficiency of supplementation. A total of 96 weaned male rabbits were divided into 4 groups (24 rabbits/group). The first group received the basal diet without any supplementation and served as a control (MT0), while 2nd, 3rd and 4th groups supplemented with MT at levels of 5 (MT5), 10 (MT10) and 15 (MT15) g/kg diet, respectively, for 10 consecutive weeks. Both of growth performance and feed utilisation were significantly enhanced by the dietary treatment, the optimum dose of MT was 12 g/kg diet for average daily gain, specific growth rate and performance index. However, it was 13 g/kg diet for feed conversation ratio. The polynomial regression analysis showed that the lowest values of rectal temperature and respiration rate were observed at doses of 11 and 13 g/kg diet respectively. The dressing percentage and the relative weights of liver and total edible giblets were significantly improved by the treatment (p = 0.0416, 0.0112 and 0.0032, respectively), maximising in the MT10 group. The MT10 and MT15 groups showed higher erythrocytes and leucocytes counts and lower levels of urea, creatinine and total cholesterol compared to the control (p < 0.05). Liver functions significantly enhanced in aforementioned two treated groups, the liver ultrastructure represented normal cytoplasmic organelles, and nucleus and mitochondria in MT10 group, while the MT15 group showed hepatocytes with dilated nucleus with most cytoplasmic organelles appeared well organised and normal except few small cytoplasms vacuolated. The levels glutathione, superoxide dismutase, catalase and total antioxidant capacity as well as immunoglobulin M, and immunoglobulin G significant improved in the MT-Treated groups compared to the control (p < 0.05). Economically, MT supplemented diets improved the net revenue of fattened rabbits during the summer season. In conclusion, the supplementation of MT extract at levels of 10 or 15 g/kg diet enhanced growth performance, feed utilisation, dressing percentage, hemato-biochemical attributes, immunity and redox balance of heat stressed growing rabbits during the hot season.

Effects of Supplementing Different Quantities of Moringa stenopetala Leaves on Plasma Metabolite and Acylcarnitine Profile, Body Condition Score and Milk Yield Performance in Zebu (Bos indicus) Cattle.

The formulation of multi-nutrient blocks based on low-cost and locally available browse feed resources can be a valid feeding strategy in Sub-Saharan Africa, where inadequate feed supply, both in quality and quantity, is a major constraint. We evaluated the four different inclusion percentages (M-0%, M-25%, M-35% and M-45%) of Moringa stenopetala leaf powder to multi-nutrient blocks on their change on blood metabolite of dairy cows under practical, ranging conditions. Multi-nutrient blocks with four inclusion rates of M. stenopetala leaves were applied as complementary feed for free ranging dairy cows. The study was performed on 24 free ranging dairy cows reared around Arba Minch town in the Southern Ethiopian Rift Valley. Blood samples were collected from the jugular vein of dairy cows both before and after supplementation. Plasma glucose, beta hydroxy butyrate (BHB), urea, creatinine, triglycerides and nonesterified fatty acids (NEFA) concentration was quantified spectrophotometrically. Dried serum spots were subject to quantitative electrospray tandem mass spectrometry to estimate changes in nutrient metabolism based on selected carnitines. Based on these measurements, the milk yield and body condition score were increased during the period of multi-nutrient block supplementation. During the supplementation period, the cows got higher plasma glucose, triglyceride and urea concentrations and lower concentrations of BHB, NEFA and creatinine. From the metabolite profiles, a more efficient nutrient use could be concluded. Although no clear dose-response relationship was observed, the highest inclusion of the M. stenopetala leaves in the multi-nutrient blocks gave the best performance. This outcome supports the idea of implementing M. stenopetala based multi-nutrient blocks on tropical smallholder farms that are not easily accessible to conventional extension services.

Rosa roxburghii tratt residue: A novel feed resource for cattle indicated by the non-deleterious performance and blood metabolites.

