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Recent investigations have revealed that the human microbiome plays an essential role in the occurrence of type 2 diabetes (T2D). However, despite the importance of understanding the involvement of the microbiota throughout the body in T2D, most studies have focused specifically on the intestinal microbiota. Extracellular vesicles (EVs) have been recently found to provide important evidence regarding the mechanisms of T2D pathogenesis, as they act as key messengers between intestinal microorganisms and the host. Herein, we explored microorganisms potentially associated with T2D by tracking changes in microbiota-derived EVs from patient urine samples collected three times over four years. Mendelian randomization analysis was conducted to evaluate the causal relationships among microbial organisms, metabolites, and clinical measurements to provide a comprehensive view of how microbiota can influence T2D. We also analyzed EV-derived metagenomic (N = 393), clinical (N = 5032), genomic (N = 8842), and metabolite (N = 574) data from a prospective longitudinal Korean community-based cohort. Our data revealed that GU174097_g, an unclassified Lachnospiraceae, was associated with T2D (β = −189.13; p = 0.00006), and it was associated with the ketone bodies acetoacetate and 3-hydroxybutyrate (r = −0.0938 and −0.0829, respectively; p = 0.0022 and 0.0069, respectively). Furthermore, a causal relationship was identified between acetoacetate and HbA1c levels (β = 0.0002; p = 0.0154). GU174097_g reduced ketone body levels, thus decreasing HbA1c levels and the risk of T2D. Taken together, our findings indicate that GU174097_g may lower the risk of T2D by reducing ketone body levels.

Obesity-mediated hypoxic stress underlies inflammatory responses, including interferon (IFN)-γ production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-γ production remain obscure. We demonstrate that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in hypertrophic adipocytes, leading to NK cell recruitment. Interestingly, the spatial proximity between NK cells and xCT-expressing adipocytes increases IFN-γ production by stimulating metabotropic glutamate receptor 5 (mGluR5) in NK cells, and IFN-γ further augments the expression of xCT and CXCL12 in adipocytes. Consequently, this vicious cycle promotes adipose tissue expansion and inflammation. In contrast, genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells combats obesity and hepatic steatosis and improves glucose tolerance in male mice. Our findings posit that adipose glutamate-induced activation of mGluR5 in NK cells is a novel therapeutic target in obesity-related metabolic disorders.

Downstream mechanisms that lead to podocyte injury following phospholipase A2 receptor (PLA2R) autoimmunity remain elusive. To help define this we compared urinary metabolomic profiles of patients with PLA2R-associated membranous nephropathy (MN) at the time of kidney biopsy with those of patients with minimal change disease (MCD) and to healthy individuals. Among the metabolites differentially expressed in patients with PLA2R-associated MN compared to healthy individuals, fumarate was the only significant differentially expressed metabolite in PLA2R-associated MN compared to MCD [fold-difference vs. healthy controls and vs. MCD: 1.76 and 1.60, respectively]. High urinary fumarate levels could predict the composite outcome of PLA2R-associated MN. Fumarate hydratase, which hydrolyzes fumarate, colocalized with podocalyxin, and its expression was lower in glomerular sections from patients with PLA2R-associated MN than in those from healthy individuals, patients with non-PLA2R-associated MN or MCD. Podocytes stimulated with IgG purified from serum with a high anti-PLA2R titer (MN-IgG) decreased expression of fumarate hydratase and increased fumarate levels. These changes were coupled to alterations in the expression of molecules involved in the phenotypic profile of podocytes (WT1, ZO-1, Snail, and fibronectin), an increase in albumin flux across the podocyte layer and the production of reactive oxygen species in podocytes. However, overexpression of fumarate hydratase ameliorated these alterations. Furthermore, knockdown of fumarate hydratase exhibited synergistic effects with MN-IgG treatment. Thus, fumarate may promote changes in the phenotypic profiles of podocytes after the development of PLA2R autoimmunity. These findings suggest that fumarate could serve as a potential target for the treatment of PLA2R-associated MN.

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia., Ageing leads to a loss of muscle mass and strength, called sarcopenia. Here, the authors show that fatty acid binding protein 3 (FABP3), a lipid chaperone, drives age-dependent lipidome remodeling in skeletal muscle and deteriorates muscle mass and contractility by modulating membrane fluidity and ER stress signaling.

