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Objective: Previous research reported that dietary addition with phytosterols improved the energy utilisation of the rumen microbiome, suggesting its potential to alleviate the negative energy balance of perinatal cows. This experiment aimed to explore the effects of feeding phytosterols on the metabolic status of perinatal cows through plasma metabolomics and faecal bacteria metabolism. Methods: Ten perinatal Holstein cows (multiparous, 2 parities) with a similar calving date were selected four weeks before calving. After 7 days for adaptation, cows were allocated to two groups (n = 5), which respectively received the basal rations supplementing commercial phytosterols at 0 and 200 mg/d during a 42-day experiment. The milk yield of each cow was recorded daily after calving. On days 1 and 42, blood and faeces samples were all collected from perinatal cows before morning feeding for analysing plasma biochemicals and metabolome, and faecal bacteria metabolism. Results: Dietary addition with phytosterols at 200 mg/d had no effects on plasma cholesterol and numerically increased milk yield by 1.82 kg/d (p>0.10) but attenuated their negative energy balance in perinatal cows as observed from the significantly decreased plasma level of β-hydroxybutyric acid (p = 0.002). Dietary addition with phytosterols significantly altered 12 and 15 metabolites (p<0.05) within the plasma and faeces of perinatal cows, respectively. Of these metabolites, 5 upregulated plasma fatty acids indicated an improved energy status (i.e., C18:1T, C14:0, C17:0, C18:0, and C16:0). Milk yield negatively correlated with plasma concentrations of ketone bodies (p = 0.035) and 5-methoxytryptamine (p = 0.039). Furthermore, dietary addition with phytosterols at 200 mg/d had no effects on fermentation characteristics and bacterial diversity of cow faeces (p>0.10) but improved potentially beneficial bacteria such as Christensenellaceae family (p<0.05) that positively correlated with feed efficiency. Conclusion: Dietary addition with phytosterols at 200 mg/d could effectively improve the energy status in perinatal cows by attenuating their negative energy balance. [ABSTRACT FROM AUTHOR]

Residual feed intake (RFI) is a metric that provides a more accurate measure of feed efficiency. The lower the RFI, the higher the feed efficiency. The changes in the host microbiome and metabolome contribute to the greater feed efficiency of low RFI (LRFI) animals. The aim of this study was to explore the differences in rumen microorganisms, rumen metabolites and plasma metabolites of Hu sheep with differing RFI through the microbiome and metabolome. A total of 80 Hu sheep were used. The experiment consisted of a 15-d pretrial period and a 128-d experimental period. The RFI in the experimental period was calculated for all sheep, and the sheep were screened into high RFI (HRFI, n = 8) and LRFI (n = 8) groups. The HRFI and LRFI sheep did not differ in their initial and final body weights, average daily gain and body measurements, but the dry matter intake of LRFI sheep was significantly decreased (28.4%, P

Background: The gut microbiota and plasma metabolites play important roles in the progression of drug-induced liver injury (DILI). We investigated the causal associations between the gut microbiota, plasma metabolome, and DILI. Methods: The summary data for gut microbiota (n = 18,340), plasma metabolome (n = 8,299), and DILI (n = 366,838) were obtained from the large genome-wide association studies. A two-sample Mendelian randomization was performed to explore the associations between the gut microbiota, plasma metabolome, and DILI. Additionally, a two-step Mendelian randomization was performed to explore the potential metabolites. Results: Five taxa were causally associated with DILI, including Oscillospira [odds ratio (OR) = 2.257, 95% confidence interval (CI) = 1.110-4.590], Blautia (OR = 2.311, 95% CI = 1.010-5.288), Roseburia (OR = 2.869, 95% CI = 1.429-5.761), Fusicatenibacter (OR = 1.995, 95% CI = 1.024-3.890), and Prevotella 7 (OR = 1.549, 95% CI = 1.065-2.253). Moreover, 53metabolites were causally associated with DILI. After mediation analysis, four taxa were found to affect DILI through fivemediationmetabolites. N6-carbamoylthreonyladenosine mediated the effect of Blautia on DILI. Acetylcarnitine mediated the effect of Fusicatenibacter on DILI. In addition, 4-cholesten-3-one mediated the effect of Prevotella 7 on DILI. Furthermore, 5,6-dihydrothymine levels and the salicylate-to-citrate ratio mediated the effect of Oscillospira on DILI. Conclusion: We found that the gut microbiota could affect DILI through plasma metabolites, which could serve as potential biomarkers for risk stratification and elucidate underlying mechanisms for further investigation of DILI. [ABSTRACT FROM AUTHOR]

BackgroundPrior research has established a correlation between immune cell activity and heart failure (HF), but the causal nature of this relationship remains unclear. Furthermore, the potential influence of metabolite levels on this interaction has not been comprehensively explored. To address these gaps, we employed a bidirectional Mendelian randomization (MR) approach in two stages to examine whether metabolite levels can mediate the causal relationship between immune cells and HF.MethodsGenetic information was extracted from summary data of genome-wide association studies. By applying a two-sample, two-step MR approach, we investigated the causal relationships among immune cells, metabolite levels, and HF, with a specific focus on the mediating effects of metabolites. Sensitivity analysis techniques were implemented to ensure the robustness of our findings.ResultsMR analysis revealed significant causal associations between HF and eight specific immune cells and five metabolites. Mediation analysis further identified three mediated relationships. Particularly, hexadecenedioate (C16:1-DC) mediated the influence of both the CD28- CD127- CD25++ CD8br%CD8br (mediation proportion: 19.2%) and CD28+ CD45RA + CD8br%T cells (mediation proportion: 11.9%) on HF. Additionally, the relationship between IgD + CD38br AC cells and HF appeared to be mediated by the phosphate to alanine ratio (mediation proportion: 16.3%). Sensitivity analyses validated that the used instrumental variables were free from pleiotropy and heterogeneity.ConclusionThis study provides evidence that certain immune cell levels are associated with the risk of HF and that metabolite levels may mediate these relationships. However, to strengthen these findings, further validation using MR analyses with larger sample sizes is essential.

ABSTRACT: Submerged cultivation using low-value agro-industrial side streams allows large-scale and efficient production of fungal mycelia, which has a high nutritional value. As the dietary properties of fungal mycelia in poultry are largely unknown, the present study aimed to investigate the effect of feeding a Pleurotus sapidus (PSA) mycelium as a feed supplement on growth performance, composition of the cecal microbiota and several physiological traits including gut integrity, nutrient digestibility, liver lipids, liver transcriptome and plasma metabolome in broilers. 72 males, 1-day-old Cobb 500 broilers were randomly assigned to 3 different groups and fed 3 different adequate diets containing either 0% (PSA-0), 2.5% (PSA-2.5) and 5% (PSA-5.0) P. sapidus mycelium in a 3-phase feeding system for 35 d. Each group consisted of 6 cages (replicates) with 4 broilers/cage. Body weight gain, feed intake and feed:gain ratio and apparent ileal digestibility of crude protein, ether extract and amino acids were not different between groups. Metagenomic analysis of the cecal microbiota revealed no differences between groups, except that one α-diversity metric (Shannon index) and the abundance of 2 low-abundance bacterial taxa (Clostridia UCG 014, Eubacteriales) differed between groups (P < 0.05). Concentrations of total and individual short-chain fatty acids in the cecal digesta and concentrations of plasma lipopolysaccharide and mRNA levels of proinflammatory genes, tight-junction proteins, and mucins in the cecum mucosa did not differ between groups. None of the plasma metabolites analyzed using targeted-metabolomics differed across the groups. Hepatic transcript profiling revealed a total of 144 transcripts to be differentially expressed between group PSA-5.0 and group PSA-0 but none of these genes was regulated greater 2-fold. Considering either the lack of effects or the very weak effects of feeding the P. sapidus mycelium in the broilers it can be concluded that inclusion of a sustainably produced fungal mycelium in broiler diets at the expense of other feed components has no negative consequences on broilers´ performance and metabolism.