Rosa roxburghii tratt residue (RRTR) is a regional and uncommon byproduct in Guizhou. Little information is available on whether RRTR can be used as feed for ruminants. In this study, the feasibility of using RRTR as a new feed resource for cattle was investigated by chemical composition analysis, in vitro gas production (Trial 1) and animal feeding experiments (Trial 2). In trial 1, compared to the commonly used fruit residues, RRTR had a proximate nutrient level; the in vitro gas production curve and dynamics fell within the normal range. In trial 2, 16 cattle were allocated to the control and treatment groups, with 8 replicates of 1 cattle each. Cattle in the control group were fed a basal diet without RRTR, while those in the treatment group were fed a diet containing 30% RRTR to replace 30% whole corn silage in basal diet. Feeding RRTR had little effect on the growth performance of the control and treatment cattle (P > 0.05). The feed-to-gain ratio was greater in the treatment group than in the control group throughout the trial period (P < 0.05). The plasma urea levels in the treatment group were lower (P < 0.05) than that in control group, and the levels of other plasma biochemical metabolites were not different between the two groups of cattle (P > 0.05). The in vivo rumen fermentation parameters did not differ between the control and treatment groups (P > 0.05). Our findings indicate that RRTR has a nutritional profile (crude protein, neutral detergent fiber, acid detergent fiber, and crude fiber) similar to that of commonly used fruit residues (such as apple, pineapple, and citrus residue et al.); improves plasma protein utilization efficiency; and has no negative impact on growth performance, albeit with limited effects on feed conversion; blood metabolites, and rumen fermentation parameters in cattle. Accordingly, we conclude, based on the above-mentioned result, that RRTR can serve as a novel feed alternative resource when considering the affordability and as a practical choice for low-cost diets for cattle.

Human blood metabolites and risk of severe COVID-19: A Mendelian randomization study.

BACKGROUND: Evidence supports the observational associations of human blood metabolites with the risk of severe COVID-19. However, little is known about the potential pathological mechanisms and the analysis of blood metabolites may offer a better understanding of the underlying biological processes. METHODS: We applied a two-sample Mendelian randomization (MR) analysis to evaluate relationships between 486 blood metabolites and the risk of severe COVID-19. The inverse-variance weighted (IVW) model was used as the primary two-sample MR analysis method to estimate the causal relationship of the exposure on the outcome. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and the funnel plot. RESULTS: Four hunderd and eighty six metabolites were included for MR analysis following rigorous genetic variants selection. After MR analyses and sensitivity analysis filtration, we found weak evidence of an association between 3-hydroxybutyrate (odds ratio [OR] = 1.21, 95% CI, 1.07-1.38, p = .0036) and the risk of severe COVID-19. A series of sensitivity analyses have been carried out to confirm the rigidity of the above results. CONCLUSION: This study suggested a causal relationship between 3-hydroxybutyrate and the severity of COVID-19, thus providing novel insights into biomarkers and pathways for COVID-19 prevention and clinical interventions.

Causal relationship between blood metabolites and risk of five infections: a Mendelian randomization study.