To explore how bariatric surgery (BS) modified the obesity-associated gut microbiome, the host metabolome, and their interactions in obese Korean patients.Stool and fasting blood samples were obtained before and 1, 3, 6, and 12 months after BS from 52 patients enrolled in the Korean Obesity Surgical Treatment Study. We analysed the gut microbiome by 16S rRNA gene sequencing and the serum metabolome, including bile acids, by nuclear magnetic resonance spectroscopy and ultrahigh-performance liquid chromatography/triple quadrupole mass spectrometry.Stool metagenomics showed that 27 microbiota were enriched and 14 microbiota were reduced after BS, whereas the abundances and diversity of observed features were increased. The levels of branched-chain amino acids and metabolites of energy metabolism in serum were decreased after surgery, whereas the levels of metabolites related to microbial metabolism, including dimethyl sulphone, glycine, and secondary bile acids, were increased in the serum samples. In addition, we found notable mutual associations among metabolites and gut microbiome changes attributed to BS.Changes in the gut microbiome community and systemic levels of amino acids and sugars were directly derived from anatomical changes in the gastrointestinal tract after BS. We hypothesized that the observed increases in microbiome-related serum metabolites were a result of complex and indirect changes derived from BS. Ethnic-specific environmental or genetic factors could affect Korean-specific postmetabolic modification in obese patients who undergo BS.

Persistent organic pollutants (POPs) are lipophilic environmental toxins, and the level of chemicals accumulated in the body through the food chain has been linked to the incidence of diseases such as type 2 diabetes, cardiovascular disease, and cancer. We analyzed the concentration of POPs and circulating metabolites and investigated the associations between the concentration of plasma metabolites and the levels of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) to determine the effect of the accumulation of POPs in human samples. Metabolic profiling of plasma from 276 Korean participants was performed using

Integrative multi-omics analysis has become a useful tool to understand molecular mechanisms and drug discovery for treatment. Especially, the couplings of genetics to metabolomics have been performed to identify the associations between SNP and metabolite. However, while the importance of integrative pathway analysis is increasing, there are few approaches to utilize pathway information to analyze phenotypes using SNP and metabolite. We propose an integrative pathway analysis of SNP and metabolite data using a hierarchical structural component model considering the structural relationships of SNPs, metabolites, pathways, and phenotypes. The proposed method utilizes genome-wide association studies on metabolites and constructs the genetic risk scores for metabolites referred to as genetic metabolomic scores. It is based on the hierarchical model using the genetic metabolomic scores and pathways. Furthermore, this method adopts a ridge penalty to consider the correlations between genetic metabolomic scores and between pathways. We apply our method to the SNP and metabolite data from the Korean population to identify pathways associated with type 2 diabetes (T2D). Through this application, we identified well-known pathways associated with T2D, demonstrating that this method adds biological insights into disease-related pathways using genetic predispositions of metabolites.

The authors have requested that this preprint be removed from Research Square.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage kidney disease. Renin&ndash, angiotensin system inhibitors such as losartan are the predominant therapeutic options in clinical practice to treat DKD. Therefore, it is necessary to identify DKD-related metabolic profiles that are affected by losartan. To investigate the change in metabolism associated with the development of DKD, we performed global and targeted metabolic profiling using 800 MHz nuclear magnetic resonance spectroscopy of urine samples from streptozotocin-induced diabetic mice (DM) with or without losartan administration. A principal component analysis plot showed that the metabolic pattern in the losartan-treated diabetic mice returned from that in the DM group toward that in the control mice (CM). We found that 33 urinary metabolites were significantly changed in DM compared with CM, and the levels of 16 metabolites among them, namely, glucose, mannose, myo-inositol, pyruvate, fumarate, 2-hydroxyglutarate, isobutyrate, glycine, threonine, dimethylglycine, methyldantoin, isoleucine, leucine, acetylcarnitine, 3-hydroxy-3-methylglutarate, and taurine, shifted closer to the control level in response to losartan treatment. Pathway analysis revealed that these metabolites were associated with branched-chain amino acid degradation, taurine and hypotaurine metabolism, glycine, serine, and threonine metabolism, the tricarboxylic acid cycle, and galactose metabolism. Our results demonstrate that metabolomic analysis is a useful tool for identifying the metabolic pathways related to the development of DKD affected by losartan administration and may contribute to the discovery of new therapeutic agents for DKD.