The causal effect and pathways of gut microbiota and plasma metabolome on lung cancer have been important topics for personalized medicine; however, the heterogeneity of lung cancer subtypes has not gained enough attention in previous studies. This study sought to employ a Mendelian randomization analysis to screen the specific gut microbiota and plasma metabolome, which may have a causal effect on lung cancer. We further extended our analysis to estimate the effects of these exposures on various pathological subtypes of lung cancer. Furthermore, a mediation analysis was performed to identify the potential pathway underlying the influence of microbiota and metabolites. Our study identified 13 taxa and 15 metabolites with a causal association with the overall risk of lung cancer. Furthermore, we found 8 taxa and 14 plasma metabolites with a causal effect on lung adenocarcinoma, 4 taxa and 10 metabolites with a causal effect on squamous cell lung carcinoma, and 7 taxa and 16 metabolites with a causal effect on SCLC. We also identified seven mediation pathways that could potentially elucidate the influence of these microbiota and metabolites on overall lung cancer or special subtypes. Our study highlighted the heterogeneity of the gut microbiome and plasma metabolome in a lung cancer subtype and elucidated the potential underlying mechanisms. This could pave the way for more personalized lung cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to investigate the causal relationship between gut microbiota and juvenile idiopathic arthritis, and to identify and quantify the potential role of plasma metabolites as mediators. Methods: Using summary-level data from genome-wide association studies, a two-sample Mendelian randomization was conducted involving 131 gut microbiota genus, 1,400 plasma metabolites, and juvenile idiopathic arthritis. Additionally, a two-step approach was employed to quantify the proportion of the effect of gut microbiota on juvenile idiopathic arthritis mediated by plasma metabolites. Effect estimation primarily utilized Inverse Variance Weighting, with further validation using Bayesian weighted Mendelian randomization. Results: In our MR analysis, a positive correlation was observed between Rikenellaceae and the risk of juvenile idiopathic arthritis, while Dorea showed a negative correlation with juvenile idiopathic arthritis risk. Mediation analysis indicated that Furaneol sulfate levels acted as a mediator between Dorea and juvenile idiopathic arthritis, with an indirect effect proportion of 19.94, 95% CI [8.86-31.03%]. Conclusion: Our study confirms a causal relationship between specific microbial genus and juvenile idiopathic arthritis, and computes the proportion of the effect mediated by plasma metabolites, offering novel insights for clinical interventions in juvenile idiopathic arthritis. [ABSTRACT FROM AUTHOR]

IntroductionThe immune response regulates the severity of COVID-19 (sCOVID-19). This study examined the cause-and-effect relationship between immune cell traits (ICTs) and the risk of severe COVID-19. Additionally, we discovered the potential role of plasma metabolome in modulating this risk.MethodsEmploying data from a genome-wide association study (GWAS), we conducted a two-sample Mendelian randomization (MR) assessment of 731 genetic ICTs and sCOVID-19 (5,101 cases, 1,383,241 controls) incidence. The MR analysis was utilized to further quantitate the degree of plasma metabolome-mediated regulation of immune traits in sCOVID-19.ResultsThe inverse variance weighted method recognized 2 plasma metabolites (PMs) responsible for casual associations between immune cells and sCOVID-19 risk. These included Tridecenedioate (C13:1-DC) which regulated the association between CD27 on IgD- CD38br (OR 0.804, 95% CI 0.699–0.925, p = 0.002) and sCOVID-19 risk (mediated proportion: 18.7%); arginine to citrulline ratio which controlled the relationship of CD39 on monocyte (OR 1.053, 95% CI 1.013–1.094, p = 0.009) with sCOVID-19 risk (mediated proportion: -7.11%). No strong evidence that genetically predicted sCOVID-19 influenced the aforementioned immune traits.ConclusionIn this study, we have successfully identified a cause-and-effect relationship between certain ICTs, PMs, and the likelihood of contracting severe COVID-19. Our findings can potentially improve the accuracy of COVID-19 prognostic evaluation and provide valuable insights into the underlying mechanisms of the disease.

ABSTRACT: Despite the existence of a number of studies investigating the effect of insect meal on the growth performance of broilers, knowledge about the metabolic effects of insect meal in broilers is still scarce. Thus, the present study investigated the effect of partial replacement of soybean meal with Hermetia illucens (HI) larvae meal on the liver transcriptome, the plasma metabolome, and the cecal microbiota in broilers. For the study, 72 male one-day-old Cobb 500 broilers were divided into three groups and fed 3 different diets with either 0% (HI0), 7.5% (HI7.5), or 15% (HI15) defatted HI meal for 35 d. Each group consisted of 6 cages (replicates) with 4 broilers/cage. While body weight (BW) gain, feed intake, and feed:gain ratio did not differ between groups, breast muscle weight, carcass yield, and apparent ileal digestibility (AID) of 5 amino acids were higher in group HI15 than in group HI0 (P < 0.05). Indicators of α-diversity (Chao1 and Observed) in the cecal digesta were higher in groups HI15 and HI7.5 than in group HI0 (P < 0.05). The abundance of 5 families and 18 genera, all of which belonged to the Firmicutes phylum, in the cecal digesta differed among groups (P < 0.05). Concentrations of butyric acid, valeric acid, and isobutyric acid in the cecal digesta were lower in group HI15 than in the other 2 groups (P < 0.05), whereas those of total and other short-chain fatty acids were not different between groups. Liver transcriptomics revealed a total of 70 and 61 differentially expressed transcripts between groups HI15 vs. HI0 and between groups HI7.5 vs. HI0, respectively, (P < 0.05). Targeted metabolomics identified 138 metabolites, most of which were triglyceride species, being different between the 3 groups (FDR < 0.05). According to this study, dietary inclusion of HI larvae meal has no detrimental impact but increases breast muscle weight and carcass weight in broilers suggesting that HI larvae meal can be recommended as a sustainable alternative protein source for broilers.

ABSTRACT: Heat stress (HS) impairs productivity, health, and welfare in dairy cows, and additionally causes metabolic changes. Hence, specific metabolites could be used as HS biomarkers. Consequently, the aim of the present study was to compare blood metabolite concentrations of German Holstein dairy cows and of their female calves suffering from high temperature-humidity index (THI) during late gestation (cows) or during their first week of life (calves) or not. According to the mean daily THI (mTHI) at the day before blood sampling, animals were classified into 2 groups: high mTHI ≥60 (hmTHI) and low mTHI

Simple Summary: Palm oil is currently the most widely used fat source for food production, but palm oil production is associated with severe environmental problems. Insect fat from Hermetia illucens larvae might be a suitable alternative fat source, because its production is more sustainable and less harmful to the environment. Thus, the present study investigated the effect of Hermetia fat, as compared to palm oil and soybean oil, on the hepatic lipid metabolism and the plasma metabolome of healthy rats, which were fed diets containing either soybean oil, palm oil, or Hermetia fat for 4 weeks. Growth performance, liver and plasma lipid concentrations, and the expression of hepatic genes involved in lipid metabolism and inflammation did not differ between groups. Plasma metabolomics revealed a clear separation of the plasma metabolomes of the soybean oil group and the other two groups, but not of those of the palm oil and the Hermetia fat group. The present study shows that Hermetia fat exerts no adverse effects on lipid metabolism and inflammatory gene expression in the liver of healthy rats compared to palm oil or soybean oil. Thus, the present findings indicate that Hermetia fat is a safe alternative fat source to palm oil for food production. Palm oil (PO) is currently the most widely used fat source for food production, but insect fat from Hermetia illucens larvae (HF) might be a suitable alternative fat source, because its production is less harmful to the environment. The present study investigated the effect of HF, as compared to PO and soybean oil (SO), on the hepatic lipid metabolism and the plasma metabolome of healthy rats, which were randomly assigned to three groups (n = 10 rats/group), and fed three different semi-synthetic diets containing either SO, PO, or HF as the main fat source for 4 weeks. Feed intake, body weight gain, liver and plasma lipid concentrations, and the hepatic mRNA levels of genes involved in lipid metabolism and inflammation did not differ between groups. Targeted plasma metabolomics revealed 294 out of 630 metabolites analyzed to be different between groups. Principal component analysis showed a clear separation of the plasma metabolomes of the SO group and the other two groups, but no separation of those of the PO and the HF groups. The present study shows that HF exerts no adverse metabolic effects in healthy rats, compared to PO or SO, indicating that HF is a safe alternative fat source to PO for food production. [ABSTRACT FROM AUTHOR]

Heat stress (HS) impairs productivity, health, and welfare in dairy cows, and additionally causes metabolic changes. Hence, specific metabolites could be used as HS biomarkers. Consequently, the aim of the present study was to compare blood metabolite concentrations of German Holstein dairy cows and of their female calves suffering from high temperature-humidity index (THI) during late gestation (cows) or during their first week of life (calves) or not. According to the mean daily THI (mTHI) at the day before blood sampling, animals were classified into 2 groups: high mTHI ≥60 (hmTHI) and low mTHI <60 (lmTHI). To perform a standard cross-sectional 2-group study, cow groups (n = 48) and calf groups (n = 47) were compared separately. Differences in metabolite concentrations between hmTHI and lmTHI animals were inferred based on a targeted metabolomics approach. In the first step, processed metabolomics data were evaluated by multivariate data analysis techniques, and were visualized using the web-based platform MetaboAnalyst V5.0. The most important metabolites with pronounced differences between groups were further analyzed in a second step using linear mixed models. We identified 9 thermally sensitive metabolites for the cows [dodecanedioic acid; 3-indolepropionic acid; sarcosine; triglycerides (14:0_34:0), (16:0_38:7), (18:0_32:1), and (18:0_36:2); phosphatidylcholine aa C38:1; and lysophosphatidylcholine a C20:3] and for the calves [phosphatidylcholines aa C38:1, ae C38:3, ae C36:0, and ae C36:2; cholesteryl esters (17:1) and (20:3); sphingomyelins C18:0 and C18:1; and p-cresol sulfate], most of them related to lipid metabolism. Apart from 2 metabolites (3-indolepropionic acid and sarcosine) in cows, the metabolite plasma concentrations were lower in hmTHI than in lmTHI groups. In our heat-stressed dry cows, results indicate an altered lipid metabolism compared with lactating heat-stressed cows, due to the missing antilipolytic effect of HS. The results also indicate alterations in lipid metabolism of calves due to high mTHI in the first week of life. From a cross-generation perspective, high mTHI directly before calving seems to reduce colostrum quality, with detrimental effects on metabolite concentrations in offspring. [ABSTRACT FROM AUTHOR]

