Targeted Metabolomics Profiling Research Articles

Targeted metabolomics profiling in pregnancy associated with vitamin D deficiency

BackgroundVitamin D deficiency is common in pregnancy, however, its effects has not been fully elucidated. Here, we conducted targeted metabolomics profiling to study the relationship.MethodsThis study enrolled 111 pregnant women, including sufficient group (n = 9), inadequate group (n = 49) and deficient group (n = 53). Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabonomics were used to characterize metabolite profiles associated with vitamin D deficiency in pregnancy.ResultsMany metabolites decreased in the inadequate and deficient group, including lipids, amino acids and others. The lipid species included fatty acyls (FA 14:3, FA 26:0; O), glycerolipids (MG 18:2), glycerophospholipids (LPG 20:5, PE-Cer 40:1; O2, PG 29:0), sterol lipids (CE 20:5, ST 28:0; O4, ST 28:1; O4). Decreased amino acids included aromatic amino acids (tryptophan, phenylalanine, tyrosine) and branched-chain amino acids (valine, isoleucine, leucine), proline, methionine, arginine, lysine, alanine, L-kynurenine,5-hydroxy-L-tryptophan, allysine.ConclusionsThis targeted metabolomics profiling indicated that vitamin D supplementation can significantly affect lipids and amino acids metabolism in pregnancy.

Antidiabetic action of the Chinese formula Shouhuitongbian and the underlying mechanism associated with alteration of gut microbiota

BackgroundThe prevalence and incidence of type 2 diabetes mellitus (T2DM) have dramatically increased. The intestinal flora and its derived metabolites are demonstrated to play vital roles in the etiology and onset of T2DM. Shouhuitongbian (SHTB) is a traditional Chinese formula to treat constipation. SHTB is composed of seven herbs and components of Colla corii asini (CCA) that are obtained from the hide of Equus asinus L.. Some of herbs in SHTB such as Aloe vera (L.) Burm.f., Cassia obtusifolia L., fruits of Lycium barbarum L., and Citrus aurantium L. have shown to improve insulin resistance (IR) and T2DM in early reports. We hypothesized that SHTB composed of these herbs has antidiabetic effects. The antidiabetic efficacy and mechanism of action of SHTB have not been previously reported. Hypothesis/PurposeTo demonstrate the antidiabetic effect and elucidate the underlying mechanisms of SHTB from the perspective of gut microbiota. Study designThe main compounds were identified and quantified by high-performance liquid chromatography (HPLC)-mass spectrometry analysis. High fat diet (HFD)-fed mice and db/db mice were used to assess the antidiabetic effects and the mechanism of SHTB. The underlying mechanisms were evaluated by enzyme-linked immunosorbent assay (ELISA), western blot analysis, quantitative real time polymerase chain reaction (qPCR) analysis, 16S rRNA high-throughput sequencing, and targeted metabolome analysis. MethodsHFD-fed mice and db/db mice were orally treated with the standard positive drug metformin (100 mg/kg/d) and with SHTB (200 and 100 mg/kg/d), which was chemically characterized according to the European Medicine Agency (EMA) guidelines. The beneficial effects of SHTB were studied by homeostasis model assessment of insulin resistance (HOMA-IR) index, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), total cholesterol (T-CHO), triglyceride (TG), and inflammation. Subsequently, 16S rDNA-based high-throughput pyrosequencing and GC-MS-based targeted metabolomics profiling were performed to analyze the gut microbiota composition and metabolites profile in the gut, respectively. Moreover, the mammalian target of rapamycin complex 1 (mTORC1) / insulin receptor substrate 1 (IRS-1) / phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) pathway was evaluated via qPCR and western blot. ResultsChemically characterized SHTB, in which six markers were quantified, effectively alleviated glucose intolerance and IR, ameliorated lipid metabolism dysfunction, and reduced inflammation. In addition, 16S rDNA sequencing found that SHTB reshaped the composition of intestinal flora, as indicated by the enrichment of Akkermansia and Parabacteroides in both HFD-fed and db/db mice. Moreover, SHTB enhanced the intestinal production of short-chain fatty acids (SCFAs) and branched short-chain fatty acids (BSCFAs), and reduced the levels of the fecal and circulating branched-chain amino acids (BCAAs). The IRS-1/PI3K/AKT signaling pathway was upregulated after treatment with SHTB. ConclusionOrally administration of SHTB effectively improved IR and reduced hyperglycemia in mice. Treatment with SHTB regulated the gut BCAAs-mTORC1/IRS-1/PI3K/AKT axis by enhancing the BCAAs catabolism in the gut, which attenuated the deleterious effect of BCAAs on the IRS-1 signaling pathway.