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) affects obese and non-obese individuals. However, mechanisms underlying non-obese non-alcoholic steatohepatitis (NASH) remain unclear. AIMS To attempt to identify metabolic perturbations associated with non-obese and obese NAFLD using a lipidomics approach. METHODS A cross-sectional analysis of 361 subjects with biopsy-proven NAFLD (157 NAFL and 138 NASH) and healthy controls (n = 66) was performed. Individuals were categorised as obese or non-obese based on the Asian cut-off for body mass index. Circulating lipidomic profiling of sera was performed based on the histological severity of NAFLD. Circulating lipidomic alterations were validated with an independent validation set (154 NAFLD subjects [93 NAFL and 61 NASH] and 21 healthy controls). RESULTS Saturated sphingomyelin (SM) species were significantly associated with visceral adiposity in non-obese NAFLD (SM d38:0; P

During pregnancy, dysbiosis in the vaginal microbiota directly affects the metabolic profiles, which might impact preterm birth (PTB). In this study, we performed cervicovaginal fluid (CVF) metabolic profiling using nuclear magnetic resonance (NMR) spectroscopy and identified the metabolic markers for predicting PTB. In this nested case-control study, 43 South Korean pregnant women with PTB (n = 22), and term birth (TB, n = 21) were enrolled with their demographic profiles, and CVF samples were collected by vaginal swabs. The PTB group had two subgroups based on post-CVF sampling birth: PTB less than (PTB &lt, 7 d) and more than 7 days (PTB &ge, 7 d). We observed significant differences in the gestational age at birth (GAB), cervical length (CL), and neonatal birth weight among the groups. The principal component analysis (PCA), and partial least square discriminant analysis (PLS-DA) scatter plot showed the separation between the PTB &lt, 7 d group, and the TB group. Out of 28 identified metabolites, acetone, ethanol, ethylene glycol, formate, glycolate, isopropanol, methanol, and trimethylamine N-oxide (TMAO) were significantly increased in the PTB group compared with the TB group. The ROC curve analysis revealed that the acetone, ethylene glycol, formate, glycolate, isopropanol, methanol, and TMAO had the best predictive values for PTB. Additionally, the correlation analysis of these metabolites showed a strong negative correlation with GAB and CL. These metabolites could be beneficial markers for the clinical application of PTB prediction.

Metabolomics is a powerful tool for the investigation of interactions between diet, nutrients, and human metabolism. Ecklonia cava is an edible brown alga that is abundantly found in Korea and Japan and contains unique polyphenols referred to as phlorotannins. However, there are few metabolomics studies related to the effects of polyphenols in humans. In this study, we performed a mass spectrometry-based metabolomics analysis of urine samples from participants with a body mass index (BMI) higher than 25 kg/m2 and lower than 30 kg/m2 to investigate the effects of the intake of seapolynol isolated from E. cava. Metabolomic profiling showed that the levels of riboflavin, urocanic acid, 5-hydroxy-6-methoxyindole glucuronide, and guanidino valeric acid were significantly increased in the seapolynol intake group compared with the placebo group. A correlation analysis was performed to identify the association between the metabolites’ levels and clinical characteristics related to body fat. Among the metabolites whose concentrations changed in the seapolynol intake group, riboflavin was associated with BMI, body weight, fat mass, and percent body fat. These findings suggest that the decreased body fat induced by the intake of seapolynol is related to an increase in the antioxidant effect of riboflavin.

In the current study, the metabolic effects of atorvastatin dose escalation versus atorvastatin/fenofibric acid combination were compared using metabolomics analyses. Men and women with combined hyperlipidaemia were initially prescribed atorvastatin (10 mg, ≥4 weeks). Patients who reached low-density lipoprotein-cholesterol targets, but had triglyceride and high-density lipoprotein-cholesterol levels ≥150 mg/dL and l-carnitine remarkably increased in the combination group. In conclusion, the atorvastatin/fenofibric acid combination induced distinct metabolite clustering. Our results provide comprehensive information regarding metabolic changes beyond conventional lipid profiles for this combination therapy.

Xanthii Fructus (XF) is known as a medicinal plant. It has been used as a traditional medicine because of its high biological efficacy. However, there have been few comprehensive studies on the specific chemical composition of the plant and consequently, the information is lacking for the mechanism of the natural product metabolites in humans. In this study, an efficient analytical method to characterize and discriminate two species of Xanthii Fructus (Xanthium canadense Mill. and Xanthium sibiricum Patrin ex Widder) was established. Volatile organic compounds (VOCs), polar metabolites, and fatty acids were classified by integrated sample preparation, which allowed a broad range for the detection of metabolites simultaneously. Gas chromatography-mass spectrometry (GC-MS) followed by a multivariate statistical analysis was employed to characterize the chemical compositions and subsequently to discriminate between the two species. The results demonstrate that the two species possess obviously diverse chemical characteristics of three different classifications, and discriminant analysis was successfully applied to a number of chemical markers that could be used for the discrimination of the two species. Additional quantitative results for the selected chemical markers consistently showed significant differences between the two species.