Saccharomyces cerevisiae fermentation product (SCFP) has been widely studied; however, its mode of action on high-concentrate diets has not been fully elucidated. This study evaluated the impact of SCFP on total tract digestibility, fecal excretions of N, P, Zn, and Cu, rumen fermentation, and plasma metabolome of finishing beef steers. Ruminally cannulated Holstein steers [n = 8; body weight (BW) = 580 ± 29.2 kg] were enrolled in a crossover design study with 25-d treatment periods and a 24-d washout period. Steers were fed ad libitum a finishing diet consisting of 20% corn silage and 80% concentrate (on DM basis). Steers were blocked based on initial BW and randomly assigned to two treatments in period 1 and switched to the other treatment in period 2. The treatments were CON (Control, basal diet only) and SCFP (basal diet top-dressed with 12 gּ·steer-1ּ ּ·d-1 SCFP, NaturSafe, Diamond V, Cedar Rapids, IA). Feed and fecal samples were collected during d 22 to 24 for determination of digestibility. Blood was collected before morning feeding on d 25. Plasma samples were analyzed for metabolome with liquid chromatography-mass spectrometry (LC-MS). Rumen fluid was collected via the rumen cannula at 0, 4, 8, and 12 h post-morning feeding on d 25 and analyzed for pH, volatile fatty acids (VFA), and NH3 -N. Performance and ruminal fermentation characteristics data were analyzed using the GLIMMIX procedure of SAS 9.4. Metabolomic data analysis was conducted with Metaboanalyst 6.0. Supplementing steers with SCFP reduced DMI (10.6 vs. 11.4 kg/d, P = 0.05) without affecting (P > 0.05) average daily gain, feed efficiency, and digestibility of organic matter, crude protein, and neutral detergent fiber. Treatment did not affect (P > 0.10) fecal excretions of N, P, Cu, and Zn. Feeding SCFP increased ruminal pH (6.29 vs. 6.01, P = 0.01), numerically reduced concentrations of NH3 -N (5.01 vs 6.25 mM, P = 0.16), and total VFA (96.8 vs. 102.5 mM, P = 0.15). SCFP also reduced the ruminal molar proportion of butyrate (11.2 vs. 12.8 molar %, P = 0.01) and tended to increase those of isobutyrate (1.03 vs. 0.90, molar %, P = 0.06) and isovalerate (2.62 vs. 2.29, molar %, P = 0.10). Supplementation of SCFP enriched (P ≤ 0.05) purine metabolism, amino sugar and nucleotide sugar metabolism, and lysine degradation pathways in the plasma. Additionally, tryptophan metabolism and pyrimidine metabolism pathways tended to be enriched (0.05 < P ≤ 0.10) by SCFP. Our findings indicate that feeding SCFP improved the ruminal pH of finishing cattle, which may be beneficial for preventing subacute ruminal acidosis in feedlot cattle. Additionally, SCFP enriched several important plasma nitrogen metabolism pathways, potentially associated with microbial nitrogen metabolism in the rumen, warranting further research. [ABSTRACT FROM AUTHOR]

Dried distiller's grains with solubles (DDGS) are rich in nutrients and can enhance animals' growth and immunity. However, there are few reports on the effects of a diet of DDGS on plasma metabolism and the related action pathways in domestic animals. In this study, groups of Guanling yellow cattle (GY) and Guanling crossbred cattle (GC) having a basal diet served as the control groups (GY-CG and GC-CG), and DDGS replacing 25% of the diet of GY and GC served as the replacement groups (GY-RG and GC-RG), with three cattle in each group. Plasma samples were prepared for metabolomic analysis. Based on multivariate statistical and univariate analyses, differential metabolites and metabolic pathways were explored. Twenty-nine significantly different metabolites (p < 0.05) were screened in GY-RG compared with those in GY-CG and were found to be enriched in the metabolic pathways, including choline metabolism in cancer, linolenic acid metabolism, and amino acid metabolism. Nine metabolites showed significant differences (p < 0.05) between GC-RG and GC-CG and were mainly distributed in the metabolic pathways of choline metabolism in cancer, glycerophospholipid metabolism, prostate cancer metabolism, and gonadotropin-releasing hormone (GnRH) secretion. These results suggest that a DDGS diet may promote healthy growth and development of experimental cattle by modulating these metabolic pathways. Our findings not only shed light on the nutritional effects of the DDGS diet and its underlying mechanisms related to metabolism but also provide scientific reference for the feed utilization of DDGS. [ABSTRACT FROM AUTHOR]

Heat stress (HS) during late gestation implies unfavorable effects on dairy cows and their in-utero heat stressed offspring. The objective of the present study was to elucidate the effect of intrauterine (maternal) HS during the last week of gestation on blood metabolite concentrations of female dairy calves during their first week of life. We defined the mean temperature humidity index (mTHI) during the last gestation week of ≥60 as threshold for maternal HS. In this regard, we compared differences in metabolite concentrations of maternally heat stressed (MHSCALVES) (n = 14) and not heat stressed (NMHSCALVES) (n = 33) calves. We identified 15 metabolites from five different biochemical classes (phosphatidylcholines, cholesteryl esters, sphingomyelins, cresols and hexoses) as potential biomarkers for maternal HS in calves. The plasma concentrations of all significantly affected metabolites were lower in MHSCALVES when compared to NMHSCALVES. The effect of maternal HS during the last week of gestation on blood metabolite concentrations of the female offspring during the first week after birth might be due to HS induced intergenerational physiological alterations, impaired colostrum quality or epigenetic modifications of the calf genome. The results of this pilot study should be validated in ongoing fully standardized studies. [ABSTRACT FROM AUTHOR]

The gut microbiome plays an important role in the mammalian host and when in proper balance helps protect health and prevent disease. Host environmental stress and its influence on the gut microbiome, health, and disease is an emerging area of research. Exposures to unnatural light cycles are becoming increasingly common due to travel and shift work. However, much remains unknown about how these changes influence the microbiome and host health. This information is needed to understand and predict the relationship between the microbiome and host response to altered sleep cycles. In the present study, we exposed three cohorts of mice to different light cycle regimens for 12 consecutive weeks; including continuous light, continuous dark, and a standard light dark regimen consisting of 12 h light followed by 12 h of dark. After exposure, motor and memory behavior, and the composition of the fecal microbiome and plasma metabolome were measured. Memory potential was significantly reduced in mice exposed to continuous light, whereas rotarod performance was minimally affected. The overall composition of the microbiome was relatively constant over time. However, Bacteroidales Rikenellaceae was relatively more abundant in mice exposed to continuous dark, while Bacteroidales S24-7 was relatively more abundant in mice exposed to continuous light. The plasma metabolome after the continuous dark exposure differed from the other exposure conditions. Several plasma metabolites, including glycolic acid, tryptophan, pyruvate, and several unidentified metabolites, were correlated to continuous dark and light exposure conditions. Networking analyses showed that serotonin was positively correlated with three microbial families (Rikenellaceae, Ruminococcaceae, and Turicibacteraceae), while tryptophan was negatively correlated with abundance of Bacteroidales S24-7 based on light exposure. This study provides the foundation for future studies into the mechanisms underlying the role of the gut microbiome on the murine host during light-dark stress.

Reducing consumption of sugar-sweetened beverages (SSBs) is a global public health priority because of their limited nutritional value and associations with increased risk of obesity and metabolic diseases. Gut microbiota-related metabolites emerged as quintessential effectors that may mediate impacts of dietary exposures on the modulation of host commensal microbiome and physiological status. This study assessed the associations among SSBs, circulating microbial metabolites, and gut microbiota–host co-metabolites, as well as metabolic health outcomes in young Chinese adults (n = 86), from the Carbohydrate Alternatives and Metabolic Phenotypes study in Shaanxi Province. Five principal component analysis-derived beverage drinking patterns were determined on self-reported SSB intakes, which were to a varying degree associated with 143 plasma levels of gut microbiota-related metabolites profiled by untargeted metabolomics. Moreover, carbonated beverages, fruit juice, energy drinks, and bubble tea exhibited positive associations with obesity-related markers and blood lipids, which were further validated in an independent cohort of 16,851 participants from the Regional Ethnic Cohort Study in Northwest China in Shaanxi Province. In contrast, presweetened coffee was negatively associated with the obesity-related traits. A total of 79 metabolites were associated with both SSBs and metabolic markers, particularly obesity markers. Pathway enrichment analysis identified the branched-chain amino acid catabolism and aminoacyl-tRNA biosynthesis as linking SSB intake with metabolic health outcomes. Our findings demonstrate the associations between habitual intakes of SSBs and several metabolic markers relevant to noncommunicable diseases, and highlight the critical involvement of gut microbiota-related metabolites in mediating such associations. • Associations between sugar-sweetened beverages, plasma metabolites and metabolic outcomes were demonstrated in young Chinese adults. • Biological pathwavs related to gut microbiota functionality were enriched to link beverages intake with metabolic health outcomes. [ABSTRACT FROM AUTHOR]