Metabolomics analysis of physicochemical properties associated with freshness degradation in frozen Antarctic krill (Euphausia superba)

This study aimed to determine the effect of different frozen temperatures during storage on the quality of Antarctic krill (Euphausia superba) and assess the change at the metabolite level via a combination of physicochemical property analysis, liquid chromatography–tandem mass spectrometry (LC–MS) based non–targeted metabolomics profiling. Regarding samples stored at –20 °C, the expressions of 7055 metabolites were elevated, while 2313 were downregulated. Lipids and lipid molecules had the highest proportion of differential metabolites. A total of 432 discriminatory metabolites with Kyoto Encyclopedia of Genes and Genomes (KEGG) IDs was obtained. We also observed that the concentrations of differential bitter free amino acids (FAAs) and oxidation products of arachidonic and linoleic acid increased. Moreover, as the storage temperature increased, the freshness, umami, and sweetness components were considerably reduced. Furthermore, results indicated that the color, pH and water–holding capacity (WHC) were potential indicators of quality deterioration, while inosinic acid was a probable biomarker for umami degradation of frozen Antarctic krill. In conclusion, this study demonstrates that storage at lower temperatures can be beneficial for maintaining the freshness of Antarctic krill from macro and micro perspectives.

Metabolic profiling during COVID-19 infection in humans: Identification of potential biomarkers for occurrence, severity and outcomes using machine learning.

After its emergence in China, the coronavirus SARS-CoV-2 has swept the world, leading to global health crises with millions of deaths. COVID-19 clinical manifestations differ in severity, ranging from mild symptoms to severe disease. Although perturbation of metabolism has been reported as a part of the host response to COVID-19 infection, scarce data exist that describe stage-specific changes in host metabolites during the infection and how this could stratify patients based on severity. Given this knowledge gap, we performed targeted metabolomics profiling and then used machine learning models and biostatistics to characterize the alteration patterns of 50 metabolites and 17 blood parameters measured in a cohort of 295 human subjects. They were categorized into healthy controls, non-severe, severe and critical groups with their outcomes. Subject's demographic and clinical data were also used in the analyses to provide more robust predictive models. The non-severe and severe COVID-19 patients experienced the strongest changes in metabolite repertoire, whereas less intense changes occur during the critical phase. Panels of 15, 14, 2 and 2 key metabolites were identified as predictors for non-severe, severe, critical and dead patients, respectively. Specifically, arginine and malonyl methylmalonyl succinylcarnitine were significant biomarkers for the onset of COVID-19 infection and tauroursodeoxycholic acid were potential biomarkers for disease progression. Measuring blood parameters enhanced the predictive power of metabolic signatures during critical illness. Metabolomic signatures are distinctive for each stage of COVID-19 infection. This has great translation potential as it opens new therapeutic and diagnostic prospective based on key metabolites.

Isomalt attenuates hepatic steatosis in rats via modulating gut microbiota and its metabolic function

Growing studies have shown the preventive effects of isomalt against metabolic diseases, nevertheless, its efficacy and action mechanisms on nonalcoholic fatty liver disease (NAFLD) remain unknown. Herein, isomalt supplementation significantly attenuated the high-sucrose diet-induced hepatic steatosis. Mechanically, dietary isomalt restored hepatic de novo lipogenesis dysfunction and intestinal epithelial integrity. Moreover, isomalt consumption regulated gut microbiota composition, including improving abundance of probiotic Akkermansia, but suppressing pathogens Acinetobacter and Corynebacterium_1. Quantification analyses of short-chain fatty acids showed that isomalt reduced faecal acetate concentrations, whereas elevated propionate and butyrate in hepatic steatosis. Additionally, targeted metabolomics profiling of tryptophan metabolism showed that isomalt increased faecal levels of 5-hydroxytryptophan, indole-3-carboxaldehyde and kynurenic acid, but reduced concentrations of 5-hydroxyindoleacetic acid and xanthurenic acid in rats. Thereby, our data demonstrate that dietary isomalt attenuates hepatic steatosis possibly via modulation of gut microbiota and its metabolic function, which provides new insights into preventing and treating NAFLD in future.