New class of superlattice nanohybrids of interstratified graphitic-carbon nitride (g-C3N4)–transition metal dichalcogenide monolayers are synthesized by employing pH-controlled g-C3N4 nanosheet (NS) as an emerging cationic building block. The interstratification of g-C3N4 and MoS2 NSs leads to strong interfacial electronic coupling, creation of nitrogen vacancy, and stabilization of 1T′-MoS2 phase. The superlattice g-C3N4–MoS2 nanohybrids display remarkably enhanced bifunctionality as photocatalysts for visible light-induced N2 fixation and electrocatalysts for hydrogen evolution. Of prime importance is that the creation of nitrogen vacancy results in the significant improvement of selectivity for photocatalytic N2 fixation (582 μmolL−1h−1) over competitive photocatalytic H2 generation. This is attributable to promoted adsorption of nitrogen, provision of many active sites, and enhancement of charge transfer kinetics, charge separation, and visible light absorptivity. This study highlights that the application of g-C3N4 NS as a cationic building block provides valuable opportunity to widen the library of multifunctional NS-based superlattice nanohybrids.

Metabolomics is a powerful tool for the investigation of interactions between diet, nutrients, and human metabolism. Ecklonia cava is an edible brown alga that is abundantly found in Korea and Japan and contains unique polyphenols referred to as phlorotannins. However, there are few metabolomics studies related to the effects of polyphenols in humans. In this study, we performed a mass spectrometry-based metabolomics analysis of urine samples from participants with a body mass index (BMI) higher than 25 kg/m2 and lower than 30 kg/m2 to investigate the effects of the intake of seapolynol isolated from E. cava. Metabolomic profiling showed that the levels of riboflavin, urocanic acid, 5-hydroxy-6-methoxyindole glucuronide, and guanidino valeric acid were significantly increased in the seapolynol intake group compared with the placebo group. A correlation analysis was performed to identify the association between the metabolites&rsquo, levels and clinical characteristics related to body fat. Among the metabolites whose concentrations changed in the seapolynol intake group, riboflavin was associated with BMI, body weight, fat mass, and percent body fat. These findings suggest that the decreased body fat induced by the intake of seapolynol is related to an increase in the antioxidant effect of riboflavin.

Inflammation is a common cause of cardiac arrhythmia. Angiotensin ІІ (Ang ІІ) is a major contributing factor in the pathogenesis of cardiac inflammation; however, its underlying molecular mechanism remains unclear. Here, we explored the effect of Ang ІІ on inflammatory mechanisms and oxidative stress using HL-1 atrial myocytes. We showed that Ang ІІ activated c-Jun N-terminal kinase (JNK) phosphorylation and other inflammatory markers, such as transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α). Ang ІІ decreased oxygen consumption rate, which resulted in reactive oxygen species (ROS) generation and inhibition of ROS blocked Ang II-mediated JNK phosphorylation and TGF-β1 induction. Ang ІІ induced the expression of its specific receptor, AT1R. Ang II-induced intracellular calcium production associated with Ang ІІ-mediated signalling pathways. In addition, the generated ROS and calcium stimulated AMPK phosphorylation. Inhibiting AMPK blocked Ang II-mediated JNK and TGF-β signalling pathways. Ang ІІ concentration, along with TGF-β1 and tumor necrosis factor-α levels, was slightly increased in plasma of patients with atrial fibrillation. Taken together, these results suggest that Ang ІІ induces inflammation mechanisms through an AMPK-related signalling pathway. Our results provide new molecular targets for the development of therapeutics for inflammation-related conditions, such as atrial fibrillation.