Data on the evolution of blood metabolites and metabolic markers in neonatal piglets are scarce, although this information is vital to detect physiological aberrations from normal development. We aimed to characterize age- and nutrition-related changes in the plasma metabolome and serum biochemistry of suckling and newly weaned piglets and assess metabolite patterns as physiological markers for the two phases. In two replicate batches (n = 10 litters/group), piglets either received sow milk alone or were additionally offered creep feed from day 10 until weaning (day 28). Blood was collected from one piglet/litter on days 7, 14, 21, 28, 31 and 35 of life, totaling five females and five males/group/day. Signature feature ranking identified plasma triglycerides (TG) as discriminative for age and nutrition during the suckling phase. Influential TG 20:4_36:5, TG 17:0_34:2 and TG 18:2_38:6 were higher in creep-fed piglets on days 14, 21 and 28 of life, respectively, compared to only sow milk-fed piglets. Metabolites belonging to pathways within histidine, D-glutamine and D-glutamate metabolism as well as hippuric acid were distinctive for the postweaning compared to the suckling period. In conclusion, plasma lipid profiles especially corresponded to the type of nutrition in the suckling phase and showed a strong weaning effect. [ABSTRACT FROM AUTHOR]

Florida Cracker sheep is a heritage sheep breed and an endangered species that was developed under natural selection in Florida, US. The objective of this study was to evaluate the effect of short-term heat stress on the plasma metabolome of Florida Cracker ewes (2 yr). A total of fourteen ewes were allocated to heat stress (HT, n = 7) or cooling (CTL, n = 7) conditions for 6 wk during the summer season. Treatment groups were grouped in covered concrete floor pens with similar dimensions and characteristics and had access to shelter, feed, and freshwater ad libitum. The HT pen was exposed to regular ambient temperatures, and for the cooling pen, an evaporative cooling fan was used. Data for ambient temperature and relative humidity of HT and CTL pens were recorded every week to estimate the temperature humidity index (THI). Blood samples were collected from each experimental ewe 1 wk before the start of the experiment (baseline) and at wk 1, 2, 3, 4, 5, and 6 post-treatment. Plasma was extracted from the blood and processed for targeted metabolomics. Targeted metabolomics was performed using Nuclear Magnetic Resonance spectroscopy to quantify a total of 50 metabolites, including organic acids, amino acids, hexoses, lipids, and carnitines. Statistical analysis for biomarker and pathway enrichment was performed using Metaboanalyst 5.0. The THI values for the HT and THI groups ranged from 81.3 to 89.5 and from 73.5 to 75.6, respectively. A total of 19 differentially abundant metabolites were identified between HT and CTL. The pathway enrichment analysis showed upregulation of fatty acid and primary bile biosynthesis, and glutathione, porphyrin, glycine, serine, and threonine metabolism (P ≤ 0.05) in HT compared with CTL sheep. These metabolic pathways could have a role in the response of the ewes to short-term HT. Our findings highlight that short-term HT alters the plasma metabolome of Florida Cracker ewes. Understanding these changes can contribute to the development of effective management strategies to mitigate the detrimental impact of HT on sheep operations in the Southern US. [ABSTRACT FROM AUTHOR]

Submerged cultivation using low-value agro-industrial side streams allows large-scale and efficient production of fungal mycelia, which has a high nutritional value. As the dietary properties of fungal mycelia in poultry are largely unknown, the present study aimed to investigate the effect of feeding a Pleurotus sapidus (PSA) mycelium as a feed supplement on growth performance, composition of the cecal microbiota and several physiological traits including gut integrity, nutrient digestibility, liver lipids, liver transcriptome and plasma metabolome in broilers. 72 males, 1-day-old Cobb 500 broilers were randomly assigned to 3 different groups and fed 3 different adequate diets containing either 0% (PSA-0), 2.5% (PSA-2.5) and 5% (PSA-5.0) P. sapidus mycelium in a 3-phase feeding system for 35 d. Each group consisted of 6 cages (replicates) with 4 broilers/cage. Body weight gain, feed intake and feed:gain ratio and apparent ileal digestibility of crude protein, ether extract and amino acids were not different between groups. Metagenomic analysis of the cecal microbiota revealed no differences between groups, except that one α-diversity metric (Shannon index) and the abundance of 2 low-abundance bacterial taxa (Clostridia UCG 014, Eubacteriales) differed between groups (P < 0.05). Concentrations of total and individual short-chain fatty acids in the cecal digesta and concentrations of plasma lipopolysaccharide and mRNA levels of proinflammatory genes, tight-junction proteins, and mucins in the cecum mucosa did not differ between groups. None of the plasma metabolites analyzed using targeted-metabolomics differed across the groups. Hepatic transcript profiling revealed a total of 144 transcripts to be differentially expressed between group PSA-5.0 and group PSA-0 but none of these genes was regulated greater 2-fold. Considering either the lack of effects or the very weak effects of feeding the P. sapidus mycelium in the broilers it can be concluded that inclusion of a sustainably produced fungal mycelium in broiler diets at the expense of other feed components has no negative consequences on broilers´ performance and metabolism. [ABSTRACT FROM AUTHOR]

Palm oil (PO) is currently the most widely used fat source for food production, but insect fat from Hermetia illucens larvae (HF) might be a suitable alternative fat source, because its production is less harmful to the environment. The present study investigated the effect of HF, as compared to PO and soybean oil (SO), on the hepatic lipid metabolism and the plasma metabolome of healthy rats, which were randomly assigned to three groups (n = 10 rats/group), and fed three different semi-synthetic diets containing either SO, PO, or HF as the main fat source for 4 weeks. Feed intake, body weight gain, liver and plasma lipid concentrations, and the hepatic mRNA levels of genes involved in lipid metabolism and inflammation did not differ between groups. Targeted plasma metabolomics revealed 294 out of 630 metabolites analyzed to be different between groups. Principal component analysis showed a clear separation of the plasma metabolomes of the SO group and the other two groups, but no separation of those of the PO and the HF groups. The present study shows that HF exerts no adverse metabolic effects in healthy rats, compared to PO or SO, indicating that HF is a safe alternative fat source to PO for food production.

Background: Prior research has established a correlation between immune cell activity and heart failure (HF), but the causal nature of this relationship remains unclear. Furthermore, the potential influence of metabolite levels on this interaction has not been comprehensively explored. To address these gaps, we employed a bidirectional Mendelian randomization (MR) approach in two stages to examine whether metabolite levels can mediate the causal relationship between immune cells and HF., Methods: Genetic information was extracted from summary data of genome-wide association studies. By applying a two-sample, two-step MR approach, we investigated the causal relationships among immune cells, metabolite levels, and HF, with a specific focus on the mediating effects of metabolites. Sensitivity analysis techniques were implemented to ensure the robustness of our findings., Results: MR analysis revealed significant causal associations between HF and eight specific immune cells and five metabolites. Mediation analysis further identified three mediated relationships. Particularly, hexadecenedioate (C16:1-DC) mediated the influence of both the CD28- CD127- CD25++ CD8br%CD8br (mediation proportion: 19.2%) and CD28+ CD45RA + CD8br%T cells (mediation proportion: 11.9%) on HF. Additionally, the relationship between IgD + CD38br AC cells and HF appeared to be mediated by the phosphate to alanine ratio (mediation proportion: 16.3%). Sensitivity analyses validated that the used instrumental variables were free from pleiotropy and heterogeneity., Conclusion: This study provides evidence that certain immune cell levels are associated with the risk of HF and that metabolite levels may mediate these relationships. However, to strengthen these findings, further validation using MR analyses with larger sample sizes is essential., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Li, Liu, Fu, Huang and Liu.)

Objective: Previous research reported that dietary addition with phytosterols improved the energy utilisation of the rumen microbiome, suggesting its potential to alleviate the negative energy balance of perinatal cows. This experiment aimed to explore the effects of feeding phytosterols on the metabolic status of perinatal cows through plasma metabolomics and faecal bacteria metabolism., Methods: Ten perinatal Holstein cows (multiparous, 2 parities) with a similar calving date were selected four weeks before calving. After 7 days for adaptation, cows were allocated to two groups (n = 5), which respectively received the basal rations supplementing commercial phytosterols at 0 and 200 mg/d during a 42-day experiment. The milk yield of each cow was recorded daily after calving. On days 1 and 42, blood and faeces samples were all collected from perinatal cows before morning feeding for analysing plasma biochemicals and metabolome, and faecal bacteria metabolism., Results: Dietary addition with phytosterols at 200 mg/d had no effects on plasma cholesterol and numerically increased milk yield by 1.82 kg/d (p>0.10) but attenuated their negative energy balance in perinatal cows as observed from the significantly decreased plasma level of β-hydroxybutyric acid (p = 0.002). Dietary addition with phytosterols significantly altered 12 and 15 metabolites (p<0.05) within the plasma and faeces of perinatal cows, respectively. Of these metabolites, 5 upregulated plasma fatty acids indicated an improved energy status (i.e., C18:1T, C14:0, C17:0, C18:0, and C16:0). Milk yield negatively correlated with plasma concentrations of ketone bodies (p = 0.035) and 5-methoxytryptamine (p = 0.039). Furthermore, dietary addition with phytosterols at 200 mg/d had no effects on fermentation characteristics and bacterial diversity of cow faeces (p>0.10) but improved potentially beneficial bacteria such as Christensenellaceae family (p<0.05) that positively correlated with feed efficiency., Conclusion: Dietary addition with phytosterols at 200 mg/d could effectively improve the energy status in perinatal cows by attenuating their negative energy balance.