Abnormal lactate metabolism is linked to albuminuria and kidney injury in diabetic nephropathy

Diabetic nephropathy (DN) is characterized by abnormal kidney energy metabolism, but its causes and contributions to DN pathogenesis are not clear. To examine this issue, we carried out targeted metabolomics profiling in a mouse model of DN that develops kidney disease resembling the human disorder. We found a distinct profile of increased lactate levels and impaired energy metabolism in kidneys of mice with DN, and treatment with an angiotensin-receptor blocker (ARB) reduced albuminuria, attenuated kidney pathology and corrected many metabolic abnormalities, restoring levels of lactate toward normal while increasing kidney ATP content. We also found enhanced expression of lactate dehydrogenase isoforms in DN. Expression of both the LdhA and LdhB isoforms were significantly increased in kidneys of mice, and treatment with ARB significantly reduced their expression. Single-cell sequencing studies showed specific up-regulation of LdhA in the proximal tubule, along with enhanced expression of oxidative stress pathways. There was a significant correlation between albuminuria and lactate in mice, and also in a Southeast Asian patient cohort consisting of individuals with type 2 diabetes and impaired kidney function. In the individuals with diabetes, this association was independent of ARB and angiotensin-converting enzyme inhibitor use. Furthermore, urinary lactate levels predicted the clinical outcomes of doubling of serum creatinine or development of kidney failure, and there was a significant correlation between urinary lactate levels and biomarkers of tubular injury and epithelial stress. Thus, we suggest that kidney metabolic disruptions leading to enhanced generation of lactate contribute to the pathogenesis of DN and increased urinary lactate levels may be a potential biomarker for risk of kidney disease progression.

Single‐grain‐based widely targeted metabolomics profiling of sixty‐four accessions of Japanese wild soybean (Glycin soja Sieb. Et Zucc.)

SummarySoybean (Glycine max L. Merr.) is a major crop worldwide, providing essential dietary proteins and edible oils for agriculture, food, animal feed and biofuel industries. However, its limited genetic variation makes it vulnerable to harsh environmental conditions, and its chemical diversity was strongly reduced after long domestication. Wild soybean (Glycine soja Sieb. et Zucc.), the ancestor of the G. max, possesses a high level of genetic diversity and thus present a precious reservoir for improving cultivated soybean. Characterising metabolomes of different G. soja accessions is crucial in exploring metabolite accumulation patterns for developing metabolic breeding strategies. This study successfully revealed the metabolomes of sixty‐four seed lines of G. soja collected throughout Japan by a widely targeted metabolomics approach, therefore, providing a good source of information for further studies to induce the production of bioactive compounds and the defence mechanism to stress.

Plasma metabolomic signatures of breast cancer.

Breast cancer is a common malignant tumor. A large number of medical evidence shows that breast cancer screening can improve the early diagnosis rate and reduce the mortality rate of breast cancer. In the present study, a wide range of targeted metabolomics profiling was conducted to investigate the plasma signatures of breast cancer. A total of 86 patients with benign breast abnormalities (L group) and 143 patients with breast cancer (E group) were recruited. We collected their plasma samples and clinical information. Metabolomic analysis, based on the coverage of a wide range of targeted metabolomics was conducted with ultraperformance liquid chromatography- triple quadrupole-linear ion trap mass spectrometer (UPLC-QTRAP-MS). We identified 716 metabolites through widely-targeted metabolomics. Serotonergic synapse was the main different metabolic pathway. The fold change of 14 metabolites was considered significantly different (fold change <0.67 or fold change >2; p < 0.05). By combining all the 14 metabolites, we achieved differentiation of L group vs. E group (AUC = 0.792, 95%Cl: 0.662-0.809). This study provided new insights into plasma biomarkers for differential diagnosis of benign abnormalities and breast cancer.