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver disease and its prevalence is a serious and growing clinical problem. Caloric restriction (CR) is commonly recommended for improvement of obesity-related diseases such as NAFLD. However, the effects of CR on hepatic metabolism remain unknown. We investigated the effects of CR on metabolic dysfunction in the liver of obese diabetic db/db mice. We found that CR of db/db mice reverted insulin resistance, hepatic steatosis, body weight and adiposity to those of db/m mice. 1H-NMR- and UPLC-QTOF-MS-based metabolite profiling data showed significant metabolic alterations related to lipogenesis, ketogenesis, and inflammation in db/db mice. Moreover, western blot analysis showed that lipogenesis pathway enzymes in the liver of db/db mice were reduced by CR. In addition, CR reversed ketogenesis pathway enzymes and the enhanced autophagy, mitochondrial biogenesis, collagen deposition and endoplasmic reticulum stress in db/db mice. In particular, hepatic inflammation-related proteins including lipocalin-2 in db/db mice were attenuated by CR. Hepatic metabolomic studies yielded multiple pathological mechanisms of NAFLD. Also, these findings showed that CR has a therapeutic effect by attenuating the deleterious effects of obesity and diabetes-induced multiple complications.

Cornus officinalis (Cornaceae) is primarily grown in Asian countries. The pericarp of C. officinalis (Corni Fructus) is a well-known traditional medicine with tonic, analgesic, and diuretic properties. We analyzed methanolic extracts of Corni Fructus (grown in Korea and China) by NMR spectroscopy. Metabolite profiling was performed to characterize the metabolic difference between different Corni Fructus origins (Korea or China). Principal components analysis revealed significant separation between Comus Fructus from different origins. The metabolites responsible for differences were identified using loading plots, coefficients plots, and variable influence on projection followed by t-tests. As a result, 16 metabolites were identified and quantified; tyrosine, acetate, sucrose, and malate differed the most between origins. These data suggest that NMR-based metabolomics can be used to identify differences between Corni Fructus samples obtained from different regions.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is increasing worldwide. One method used to restore sinus rhythm is direct current cardioversion (DCCV). Despite the high success rate of DCCV, AF typically recurs within the first 2 weeks. However, our understanding of the pathophysiology of AF recurrence, incidence, and progression are highly limited. Lipidomic profiling was applied to identify altered lipids in plasma from patients with AF using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry coupled with multivariate statistical analysis. Partial least-squares discriminant analysis revealed a clear separation between AF patients and healthy controls. The levels of several lipid species, including fatty acids and phospholipids, were different between AF patients and healthy controls, indicating that oxidative stress and inflammation are associated with the pathogenesis of AF. Similar patterns were also detected between recurrent and non-recurrent AF patients. These results suggest that the elevated saturated fatty acid and reduced polyunsaturated fatty acid levels in AF patients may be associated with enhanced inflammation and that free fatty acid levels may play a crucial role in the development and progression of AF.

Obesity is a multifactorial health problem resulting from genetic, environmental and behavioral factors. A particularly interesting aspect of obesity is the differences observed in response to the same high-fat diet (HFD). In this study, we performed lipidomic profiling on livers from HFD-fed C57BL/6J mice using ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry. Mice were divided into three groups: normal diet (ND), HFD-obesity prone (HFD-OP) and HFD-obesity resistant (HFD-OR). Principal components analyses showed a difference between the HFD-OP and HFD-OR groups. Individuals in the HFD-OR group were closer to those in the ND group compared with those in the HFD-OP group. In particular, phosphocholine (PC) and triglyceride (TG) levels differed significantly depending on the length of the acyl chain and degree of unsaturation, respectively. PC species were either positively or negatively correlated with concentrations of glucose, insulin, leptin and hepatic cholesterol according to the length of the acyl chain. Decreased expression of the scavenger receptor B1 and ATP-binding cassette A1 in HFD-OP mice indicated that the acyl chain length of PC species may be related to high-density lipoprotein cholesterol metabolism. This study demonstrates that lipidomic profiling is an effective approach to analyzing global lipid alterations as they pertain to obesity.