Dried distiller’s grains with solubles (DDGS) are rich in nutrients and can enhance animals’ growth and immunity. However, there are few reports on the effects of a diet of DDGS on plasma metabolism and the related action pathways in domestic animals. In this study, groups of Guanling yellow cattle (GY) and Guanling crossbred cattle (GC) having a basal diet served as the control groups (GY-CG and GC-CG), and DDGS replacing 25% of the diet of GY and GC served as the replacement groups (GY-RG and GC-RG), with three cattle in each group. Plasma samples were prepared for metabolomic analysis. Based on multivariate statistical and univariate analyses, differential metabolites and metabolic pathways were explored. Twenty-nine significantly different metabolites (p < 0.05) were screened in GY-RG compared with those in GY-CG and were found to be enriched in the metabolic pathways, including choline metabolism in cancer, linolenic acid metabolism, and amino acid metabolism. Nine metabolites showed significant differences (p < 0.05) between GC-RG and GC-CG and were mainly distributed in the metabolic pathways of choline metabolism in cancer, glycerophospholipid metabolism, prostate cancer metabolism, and gonadotropin-releasing hormone (GnRH) secretion. These results suggest that a DDGS diet may promote healthy growth and development of experimental cattle by modulating these metabolic pathways. Our findings not only shed light on the nutritional effects of the DDGS diet and its underlying mechanisms related to metabolism but also provide scientific reference for the feed utilization of DDGS.

Rosa roxburghii fruit is an underutilized functional food abundant in polyphenols. Polyphenols have been proved to have antidiabetic effects. This study investigates the effects of Rosa roxburghii fruit polyphenols extract (RPE) on plasma metabolites and gut microbiota composition in streptozotocin (STZ)- and high-fat diet- induced type 2 diabetes using metabolomics and 16S rRNA gene sequencing. The induced diabetic mice were fed with 400 mg/kg body weight RPE for 8 weeks. RPE demonstrated hypoglycemic, hypolipidemic, and anti-inflammatory effects. Colonic oxidative stress biomarkers were also lowered by RPE. Besides, RPE decreased plasma ceramides and tyrosine levels and increased carnitine and phosphatidylinositols levels, indicating improved insulin resistance, lipid metabolism, and immune response. Furthermore, RPE decreased abundances of Lachnospiraceae and Rikenellaceae and increased abundances of Erysipelotrichaceae and Faecalibaculum. Metabolic function prediction of the gut microbiota by PICRUSt demonstrated that RPE downregulated the phosphotransferase system. Taken together, these findings demonstrated that RPE has the potential to prevent type 2 diabetes by regulating the plasma metabolites and gut microbes. [ABSTRACT FROM AUTHOR]

Heat stress (HS) during late gestation implies unfavorable effects on dairy cows and their in-utero heat stressed offspring. The objective of the present study was to elucidate the effect of intrauterine (maternal) HS during the last week of gestation on blood metabolite concentrations of female dairy calves during their first week of life. We defined the mean temperature humidity index (mTHI) during the last gestation week of ≥60 as threshold for maternal HS. In this regard, we compared differences in metabolite concentrations of maternally heat stressed (MHSCALVES) (n = 14) and not heat stressed (NMHSCALVES) (n = 33) calves. We identified 15 metabolites from five different biochemical classes (phosphatidylcholines, cholesteryl esters, sphingomyelins, cresols and hexoses) as potential biomarkers for maternal HS in calves. The plasma concentrations of all significantly affected metabolites were lower in MHSCALVES when compared to NMHSCALVES. The effect of maternal HS during the last week of gestation on blood metabolite concentrations of the female offspring during the first week after birth might be due to HS induced intergenerational physiological alterations, impaired colostrum quality or epigenetic modifications of the calf genome. The results of this pilot study should be validated in ongoing fully standardized studies.

Data on the evolution of blood metabolites and metabolic markers in neonatal piglets are scarce, although this information is vital to detect physiological aberrations from normal development. We aimed to characterize age- and nutrition-related changes in the plasma metabolome and serum biochemistry of suckling and newly weaned piglets and assess metabolite patterns as physiological markers for the two phases. In two replicate batches (n = 10 litters/group), piglets either received sow milk alone or were additionally offered creep feed from day 10 until weaning (day 28). Blood was collected from one piglet/litter on days 7, 14, 21, 28, 31 and 35 of life, totaling five females and five males/group/day. Signature feature ranking identified plasma triglycerides (TG) as discriminative for age and nutrition during the suckling phase. Influential TG 20:4_36:5, TG 17:0_34:2 and TG 18:2_38:6 were higher in creep-fed piglets on days 14, 21 and 28 of life, respectively, compared to only sow milk-fed piglets. Metabolites belonging to pathways within histidine, D-glutamine and D-glutamate metabolism as well as hippuric acid were distinctive for the postweaning compared to the suckling period. In conclusion, plasma lipid profiles especially corresponded to the type of nutrition in the suckling phase and showed a strong weaning effect.

Introduction: The immune response regulates the severity of COVID-19 (sCOVID-19). This study examined the cause-and-effect relationship between immune cell traits (ICTs) and the risk of severe COVID-19. Additionally, we discovered the potential role of plasma metabolome in modulating this risk., Methods: Employing data from a genome-wide association study (GWAS), we conducted a two-sample Mendelian randomization (MR) assessment of 731 genetic ICTs and sCOVID-19 (5,101 cases, 1,383,241 controls) incidence. The MR analysis was utilized to further quantitate the degree of plasma metabolome-mediated regulation of immune traits in sCOVID-19., Results: The inverse variance weighted method recognized 2 plasma metabolites (PMs) responsible for casual associations between immune cells and sCOVID-19 risk. These included Tridecenedioate (C13:1-DC) which regulated the association between CD27 on IgD- CD38br (OR 0.804, 95% CI 0.699-0.925, p = 0.002) and sCOVID-19 risk (mediated proportion: 18.7%); arginine to citrulline ratio which controlled the relationship of CD39 on monocyte (OR 1.053, 95% CI 1.013-1.094, p = 0.009) with sCOVID-19 risk (mediated proportion: -7.11%). No strong evidence that genetically predicted sCOVID-19 influenced the aforementioned immune traits., Conclusion: In this study, we have successfully identified a cause-and-effect relationship between certain ICTs, PMs, and the likelihood of contracting severe COVID-19. Our findings can potentially improve the accuracy of COVID-19 prognostic evaluation and provide valuable insights into the underlying mechanisms of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Hua and Chen.)

Background: The gut microbiota and plasma metabolites play important roles in the progression of drug-induced liver injury (DILI). We investigated the causal associations between the gut microbiota, plasma metabolome, and DILI., Methods: The summary data for gut microbiota ( n = 18,340), plasma metabolome ( n = 8,299), and DILI ( n = 366,838) were obtained from the large genome-wide association studies. A two-sample Mendelian randomization was performed to explore the associations between the gut microbiota, plasma metabolome, and DILI. Additionally, a two-step Mendelian randomization was performed to explore the potential metabolites., Results: Five taxa were causally associated with DILI, including Oscillospira [odds ratio (OR) = 2.257, 95% confidence interval (CI) = 1.110-4.590], Blautia (OR = 2.311, 95% CI = 1.010-5.288), Roseburia (OR = 2.869, 95% CI = 1.429-5.761), Fusicatenibacter (OR = 1.995, 95% CI = 1.024-3.890), and Prevotella 7 (OR = 1.549, 95% CI = 1.065-2.253). Moreover, 53 metabolites were causally associated with DILI. After mediation analysis, four taxa were found to affect DILI through five mediation metabolites. N6-carbamoylthreonyladenosine mediated the effect of Blautia on DILI. Acetylcarnitine mediated the effect of Fusicatenibacter on DILI. In addition, 4-cholesten-3-one mediated the effect of Prevotella 7 on DILI. Furthermore, 5,6-dihydrothymine levels and the salicylate-to-citrate ratio mediated the effect of Oscillospira on DILI., Conclusion: We found that the gut microbiota could affect DILI through plasma metabolites, which could serve as potential biomarkers for risk stratification and elucidate underlying mechanisms for further investigation of DILI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fu, Zhao, Song and Xie.)