Discovery and validation of circulating stroke metabolites by NMR-based analyses using patients from the MISS and UK Biobank

BackgroundStroke is a significant health issue in the United States, and identifying biomarkers for the prevention and functional recovery after an acute stroke remains the highest priority. This study aims to identify circulating metabolite signatures that may be associated with stroke pathophysiology by performing discovery and validation studies. MethodsWe performed targeted metabolomics profiling of 420 participants of the discovery dataset of Metabolome in an Ischemic Stroke Study (MISS) using high-throughput nuclear magnetic resonance (NMR) spectroscopy. A validation study of significantly altered metabolites was conducted using an independent cohort of 117,988 participants from the UK Biobank, whose metabolomics profiles were generated using the same NMR technology. Results and conclusionOur study identified 16 metabolites to be significantly perturbed during acute stroke. Amino acid phenylalanine was significantly increased, while glutamine and histidine were significantly lowered in stroke. Serum levels of apolipoprotein A-1, HDL particles, small HDL particles, essential fatty acids, and phosphatidylcholine were reduced, while ketone bodies like 3-hydroxybutyrate and acetoacetate were markedly increased in stroke. Based on the robust validation in a large independent UK Biobank dataset, some of these analytes may become clinically meaningful biomarkers to predict or prevent stroke in humans.

Inulin intervention attenuates hepatic steatosis in rats via modulating gut microbiota and maintaining intestinal barrier function

Increasing evidence has suggested the mitigatory efficacy of prebiotic inulin on nonalcoholic fatty liver disease (NAFLD), nevertheless, its action mechanisms remain elusive. Herein, inulin consumption effectively ameliorated high-sucrose diet-induced hepatic steatosis and inflammation, and rehabilitated liver lipogenesis regulators, including carbohydrate response element-binding protein, stearoyl-CoA desaturase-1 and peroxisome proliferator-activated receptor alpha. Furthermore, inulin supplementation restored the intestinal barrier integrity and function by up-regulating expressions of tight junction proteins (zonula occludens-1, claudin-1 and occludin). High-throughput sequencing demonstrated that inulin administration regulated the gut microbiota composition, wherein abundance of short-chain fatty acid (SCFA)-producers, including Bifidobacterium, Phascolarctobacterium and Blautia, was significantly enhanced in the inulin-treated rats, conversely, opportunistic pathogens, such as Acinetobacter and Corynebacterium_1, were suppressed. SCFA quantitative analysis showed that dietary inulin suppressed faecal acetate levels, but improved propionate and butyrate concentrations in rats with NAFLD. Functional prediction showed that tryptophan metabolism was one of the key metabolic pathways affected by gut microbiota changes. A targeted metabolomics profiling of tryptophan metabolism demonstrated that inulin intervention up-regulated faecal contents of indole-3-acetic acid and kynurenic acid, whereas down-regulated levels of kynurenine and 5-hydoxyindoleacetic acid in NAFLD rats. Therefore, this study demonstrated that inulin intake alleviated hepatic steatosis likely by regulating the gut microbiota composition and function and restoring the intestinal barrier integrity, which may provide a novel notion for the prevention and treatment of NAFLD in future.

Interactions between brain and bile acid ratio profiles predict baseline cognitive status

AbstractBackgroundAlterations in the brain‐gut microbiome system are thought to play an important role in the development of neurodegenerative diseases. While the great majority of secreted primary bile acids (BAs) are reabsorbed in the ileum, about 5% are metabolized by gut microbes and reabsorbed. Alterations in secondary BAs metabolism associated with specific gut‐microbial species, and reflected in altered ratios of primary and secondary BAs have recently been linked with brain atrophy and cognitive decline. The aim of this study was to investigate whether interactions between brain‐derived morphometric phenotypes and BA profiles can predict baseline cognitive status (cognitively normal (CN), mild cognitive impairment (MCI), Dementia (AD)) or conversion status (MCI to AD).MethodThe sample included 1013 CN, MCI, and AD participants from the Alzheimer’s Disease Neuroimaging Initiative cohort. Regional brain morphometry was derived using Freesurfer v5.1 and Desikan‐Killany atlas. Targeted metabolomics profiling quantifed concentrations of 20 BAs from serum samples. Analysis was performed using Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO). Data was split into a training and test sets (70/30 split) to determine predictive accuracy.ResultA correlated brain and BA ratio signature predicted cognitive status (CN vs AD) with high predictive accuracy (see Figure 1). The brain signature of AD, compared to CN was characterized by gray matter atrophy in a limited number of regions including the hippocampus, entorhinal cortex, amygdala and medial temporal regions. The BA ratio signature was characterized by higher ratio of glycolithocholic acid and glycodeoxycholic acid to ursodeoxycholic acid, GLCA:UDCA, GDCA:UDCA along with a lower ratio of cholic acid to GLCA in AD. Predicted conversion from MCI to AD at 2 and 4 years had lower predictive accuracy (BER∼ = 34%)ConclusionThese findings demonstrate that interactions between brain signatures and secondary BA profiles predict baseline cognitive status with high accuracy. They support the concept that differences in gut microbial metabolism of certain BAs, possibly related to diet, play a role in shaping the brain signature in AD patients. Compared to previously employed univariate approaches, the supervised multi‐omics multivariate integration approach complements and elucidates the interactions along the brain gut microbiome axis that contribute to AD.