Tsutsugamushi disease is an infectious disease transmitted to humans through the bite of the Orientia tsutsugamushi-infected chigger mite; however, host-pathogen interactions and the precise mechanisms of damage in O. tsutsugamushi infections have not been fully elucidated. Here, we analyzed the global metabolic effects of O. tsutsugamushi infection on the host using 1H-NMR and UPLC-Q-TOF mass spectroscopy coupled with multivariate statistical analysis. In addition, the effect of O. tsutsugamushi infection on metabolite concentrations over time was analyzed by two-way ANOVAs. Orthogonal partial least squares-discriminant analysis (OPLS-DA) showed distinct metabolic patterns between control and O. tsutsugamushi-infected mice in liver, spleen, and serum samples. O. tsutsugamushi infection caused decreased energy production and deficiencies in both remethylation sources and glutathione. In addition, O. tsutsugamushi infection accelerated uncommon energy production pathways (i.e., excess fatty acid and protein oxidation) in host body. Infection resulted in an enlarged spleen with distinct phospholipid and amino acid characteristics. This study suggests that metabolite profiling of multiple organ tissues and serum could provide insight into global metabolic changes and mechanisms of pathology in O. tsutsugamushi-infected hosts., Author Summary Scrub typhus is an acute febrile illness caused by attacks of Orientia tsutsugamushi-carrying mites, and is the most prevalent febrile illness in the Asia-Pacific region. If not properly treated with antibiotics, patients often develop severe vasculitis that affects multiple organs, and the mortality rate can reach 30%. To explore the pathogenic mechanisms underlying the host-pathogen interaction, we characterized metabolic changes in various organs and the serum of O. tsutsugamushi-infected hosts. After O. tsutsugamushi infection, the host experienced decreased energy production, as well as a severe deficiency in re-methylation sources and glutathione, which impaired purine synthesis, DNA and protein methylation. In addition, abnormal pathways for phosphatidylcholine (PC) biosynthesis and phosphoethanolamine methylation were utilized in the enlarged spleen of O. tsutsugamushi-infected hosts. These results suggested that metabolic profiling could provide insight into global metabolic changes in O. tsutsugamushi-infected hosts, and increase our understanding of the pathogenic mechanisms of O. tsutsugamushi, as well as providing novel therapeutic targets for scrub typhus.

Curcuma, a genus of rhizomatous herbaceous species, has been used as a spice, traditional medicine, and natural dye. In this study, the metabolite profile of Curcuma extracts was determined using gas chromatography-time of flight mass spectrometry (GC/TOF MS) and ultrahigh-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) to characterize differences between Curcuma aromatica and Curcuma longa grown on the Jeju-do or Jin-do islands, South Korea. Previous studies have performed primary metabolite profiling of Curcuma species grown in different regions using NMR-based metabolomics. This study focused on profiling of secondary metabolites from the hexane extract of Curcuma species. Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) plots showed significant differences between the C. aromatica and C. longa metabolite profiles, whereas geographical location had little effect. A t-test was performed to identify statistically significant metabolites, such as terpenoids. Additionally, targeted profiling using UPLC/Q-TOF MS showed that the concentration of curcuminoids differed depending on the plant origin. Based on these results, a combination of GC- and LC-MS allowed us to analyze curcuminoids and terpenoids, the typical bioactive compounds of Curcuma, which can be used to discriminate Curcuma samples according to species or geographical origin.

Kimchi is a well-known traditional Korean food. Its geographical origins can be determined by its biochemical composition. This study identified the biochemical compositions of kimchi extracts from Korea and China by (1)H nuclear magnetic resonance (NMR) spectroscopy followed by multivariate data analysis. Principal component analyses (PCA) clearly discriminated between extracts prepared in the two countries. The identified metabolites, including amino acids, organic acids, sugars, and ethanol, contributed to discriminating the geographical origin of kimchi extracts. Furthermore, differences in composition by origin were predicted with high accuracy in external validation models. These results establish biochemical profiles for kimchi extracts, and indicate that metabolomics can be used in the discrimination of food origins.

Despite the numerous metabolic studies on obesity, gender bias in obesity has rarely been investigated. Here, we report the metabolomic analysis of obesity by using leptin-deficient ob/ob mice based on the gender. Metabolomic analyses of urine and serum from ob/ob mice compared with those from C57BL/6J lean mice, based on the (1)H NMR spectroscopy in combination with multivariate statistical analysis, revealed clear metabolic differences between obese and lean mice. We also identified 48 urine and 22 serum metabolites that were statistically significantly altered in obese mice compared to lean controls. These metabolites are involved in amino acid metabolism (leucine, alanine, ariginine, lysine, and methionine), tricarbocylic acid cycle and glucose metabolism (pyruvate, citrate, glycolate, acetoacetate, and acetone), lipid metabolism (cholesterol and carnitine), creatine metabolism (creatine and creatinine), and gut-microbiome-derived metabolism (choline, TMAO, hippurate, p-cresol, isobutyrate, 2-hydroxyisobutyrate, methylamine, and trigonelline). Notably, our metabolomic studies showed distinct gender variations. The obese male mice metabolism was specifically associated with insulin signaling, whereas the obese female mice metabolism was associated with lipid metabolism. Taken together, our study identifies the biomarker signature for obesity in ob/ob mice and provides biochemical insights into the metabolic alteration in obesity based on gender.