Residual feed intake (RFI) is a metric that provides a more accurate measure of feed efficiency. The lower the RFI, the higher the feed efficiency. The changes in the host microbiome and metabolome contribute to the greater feed efficiency of low RFI (LRFI) animals. The aim of this study was to explore the differences in rumen microorganisms, rumen metabolites and plasma metabolites of Hu sheep with differing RFI through the microbiome and metabolome. A total of 80 Hu sheep were used. The experiment consisted of a 15-d pretrial period and a 128-d experimental period. The RFI in the experimental period was calculated for all sheep, and the sheep were screened into high RFI (HRFI, n  = 8) and LRFI ( n  = 8) groups. The HRFI and LRFI sheep did not differ in their initial and final body weights, average daily gain and body measurements, but the dry matter intake of LRFI sheep was significantly decreased (28.4%, P  < 0.001). The sheep with LRFI had higher digestibility of crude protein ( P  = 0.010) and ether extract ( P  = 0.010) compared to HRFI group. The concentrations of acetate ( P  = 0.036), propionate ( P  = 0.010), valerate ( P  = 0.027) and total volatile fatty acids ( P  = 0.048) in rumen of LRFI group were higher compared to HRFI group. The results of 16S rDNA sequencing indicated that the sheep with LRFI had higher proportions of Prevotella genus in rumen liquid ( P  = 0.031). The rumen metabolome and plasma metabolome results showed that the citrate cycle, pyruvate metabolism and alanine, aspartate and glutamate metabolism processes were more active for sheep in LRFI group, which provided more energy substrate such as malic acid, oxoglutaric acid and citric acid. In conclusion, sheep with LRFI can utilize feed more efficiently, and the more active energy metabolism pathway and the production of energy substances may account for the higher feed efficiency., Competing Interests: We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, and there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the content of this paper., (© 2024 The Authors.)

Male breast cancer, while uncommon, is a highly malignant disease. Monocyte chemotactic protein-1 (MCP-1) is an adipokine; its concentration in adipose tissue is elevated in obesity. This study tested the hypothesis that adipose-derived MCP-1 contributes to male breast cancer. In a 2x2 design, male MMTV-PyMT mice with or without adipose-specific Mcp-1 knockout [designated as Mcp-1-/- or wild-type (WT)] were fed the AIN93G standard diet or a high-fat diet (HFD) for 25 weeks. Mcp-1-/- mice had lower adipose Mcp-1 expression than WT mice. Adipose Mcp-1 deficiency reduced plasma concentrations of MCP-1 in mice fed the HFD compared to their WT counterparts. Mcp-1-/- mice had a longer tumor latency (25.2 weeks vs. 18.0 weeks) and lower tumor incidence (19% vs. 56%), tumor progression (2317% vs. 4792%), and tumor weight (0.23 g vs. 0.64 g) than WT mice. Plasma metabolomics analysis identified 56 metabolites that differed among the four dietary groups, including 22 differed between Mcp-1-/- and WT mice. Pathway and network analyses along with discriminant analysis showed that pathways of amino acid and carbohydrate metabolisms are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-derived MCP-1 contributes to mammary tumorigenesis in male MMTV-PyMT. The potential involvement of adipose-derived MCP-1 in metabolomics warrants further investigation on its role in causal relationships between cancer metabolism and mammary tumorigenesis in this male MMTV-PyMT model. [ABSTRACT FROM AUTHOR]

Male breast cancer, while uncommon, is a highly malignant disease. Monocyte chemotactic protein-1 (MCP-1) is an adipokine; its concentration in adipose tissue is elevated in obesity. This study tested the hypothesis that adipose-derived MCP-1 contributes to male breast cancer. In a 2x2 design, male MMTV-PyMT mice with or without adipose-specific Mcp-1 knockout [designated as Mcp-1-/- or wild-type (WT)] were fed the AIN93G standard diet or a high-fat diet (HFD) for 25 weeks. Mcp-1-/- mice had lower adipose Mcp-1 expression than WT mice. Adipose Mcp-1 deficiency reduced plasma concentrations of MCP-1 in mice fed the HFD compared to their WT counterparts. Mcp-1-/- mice had a longer tumor latency (25.2 weeks vs. 18.0 weeks) and lower tumor incidence (19% vs. 56%), tumor progression (2317% vs. 4792%), and tumor weight (0.23 g vs. 0.64 g) than WT mice. Plasma metabolomics analysis identified 56 metabolites that differed among the four dietary groups, including 22 differed between Mcp-1-/- and WT mice. Pathway and network analyses along with discriminant analysis showed that pathways of amino acid and carbohydrate metabolisms are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-derived MCP-1 contributes to mammary tumorigenesis in male MMTV-PyMT. The potential involvement of adipose-derived MCP-1 in metabolomics warrants further investigation on its role in causal relationships between cancer metabolism and mammary tumorigenesis in this male MMTV-PyMT model.

The Mediterranean Diet (MedDiet) may decrease the cardiometabolic risk through modulation of metabolic pathways. Furthermore, the interplay between MedDiet, metabolites and microbial metabolism may improve our understanding on the metabolic effects of this diet. We aimed to evaluate the effect of the MedDiet compared to nuts supplementation on circulating metabolites and their relationship with cardiometabolic health. We further examined whether changes in the metabolomic profiles were associated with changes in gut microbiota composition in a multi-omics integrative approach. Forty-four adults with Metabolic Syndrome (MetS), (aged 37–65) participated in a randomized controlled, crossover 2-months dietary-intervention trial with a 1-month wash-out period, consuming a MedDiet or a non MedDiet plus nuts (50 g/day). Nutritional data were collected at the beginning and the end of each intervention period using 3-day dietary records, as well as fasting blood and fecal samples. Plasma metabolites (m = 378) were profiled using targeted metabolomics. Associations of these metabolites with the interventions were assessed with elastic net regression analyses. Gut microbiota composition was assessed by 16S rRNA sequencing. A sparse least regression analysis combined with a canonical correlation analysis was conducted between the plasma selected metabolites and genera in order to identify the relevant dual-omics signatures discriminating the dietary interventions. Changes in 65 circulating metabolites were significantly associated with the MedDiet (mainly lipids, acylcarnitines, amino acids, steroids and TCA intermediates). Importantly, these changes were associated with decreases in glucose, insulin and HOMA-IR. The network analysis identified two main clusters of genera with an opposite behaviour towards selected metabolites, mainly PC species, ChoE(20:5), TGs and medium/long-chain acylcarnitines. Following a MedDiet, rather than consuming nuts in the context of a non-MedDiet was associated with a specific plasma metabolomic profile, which was also related to metabolic improvements in adults with MetS. The identified correlated network between specific bacteria and metabolites suggests interplay between diet, circulating metabolites and gut microbiota. The trial was registered in the ISRCTN with identifier ISRCTN88780852, https://doi.org/10.1186/ISRCTN88780852. [ABSTRACT FROM AUTHOR]

• Specific immune cells are associated with the onset and development of ICH as indicated by advanced Mendelian randomization analysis. • A novel association has been identified between plasma hypotaurine levels and the progression of ICH. • Hypotaurine-influenced switched memory B cells play a significant role in the progression of ICH, highlighting immune cell modulation as a promising strategy for ICH treatment. The evidence supports a strong link between immune cells and intracerebral hemorrhage (ICH). Nonetheless, the specific cause-and-effect associations between immune cells and ICH remain indeterminate. Here, our primary investigation compared immune cell infiltration in the ICH and sham groups using the GSE24265 dataset. Afterward, we extensively examined the relationship between immune cells and ICH by applying a two-sample Mendelian randomization (MR) analysis to identify the particular immune cells that may be associated with the initiation and advancement of ICH. Nevertheless, the specific processes that regulate the cause-and-effect connection between immune cells and ICH remain unknown. In this study, our objective was to investigate the connections between immune cell characteristics and plasma metabolites, as well as the links between plasma components and ICH. Our investigation uncovered that the levels of hypotaurine play a key role in the advancement of ICH, influencing the ratio of switched memory B cells among lymphocytes. Thus, our findings provide novel insights into the potential biological mechanisms underlying immune cell-mediated ICH. [ABSTRACT FROM AUTHOR]

Despite the existence of a number of studies investigating the effect of insect meal on the growth performance of broilers, knowledge about the metabolic effects of insect meal in broilers is still scarce. Thus, the present study investigated the effect of partial replacement of soybean meal with Hermetia illucens (HI) larvae meal on the liver transcriptome, the plasma metabolome, and the cecal microbiota in broilers. For the study, 72 male one-day-old Cobb 500 broilers were divided into three groups and fed 3 different diets with either 0% (HI0), 7.5% (HI7.5), or 15% (HI15) defatted HI meal for 35 d. Each group consisted of 6 cages (replicates) with 4 broilers/cage. While body weight (BW) gain, feed intake, and feed:gain ratio did not differ between groups, breast muscle weight, carcass yield, and apparent ileal digestibility (AID) of 5 amino acids were higher in group HI15 than in group HI0 (P < 0.05). Indicators of α-diversity (Chao1 and Observed) in the cecal digesta were higher in groups HI15 and HI7.5 than in group HI0 (P < 0.05). The abundance of 5 families and 18 genera, all of which belonged to the Firmicutes phylum, in the cecal digesta differed among groups (P < 0.05). Concentrations of butyric acid, valeric acid, and isobutyric acid in the cecal digesta were lower in group HI15 than in the other 2 groups (P < 0.05), whereas those of total and other short-chain fatty acids were not different between groups. Liver transcriptomics revealed a total of 70 and 61 differentially expressed transcripts between groups HI15 vs. HI0 and between groups HI7.5 vs. HI0, respectively, (P < 0.05). Targeted metabolomics identified 138 metabolites, most of which were triglyceride species, being different between the 3 groups (FDR < 0.05). According to this study, dietary inclusion of HI larvae meal has no detrimental impact but increases breast muscle weight and carcass weight in broilers suggesting that HI larvae meal can be recommended as a sustainable alternative protein source for broilers. [ABSTRACT FROM AUTHOR]