Target Metabolome Profiling-Based Machine Learning as a Diagnostic Approach for Cardiovascular Diseases in Adults.

Metabolomics is a promising technology for the application of translational medicine to cardiovascular risk. Here, we applied a liquid chromatography/tandem mass spectrometry approach to explore the associations between plasma concentrations of amino acids, methylarginines, acylcarnitines, and tryptophan catabolism metabolites and cardiometabolic risk factors in patients diagnosed with arterial hypertension (HTA) (n = 61), coronary artery disease (CAD) (n = 48), and non-cardiovascular disease (CVD) individuals (n = 27). In total, almost all significantly different acylcarnitines, amino acids, methylarginines, and intermediates of the kynurenic and indolic tryptophan conversion pathways presented increased (p &lt; 0.05) in concentration levels during the progression of CVD, indicating an association of inflammation, mitochondrial imbalance, and oxidative stress with early stages of CVD. Additionally, the random forest algorithm was found to have the highest prediction power in multiclass and binary classification patients with CAD, HTA, and non-CVD individuals and globally between CVD and non-CVD individuals (accuracy equal to 0.80 and 0.91, respectively). Thus, the present study provided a complex approach for the risk stratification of patients with CAD, patients with HTA, and non-CVD individuals using targeted metabolomics profiling.

Kynurenic acid as a biochemical factor underlying the association between Western-style diet and depression: A cross-sectional study.

Consumption of a Western-style diet (WS-diet), high in saturated fat and added sugar, is associated with increased depression risk. However, the physiological mechanisms underlying the relationship requires elucidation. Diet can alter tryptophan metabolism along the kynurenine pathway (KP), potentially linking inflammation and depression. This study aimed to examine whether urinary inflammatory markers and KP metabolites differed according to WS-diet consumption and depression severity. Depression symptoms and habitual WS-diet consumption were assessed in 169 healthy adults aged 17–35 recruited from two experimental studies. Targeted metabolomics profiling of seven KP metabolites, ELISA-based assays of interleukin-6 (IL-6) and C-reactive protein (CRP) were performed using urine samples collected from the participants. Parametric tests were performed for group comparison and associations analysis. Multilevel mixed-effect modelling was applied to control for biases. Higher intake of WS-diet was associated with lower levels of neuroprotective kynurenic acid (KA; R = −0.17, p = 0.0236). There were no differences in IL-6 or CRP across diet groups (p > 0.05). Physical activity had negative associations with most KP metabolites. Mixed-effects regression analysis showed the glutamatergic inhibitor, KA, was the only biomarker to have a significant association with depression symptoms in a model adjusted for demographic and lifestyle variables: a unit increase in KA was associated with 0.21 unit decrease in Depression Anxiety and Stress Scale-21 depression score (p = 0.009). These findings suggest that urinary KA is associated with both habitual WS-diet intake, and levels of depression symptoms, independent of inflammation. Findings support the role of neuroprotection and glutamatergic modulation in depression. We propose that KA may act as endogenous glutamatergic inhibition in regulating depression severity in the absence of inflammation. Further comparison with blood-based markers will assist in validating the utility of non-invasive urine samples for measuring KP metabolites.

Targeted bile acid profiles reveal the liver injury amelioration of Da-Chai-Hu decoction against ANIT- and BDL-induced cholestasis.

Multiple types of liver diseases, particularly cholestatic liver diseases (CSLDs) and biliary diseases, can disturb bile acid (BA) secretion; however, BA accumulation is currently seen as an important incentive of various types of liver diseases’ progression. Da-Chai-Hu decoction (DCHD) has long been used for treating cholestatic liver diseases; however, the exact mechanisms remain unclear. Currently, our study indicates that the liver damage and cholestasis status of the α-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis and bile duct ligation (BDL)-induced extrahepatic cholestasis, following DCHD treatment, were improved; the changes of BA metabolism post-DCHD treatment were investigated by targeted metabolomics profiling by UPLC-MS/MS. DCHD treatment severely downregulated serum biochemical levels and relieved inflammation and the corresponding pathological changes including necrosis, inflammatory infiltration, ductular proliferation, and periductal fibrosis in liver tissue. The experimental results suggested that DCHD treatment altered the size, composition, and distribution of the BAs pool, led the BAs pool of the serum and liver to sharply shrink, especially TCA and TMCA, and enhanced BA secretion into the gallbladder and the excretion of BAs by the urinary and fecal pathway; the levels of BAs synthesized by the alternative pathway were increased in the liver, and the conjugation of BAs and the pathway of BA synthesis were actually affected. In conclusion, DCHD ameliorated ANIT- and BDL-induced cholestatic liver injury by reversing the disorder of BAs profile.