OBJECTIVE: Infectious diseases continue to pose a significant threat in the field of global public health, and our understanding of their metabolic pathogenesis remains limited. However, the advent of genome-wide association studies (GWAS) offers an unprecedented opportunity to unravel the relationship between metabolites and infections. METHODS: Univariable and multivariable Mendelian randomization (MR) was commandeered to elucidate the causal relationship between blood metabolism and five high-frequency infection phenotypes: sepsis, pneumonia, upper respiratory tract infections (URTI), urinary tract infections (UTI), and skin and subcutaneous tissue infection (SSTI). GWAS data for infections were derived from UK Biobank and the FinnGen consortium. The primary analysis was conducted using the inverse variance weighted method on the UK Biobank data, along with a series of sensitivity analyses. Subsequently, replication and meta-analysis were performed on the FinnGen consortium data. RESULTS: After primary analysis and a series of sensitivity analyses, 17 metabolites were identified from UK Biobank that have a causal relationship with five infections. Upon joint analysis with the FinGen cohort, 7 of these metabolites demonstrated consistent associations. Subsequently, we conducted a multivariable Mendelian randomization analysis to confirm the independent effects of these metabolites. Among known metabolites, genetically predicted 1-stearoylglycerol (1-SG) (odds ratio [OR] = 0.561, 95% confidence interval [CI]: 0.403-0.780, P < 0.001) and 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) (OR = 0.780, 95%CI: 0.689-0.883, P < 0.001) was causatively associated with a lower risk of sepsis, and genetically predicted phenylacetate (PA) (OR = 1.426, 95%CI: 1.152-1.765, P = 0.001) and cysteine (OR = 1.522, 95%CI: 1.170-1.980, P = 0.002) were associated with an increased risk of UTI. Ursodeoxycholate (UDCA) (OR = 0.906, 95%CI: 0.829-0.990, P = 0.029) is a protective factor against pneumonia. Two unknown metabolites, X-12407 (OR = 1.294, 95%CI: 1.131-1.481, P < 0.001), and X-12847 (OR = 1.344, 95%CI: 1.152-1.568, P < 0.001), were also identified as independent risk factors for sepsis. CONCLUSIONS: In this MR study, we demonstrated a causal relationship between blood metabolites and the risk of developing sepsis, pneumonia, and UTI. However, there was no evidence of a causal connection between blood metabolites and the risk of URTI or SSTI, indicating a need for larger-scale studies to further investigate susceptibility to certain infection phenotypes.

Identification of blood metabolites linked to the risk of intervertebral disc diseases: a comprehensive Mendelian randomization study.

BACKGROUND: Intervertebral disc degeneration (IVDD) has affected millions of people worldwide and dramatically affects human beings' quality of life. Observational studies hypothesize that metabolites play key roles as markers and effectors of IVDD, but their causality has not yet been illustrated. METHODS: We conducted comprehensive Mendelian randomization (MR) to determine the causal relationship between 249 plasma metabolites and IVDD. Inverse-variance weighting was used as the primary estimate, whereas MR-Egger and weighed median were used to detect robustness. A series of sensitivity analyses including Cochran Q test, leave one out, and MR-Egger intercept analysis were also conducted. RESULTS: In total, we found 13 blood metabolites significantly associated with IVDD, including phospholipids in very large high-density lipoprotein (HDL), free cholesterol to total lipids ratio in very large HDL, average diameter for HDL particles, cholesteryl esters to total lipids ratio in large HDL, free cholesterol to total lipids ratio in medium HDL, creatinine, free cholesterol to total lipids ratio in large HDL, phospholipids to total lipids ratio in very large HDL, cholesterol to total lipids ratio in very large HDL, cholesteryl esters to total lipids ratio in large HDL, phospholipids in large HDL, total lipids in very large HDL, and total lipids in large HDL. No pleiotropy was detected. Heterogeneity existed in several estimates and random-effect inverse-variance weighting was applied. CONCLUSIONS: Our study highlighted the causal association of blood metabolites with the risk of IVDD. Our results provide new insights into possible treatment protocols controlling the concentration of specific blood metabolites in IVDD patients. Key messages What is already known on this topic Low back pain is the most common symptom for patients with intervertebral disc degeneration (IVDD) and influences the quality of life of large populations. Observational studies have indicated the association between metabolites and IVDD. However, causality has not been determined yet. What this study adds We conducted a comprehensive Mendelian randomization study to reveal the causal effect from 249 blood metabolites on low back pain. A total of 13 metabolites were found to causally affect the risk of IVDD, among which 11 were negatively associated and 2 were positively asscociated. How this study might affect research, practice, or policy These 13 significant metabolites could serve as biomarkers for IVDD and our results provide new insights into possible treatment protocols for IVDD patients.