Rosa roxburghii fruit is an underutilized functional food abundant in polyphenols. Polyphenols have been proved to have antidiabetic effects. This study investigates the effects of Rosa roxburghii fruit polyphenols extract (RPE) on plasma metabolites and gut microbiota composition in streptozotocin (STZ)- and high-fat diet- induced type 2 diabetes using metabolomics and 16S rRNA gene sequencing. The induced diabetic mice were fed with 400 mg/kg body weight RPE for 8 weeks. RPE demonstrated hypoglycemic, hypolipidemic, and anti-inflammatory effects. Colonic oxidative stress biomarkers were also lowered by RPE. Besides, RPE decreased plasma ceramides and tyrosine levels and increased carnitine and phosphatidylinositols levels, indicating improved insulin resistance, lipid metabolism, and immune response. Furthermore, RPE decreased abundances of Lachnospiraceae and Rikenellaceae and increased abundances of Erysipelotrichaceae and Faecalibaculum. Metabolic function prediction of the gut microbiota by PICRUSt demonstrated that RPE downregulated the phosphotransferase system. Taken together, these findings demonstrated that RPE has the potential to prevent type 2 diabetes by regulating the plasma metabolites and gut microbes.

Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene BRCA1 (gBRCA1+) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in gBRCA1+ individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 gBRCA1+ women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between gBRCA1+ and controls in ~82%. The results of this study point to innate systemic metabolic differences in gBRCA1+ women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of BRCA1-associated breast cancer.

Psoriasis is a chronic inflammatory skin disease that affects millions of people worldwide. There is still no effective approach for the clinical treatment of psoriasis. This is largely due to the lack of understanding of the pathological mechanism. Here, we comprehensively characterized the skin microbiome and plasma metabolome alterations of psoriasis patients. We observed that some pathogenic bacteria, including Vibrio, were significantly increased in psoriasis patients. The metabolomics results showed alterations in some metabolic pathways, especially pathways for lipid metabolism. In addition, microbiome-specific metabolites, including bile acids and kynurenine, were significantly changed. Correlation analysis revealed the interplay between the skin microbiota and plasma metabolites, especially between Vibrio and several lipids. Our results provide new evidence for the interplay between the skin microbiome and plasma metabolites, which is dramatically disrupted in psoriasis patients. This study also revealed the mechanism underlying the pathogenesis of psoriasis.

Fine particulate matter (PM2.5) air pollution exposure increases the risk of developing cardiovascular disease (CVD). Although the precise mechanisms by which air pollution exposure increases CVD risk remain uncertain, research indicates that PM2.5-induced endothelial dysfunction contributes to CVD risk. Previous studies demonstrate that concentrated ambient PM2.5 (CAP) exposure induces vascular inflammation and impairs insulin and vascular endothelial growth factor (VEGF) signaling dependent on pulmonary oxidative stress. To assess whether CAP exposure induces these vascular effects via plasmatic factors, we incubated aortas from naïve mice with plasma isolated from mice exposed to HEPA-filtered air or CAP (9 days) and examined vascular inflammation and insulin and VEGF signaling. We found that treatment of naïve aortas with plasma from CAP-exposed mice activates NF-κBα and induces insulin and VEGF resistance, indicating transmission by plasmatic factor(s). To identify putative factors, we exposed lung-specific ecSOD-transgenic (ecSOD-Tg) mice and wild-type (WT) littermates to CAP at concentrations of either ~60 µg/m³ (CAP60) or ~100 µg/m³ (CAP100) and measured the abundance of plasma metabolites by mass spectrometry. In WT mice, both CAP concentrations increased levels of fatty acids such as palmitate, myristate, and palmitoleate and decreased numerous phospholipid species; however, these CAP-induced changes in the plasma lipidome were prevented in ecSOD-Tg mice. Consistent with the literature, we found that fatty acids such as palmitate are sufficient to promote endothelial inflammation. Collectively, our findings suggest that PM2.5 exposure, by inducing pulmonary oxidative stress, promotes unique lipidomic changes characterized by high levels of circulating fatty acids, which are sufficient to trigger vascular pathology. [ABSTRACT FROM AUTHOR]

Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene BRCA1 (g BRCA1 +) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in g BRCA1 + individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 g BRCA1 + women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between g BRCA1 + and controls in ~82%. The results of this study point to innate systemic metabolic differences in g BRCA1 + women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of BRCA1 -associated breast cancer. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disease that affects millions of people worldwide. There is still no effective approach for the clinical treatment of psoriasis. This is largely due to the lack of understanding of the pathological mechanism. Here, we comprehensively characterized the skin microbiome and plasma metabolome alterations of psoriasis patients. We observed that some pathogenic bacteria, including Vibrio , were significantly increased in psoriasis patients. The metabolomics results showed alterations in some metabolic pathways, especially pathways for lipid metabolism. In addition, microbiome-specific metabolites, including bile acids and kynurenine, were significantly changed. Correlation analysis revealed the interplay between the skin microbiota and plasma metabolites, especially between Vibrio and several lipids. Our results provide new evidence for the interplay between the skin microbiome and plasma metabolites, which is dramatically disrupted in psoriasis patients. This study also revealed the mechanism underlying the pathogenesis of psoriasis. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to investigate the causal relationship between gut microbiota and juvenile idiopathic arthritis, and to identify and quantify the potential role of plasma metabolites as mediators., Methods: Using summary-level data from genome-wide association studies, a two-sample Mendelian randomization was conducted involving 131 gut microbiota genus, 1,400 plasma metabolites, and juvenile idiopathic arthritis. Additionally, a two-step approach was employed to quantify the proportion of the effect of gut microbiota on juvenile idiopathic arthritis mediated by plasma metabolites. Effect estimation primarily utilized Inverse Variance Weighting, with further validation using Bayesian weighted Mendelian randomization., Results: In our MR analysis, a positive correlation was observed between Rikenellaceae and the risk of juvenile idiopathic arthritis, while Dorea showed a negative correlation with juvenile idiopathic arthritis risk. Mediation analysis indicated that Furaneol sulfate levels acted as a mediator between Dorea and juvenile idiopathic arthritis, with an indirect effect proportion of 19.94, 95% CI [8.86-31.03%]., Conclusion: Our study confirms a causal relationship between specific microbial genus and juvenile idiopathic arthritis, and computes the proportion of the effect mediated by plasma metabolites, offering novel insights for clinical interventions in juvenile idiopathic arthritis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gao, Wang, Wang, Lei, Zhuang, Zhou and Chen.)

Aims/hypothesis: Abnormal gut microbiota and blood metabolome profiles have been reported both in children and adults with uncomplicated type 1 diabetes as well as in adults with type 1 diabetes and advanced stages of diabetic nephropathy. In this study we aimed to investigate the gut microbiota and a panel of targeted plasma metabolites in individuals with type 1 diabetes of long duration without and with different levels of albuminuria. Methods: In a cross-sectional study we included 161 individuals with type 1 diabetes and 50 healthy control individuals. Individuals with type 1 diabetes were categorised into three groups according to historically measured albuminuria: (1) normoalbuminuria (<3.39 mg/mmol); (2) microalbuminuria (3.39–33.79 mg/mmol); and (3) macroalbuminuria (≥33.90 mg/mmol). From faecal samples, the gut microbiota composition at genus level was characterised by 16S rRNA gene amplicon sequencing and in plasma a targeted profile of 31 metabolites was analysed with ultra HPLC coupled to MS/MS. Results: Study participants were aged 60 ± 11 years (mean ± SD) and 42% were women. The individuals with type 1 diabetes had had diabetes for a mean of 42 ± 15 years and had an eGFR of 75 ± 25 ml min−1 (1.73 m)−2. Measures of the gut microbial beta diversity differed significantly between healthy controls and individuals with type 1 diabetes, either with micro- or macroalbuminuria. Taxonomic analyses showed that 79 of 324 genera differed in relative abundance between individuals with type 1 diabetes and healthy controls and ten genera differed significantly among the three albuminuria groups with type 1 diabetes. For the measured plasma metabolites, 11 of 31 metabolites differed significantly between individuals with type 1 diabetes and healthy controls. When individuals with type 1 diabetes were stratified by the level of albuminuria, individuals with macroalbuminuria had higher plasma concentrations of indoxyl sulphate and l-citrulline than those with normo- or microalbuminuria and higher plasma levels of homocitrulline and l-kynurenine compared with individuals with normoalbuminuria. Whereas plasma concentrations of tryptophan were lower in individuals with macroalbuminuria compared with those with normoalbuminuria. Conclusions/interpretation: We demonstrate that individuals with type 1 diabetes of long duration are characterised by aberrant profiles of gut microbiota and plasma metabolites. Moreover, individuals with type 1 diabetes with initial stages of diabetic nephropathy show different gut microbiota and plasma metabolite profiles depending on the level of albuminuria. [ABSTRACT FROM AUTHOR]