Widely Targeted Metabolomics Profiling Reveals the Effect of Powdery Mildew on Wine Grape Varieties with Different Levels of Tolerance to the Disease.

Powdery mildew is an economic threat for viticulture because it not only affects grape yield, but also causes a series of impacts on the qualities of fruit and wine, especially the flavors and various metabolites. Different grape varieties may have different levels of powdery mildew resistance/tolerance and their components of their metabolome are also various. In this study, two wine grape varieties, Guipu No.6 (GP6) and Marselan (Mar) with different levels of powdery mildew tolerance, were used to compare the quality differences in metabolism level by using the widely targeted metabolomics method. The results show that GP6 has a better powdery mildew leaf tolerance than Mar. A total of 774 metabolites were detected by using a UPLC-QQQ-MS-based metabolomics approach, and 57 differential metabolites were identified as key metabolites that were accumulated after infection with powdery mildew in GP6 and Mar, including phenolic acids, flavonoids, terpenoids, stilbenes, lipids, nucleotides and derivatives, lignans and coumarins, and quinones. This finding indicates that the defense mechanisms of grape fruit are mainly associated with phenylpropane-flavonoid metabolism. Specifically, stilbenes had greater variations after powdery mildew infection in GP6; while in Mar, the variations of flavonoids, especially kaempferol-3-O-glucuronide and luteolin-7-O-glucuronide, were more remarkable. The above results demonstrate that stilbenes may play a more important role than flavonoids in resisting powdery mildew infection in GP6’s fruits, and the drastic variations of these phenolic compounds in different wine grapes after powdery mildew infection might also lead to quality difference in the flavors. This study can provide new insights into the understanding of the cause of powdery mildew tolerance in different grape varieties and the effects on the quality of wine grapes infected with the disease exerted by metabolism level.

Dietary alfalfa powder supplementation improves growth and development, body health, and meat quality of Tibetan sheep

The application of alfalfa powder (AP) in Tibetan sheep to explore its healthy effects and meat quality improvement potential has not been reported. Our study found that AP improved the growth performance, serum metabolism, and antioxidation of Tibetan sheep. The edible quality, sensory quality, and nutritional quality of longissimus dorsi (LD) were analyzed. We observed lower drip loss and hue angle of meat after AP supplementation. AP also increased the cooked meat percentage, pH24h, a*24h, chroma24h, and the contents of protein and fat. The targeted metabolomics profiling revealed that the contents of essential amino acids and flavor amino acids in mutton increased by AP treatments. AP also promoted the deposition of MUFA and PUFA. Therefore, as a promising botanical supplement, AP has a positive effect on the growth, development, and body health of Tibetan sheep, and is also conductive to providing healthy and nutritious high-quality livestock products.

Characterization of antipsychotic medications, amino acid signatures, and platelet-activating factor in first-episode psychosis

First-episode psychosis refers to individuals early in the course of psychotic illness. Identifying the underlying biological processes, including biomarkers, is essential for improving diagnosis and treatment. We performed metabolomics profiling of plasma from a group of first-episode psychosis patients and matched neurotypical controls. Using global metabolomics profiling, we identified antipsychotic or antidepressant medication in 22 individuals diagnosed with first-episode psychosis, closely matching the drug prescription history. There were significant differences in levels of amino acids or their derivatives, including decreases in D L -arginine, L -histidine, DL-serine and threonine as well as increases in L -glutamic acid, ornithine, and proline. Using targeted metabolomics profiling of 408 compounds in plasma samples we identified significant differences in six compounds including decreases in serotonin and arginine as well as increased levels of sarcosine, proline, cis-4-hydroxyproline and trans-4-hydroxyproline. Platelet-activating factor levels were significantly elevated in the FEP cohort. These findings suggest potential biomarkers that require validation in independent cohorts, and in several cases provide supporting evidence for previously reported observations.