Background A vegetarian diet (VD) may reduce future cardiovascular risk in patients with ischemic heart disease. Methods and Results A randomized crossover study was conducted in subjects with ischemic heart disease, assigned to 4‐week intervention periods of isocaloric VD and meat diet (MD) with individually designed diet plans, separated by a 4‐week washout period. The primary outcome was difference in oxidized low‐density lipoprotein cholesterol (LDL‐C) between diets. Secondary outcomes were differences in cardiometabolic risk factors, quality of life, gut microbiota, fecal short‐chain and branched‐chain fatty acids, and plasma metabolome. Of 150 eligible patients, 31 (21%) agreed to participate, and 27 (87%) participants completed the study. Mean oxidized LDL‐C (−2.73 U/L), total cholesterol (−5.03 mg/dL), LDL‐C (−3.87 mg/dL), and body weight (−0.67 kg) were significantly lower with the VD than with the MD. Differences between VD and MD were observed in the relative abundance of several microbe genera within the families Ruminococcaceae, Lachnospiraceae, and Akkermansiaceae. Plasma metabolites, including l‐carnitine, acylcarnitine metabolites, and phospholipids, differed in subjects consuming VD and MD. The effect on oxidized LDL‐C in response to the VD was associated with a baseline gut microbiota composition dominated by several genera of Ruminococcaceae. Conclusions The VD in conjunction with optimal medical therapy reduced levels of oxidized LDL‐C, improved cardiometabolic risk factors, and altered the relative abundance of gut microbes and plasma metabolites in patients with ischemic heart disease. Our results suggest that composition of the gut microbiota at baseline may be related to the reduction of oxidized LDL‐C observed with the VD. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02942628.

Abstract Background Microbiota and bile acids in the gastrointestinal tract profoundly alter systemic metabolic processes. In obese subjects, gradual weight loss ameliorates adipose tissue inflammation and related systemic changes. We assessed how rapid weight loss due to a very low calorie diet (VLCD) affects the fecal microbiome and fecal bile acid composition, and their interactions with the plasma metabolome and subcutaneous adipose tissue inflammation in obesity. Methods We performed a prospective cohort study of VLCD-induced weight loss of 10% in ten grades 2–3 obese postmenopausal women in a metabolic unit. Baseline and post weight loss evaluation included fasting plasma analyzed by mass spectrometry, adipose tissue transcription by RNA sequencing, stool 16S rRNA sequencing for fecal microbiota, fecal bile acids by mass spectrometry, and urinary metabolic phenotyping by 1H-NMR spectroscopy. Outcome measures included mixed model correlations between changes in fecal microbiota and bile acid composition with changes in plasma metabolite and adipose tissue gene expression pathways. Results Alterations in the urinary metabolic phenotype following VLCD-induced weight loss were consistent with starvation ketosis, protein sparing, and disruptions to the functional status of the gut microbiota. We show that the core microbiome was preserved during VLCD-induced weight loss, but with changes in several groups of bacterial taxa with functional implications. UniFrac analysis showed overall parallel shifts in community structure, corresponding to reduced abundance of the genus Roseburia and increased Christensenellaceae;g__ (unknown genus). Imputed microbial functions showed changes in fat and carbohydrate metabolism. A significant fall in fecal total bile acid concentration and reduced deconjugation and 7-α-dihydroxylation were accompanied by significant changes in several bacterial taxa. Individual bile acids in feces correlated with amino acid, purine, and lipid metabolic pathways in plasma. Furthermore, several fecal bile acids and bacterial species correlated with altered gene expression pathways in adipose tissue. Conclusions VLCD dietary intervention in obese women changed the composition of several fecal microbial populations while preserving the core fecal microbiome. Changes in individual microbial taxa and their functions correlated with variations in the plasma metabolome, fecal bile acid composition, and adipose tissue transcriptome. Trial Registration ClinicalTrials.gov NCT01699906, 4-Oct-2012, Retrospectively registered. URL-https://clinicaltrials.gov/ct2/show/NCT01699906

Methotrexate (MTX) is widely used in the treatment of autoimmune arthritis but is limited by its unpredictable and variable response profile. Currently, no biomarkers exist to predict or monitor early therapeutic responses to MTX. Using a collagen-induced arthritis (CIA) mouse model, this study aimed to identify biochemical pathways and biomarkers associated with MTX efficacy in autoimmune arthritis. Following arthritis disease induction, DBA/1J mice were treated with subcutaneous MTX (20 mg/kg/week) and disease activity was assessed based on disease activity scores (DAS) and paw volume (PV) measurements. Red blood cell (RBC) and plasma samples were collected at the end of the study and were assessed for folate and MTX content. Plasma samples were analyzed by semitargeted global metabolomic profiling and analyzed by univariate and multivariate analysis. Treatment with MTX was associated with significant reductions in disease activity based on both DAS (p = 0.0006) and PV (p = 0.0006). MTX therapy resulted in significant reductions in 5-methyltetrahydrofolate (5mTHF) levels in plasma (p = 0.02) and RBCs (p = 0.001). Reductions in both RBC and plasma 5mTHF were associated with lower DAS (p = 0.0007, p = 0.01, respectively) and PV (p = 0.001, p = 0.005, respectively). Increases in RBC MTX were associated with lower DAS (p = 0.003) but not PV (p = 0.23). Metabolomic analysis identified N-methylisoleucine (NMI) and quinolone as metabolites significantly altered in disease mice, which were corrected towards healthy control levels in mice treated with MTX. Reductions in plasma NMI were associated with lower DAS (p = 0.0002) and PV (p = 9.5 × 10−6). Increases in plasma quinolone were associated with lower DAS (p = 0.02) and PV (p = 0.01). Receiver-operating characteristic curve analysis identified plasma NMI (AUC = 1.00, p = 2.4 × 10−8), RBC 5mTHF (AUC = 0.99, p = 2.4 × 10−5), and plasma quinolone (AUC = 0.89, p = 0.01) as top discriminating metabolites of MTX treatment. Our data support a relationship between MTX efficacy and its effect on circulating folates and identified 5mTHF, NMI, and quinolone as potential therapeutic biomarkers of disease activity and MTX response in the CIA mouse model of autoimmune arthritis.

Methotrexate (MTX) efficacy in the treatment of rheumatoid arthritis (RA) is variable and unpredictable, resulting in a need to identify biomarkers to guide drug therapy. This study evaluates changes in the plasma metabolome associated with response to MTX in RA with the goal of understanding the metabolic basis for MTX efficacy towards the identification of potential metabolic biomarkers of MTX response. Plasma samples were collected from healthy control subjects (n = 20), and RA patients initiating MTX therapy (n = 20, 15 mg/week) before and after 16 weeks of treatment. The samples were analyzed by a semi-targeted metabolomic analysis, and then analyzed by univariate and multivariate methods, as well as an enrichment analysis. An MTX response was defined as a clinically significant reduction in the disease activity score in 28 joints (DAS-28) of greater than 1.2; achievement of clinical remission, defined as a DAS-28 < 2.6, was also utilized as an additional measure of response. In this study, RA is associated with an altered plasma metabolome that is normalized following initiation of MTX therapy. Metabolite classes found to be altered in RA and corrected by MTX therapy were diverse and included triglycerides (p = 1.1 × 10−16), fatty acids (p = 8.0 × 10−12), and ceramides (p = 9.8 × 10−13). Stratification based on responses to MTX identified various metabolites differentially impacted in responders and non-responders including glucosylceramides (GlcCer), phosphatidylcholines (PC), sphingomyelins (SM), phosphatidylethanolamines (PE), choline, inosine, hypoxanthine, guanosine, nicotinamide, and itaconic acid (p < 0.05). In conclusion, RA is associated with significant alterations to the plasma metabolome displaying at least partial normalization following 16 weeks of MTX therapy. Changes in multiple metabolites were found to be associated with MTX efficacy, including metabolites involved in fatty acid/lipid, nucleotide, and energy metabolism.

Cold exposure results in activation of metabolic processes required for fueling thermogenesis, potentially promoting improved metabolic health. However, the metabolic complexity underlying this process is not completely understood. We aimed to analyze changes in plasma metabolites related to acute cold exposure and their relationship to cold-acclimatization level and metabolic health in cold-acclimatized humans. Blood samples were obtained before and acutely after 10–15 min of ice-water swimming (