Targeted Metabolomics Reveals Birth Screening Biomarkers for Biliary Atresia in Dried Blood Spots

Early diagnosis and timely surgical Kasai portoenterostomy greatly improve the survival of patients with biliary atresia (BA), a neonatal cholestatic disease, which has encouraged investigators to develop newborn screening for BA. In this study, we used ultraperformance liquid chromatography-triple quadrupole mass spectrometry-based targeted metabolomics profiling to identify potential BA biomarkers in dried blood spots (DBS) collected from BA patients (n = 21) and healthy controls (n = 100). A distinctive metabolic profile comprising eight significantly differentially expressed metabolites, taurohyocholic acid (THCA), glutamic acid, 2-hydroxyglutaric acid, ketoleucine, indoleacetic acid, alpha-ketoisovaleric acid, glycocholic acid, and taurocholic acid (TCA), clearly distinguished BA infants from control neonates. Three metabolites, THCA, 2-hydroxyglutaric acid, and indoleacetic acid, were selected using linear regression and receiver operating characteristic (ROC) curve analysis and model construction. The area under the ROC curve for this model to discriminate between BA and comparison infants was 0.938 (95% confidence interval, CI: 0.874-1.000). A cutoff value of -0.336 produced a sensitivity of 90.48% (95% CI: 69.62% - 98.83%) and specificity of 92% (95% CI: 84.84% - 96.48%). In conclusion, the results suggest that metabolic markers in DBS obtained from newborns have a great potential for BA screening.

The use of widely targeted metabolomics profiling to quantify differences in medicinally important compounds from five Curcuma (Zingiberaceae) species

The genus Curcuma is widely recognized for its diversity of medicinal and culinary uses yet metabolomic differences among Curcuma species are largely unknown, due to the lack of broadly targeted analytical studies. Here, Ultra-Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (UPLC-MS/MS) analysis was employed to interrogate the metabolomes of five Curcuma species which are commonly used in Chinese herbal medicine (C. aromatica, C. elata, C. longa, C. caesia and C. phaeocaulis). By processing these results through a pathway enrichment analysis, 432 metabolites (some associated with the curcumin pathway) were identified that varied by species. The quantity of curcuminoids in C. longa were found to be higher than that in the other four Curcuma species analyzed in this study. In addition, C. longa was found to have a greater diversity of phenolic acids, amino acid derivatives, and flavonoids associated with the curcumin biosynthesis pathway. However, medicinal compounds such as 6-gingerol were found in lower quantities in C. longa compared to all other species in this study. This study provides new insights into Curcuma phytochemical pathways and allows for the development of functional foods tailored to specific needs from these species.

Biogeography of the large intestinal mucosal and luminal microbiome in cynomolgus macaques with depressive-like behavior

Most previous studies in the pathophysiology of major depressive disorder (MDD) focused on fecal samples, which limit the identification of the gut mucosal and luminal microbiome in depression. Here, we address this knowledge gap. Male cynomolgus macaques (Macaca fascicularis) were randomly assigned to a chronic unpredictable mild stress (CUMS) group, or to an unstressed control group. Behavioral tests were completed in both groups. At endpoint, microbe composition of paired mucosal and luminal samples from cecum, ascending, transverse, and descending colons were determined by 16S ribosomal RNA gene sequencing. The levels of 34 metabolites involved in carbohydrate or energy metabolism in luminal samples were measured by targeted metabolomics profiling. CUMS macaques demonstrated significantly more depressive-like behaviors than controls. We found differences in mucosal and luminal microbial composition between the two groups, which were characterized by Firmicutes and Bacteriodetes at the phylum level, as well as Prevotellaceae and Lachnospiraceae at the family level. The majority of discriminative microbes correlated with the depressive-like behavioral phenotype. In addition, we found 27 significantly different microbiome community functions between the two groups in mucosa, and one in lumen, which were mainly involved in carbohydrate and energy metabolism. A total of nine metabolites involved in these pathways were depleted in CUMS animals. Together, CUMS macaques with depressive-like behaviors associated with distinct alterations of covarying microbiota, carbohydrate and energy metabolism in mucosa and lumen. Further studies should focus on the mucosal and luminal microbiome to provide a deeper spatiotemporal perspective of microbial alterations in the pathogenesis of MDD.