GC-biased gene conversion drives accelerated evolution of ultraconserved elements in mammalian and avian genomes.

Ultraconserved elements (UCEs) are the most conserved regions among the genomes of evolutionarily distant species and are thought to play critical biological functions. However, some UCEs rapidly evolved in specific lineages, and whether they contributed to adaptive evolution is still controversial. Here, using an increased number of sequenced genomes with high taxonomic coverage, we identified 2191 mammalian UCEs and 5938 avian UCEs from 95 mammal and 94 bird genomes, respectively. Our results show that these UCEs are functionally constrained and that their adjacent genes are prone to widespread expression with low expression diversity across tissues. Functional enrichment of mammalian and avian UCEs shows different trends indicating that UCEs may contribute to adaptive evolution of taxa. Focusing on lineage-specific accelerated evolution, we discover that the proportion of fast-evolving UCEs in nine mammalian and 10 avian test lineages range from 0.19% to 13.2%. Notably, up to 62.1% of fast-evolving UCEs in test lineages are much more likely to result from GC-biased gene conversion (gBGC). A single cervid-specific gBGC region embracing the uc.359 allele significantly alters the expression of Nova1 and other neural-related genes in the rat brain. Combined with the altered regulatory activity of ancient gBGC-induced fast-evolving UCEs in eutherians, our results provide evidence that synergy between gBGC and selection shaped lineage-specific substitution patterns, even in the most constrained regulatory elements. In summary, our results show that gBGC played an important role in facilitating lineage-specific accelerated evolution of UCEs, and further support the idea that a combination of multiple evolutionary forces shapes adaptive evolution.

Chromatin accessibility memory of donor cells disrupts bovine somatic cell nuclear transfer blastocysts development.

The post-transfer developmental capacity of bovine somatic cell nuclear transfer (SCNT) blastocysts is reduced, implying that abnormalities in gene expression regulation are present at blastocyst stage. Chromatin accessibility, as an indicator for transcriptional regulatory elements mediating gene transcription activity, has heretofore been largely unexplored in SCNT embryos, especially at blastocyst stage. In the present study, single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) of in vivo and SCNT blastocysts were conducted to segregate lineages and demonstrate the aberrant chromatin accessibility of transcription factors (TFs) related to inner cell mass (ICM) development in SCNT blastocysts. Pseudotime analysis of lineage segregation further reflected dysregulated chromatin accessibility dynamics of TFs in the ICM of SCNT blastocysts compared to their in vivo counterparts. ATAC- and ChIP-seq results of SCNT donor cells revealed that the aberrant chromatin accessibility in the ICM of SCNT blastocysts was due to the persistence of chromatin accessibility memory at corresponding loci in the donor cells, with strong enrichment of trimethylation of histone H3 at lysine 4 (H3K4me3) at these loci. Correction of the aberrant chromatin accessibility through demethylation of H3K4me3 by KDM5B diminished the expression of related genes (e.g., BCL11B) and significantly improved the ICM proliferation in SCNT blastocysts. This effect was confirmed by knocking down BCL11B in SCNT embryos to down-regulate p21 and alleviate the inhibition of ICM proliferation. These findings expand our understanding of the chromatin accessibility abnormalities in SCNT blastocysts and BCL11B may be a potential target to improve SCNT efficiency.

Convergent molecular evolution of thermogenesis and circadian rhythm in Arctic ruminants.

The muskox and reindeer are the only ruminants that have evolved to survive in harsh Arctic environments. However, the genetic basis of this Arctic adaptation remains largely unclear. Here, we compared a de novo assembled muskox genome with reindeer and other ruminant genomes to identify convergent amino acid substitutions, rapidly evolving genes and positively selected genes among the two Arctic ruminants. We found these candidate genes were mainly involved in brown adipose tissue (BAT) thermogenesis and circadian rhythm. Furthermore, by integrating transcriptomic data from goat adipose tissues (white and brown), we demonstrated that muskox and reindeer may have evolved modulating mitochondrion, lipid metabolism and angiogenesis pathways to enhance BAT thermogenesis. In addition, results from co-immunoprecipitation experiments prove that convergent amino acid substitution of the angiogenesis-related gene hypoxia-inducible factor 2alpha (HIF2A), resulting in weakening of its interaction with prolyl hydroxylase domain-containing protein 2 (PHD2), may increase angiogenesis of BAT. Altogether, our work provides new insights into the molecular mechanisms involved in Arctic adaptation.

3MCor: an integrative web server for metabolome-microbiome-metadata correlation analysis.

MOTIVATION: The metabolome and microbiome disorders are highly associated with human health, and there are great demands for dual-omics interaction analysis. Here, we designed and developed an integrative platform, 3MCor, for metabolome and microbiome correlation analysis under the instruction of phenotype and with the consideration of confounders. RESULTS: Many traditional and novel correlation analysis methods were integrated for intra- and inter-correlation analysis. Three inter-correlation pipelines are provided for global, hierarchical and pairwise analysis. The incorporated network analysis function is conducive to rapid identification of network clusters and key nodes from a complicated correlation network. Complete numerical results (csv files) and rich figures (pdf files) will be generated in minutes. To our knowledge, 3MCor is the first platform developed specifically for the correlation analysis of metabolome and microbiome. Its functions were compared with corresponding modules of existing omics data analysis platforms. A real-world dataset was used to demonstrate its simple and flexible operation, comprehensive outputs and distinctive contribution to dual-omics studies. AVAILABILITYAND IMPLEMENTATION: 3MCor is available at http://3mcor.cn and the backend R script is available at https://github.com/chentianlu/3MCorServer. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Farnesoid X receptor is an important target for the treatment of disorders of bile acid and fatty acid metabolism in mice with nonalcoholic fatty liver disease combined with cholestasis.

BACKGROUND AND AIM: The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rising globally. NAFLD patients combined with cholestasis have more obvious liver fibrosis, impaired bile acid (BA), and fatty acid (FA) metabolism and severer liver injury; however, its therapeutic options are limited, and the underlying metabolic mechanisms are understood. Here, we aimed to investigate the effects of farnesoid X receptor (FXR) on BA and FA metabolism in NAFLD combined with cholestasis and related signaling pathways. METHODS: A mouse model of NAFLD combined with cholestasis was established by joint intervention with high-fat diet (HFD) and alpha-naphthylisothiocyanate. The effects of FXR on BA and FA metabolism were evaluated by serum biochemical analysis. Liver damage was identified by histopathology. The expression of nuclear hormone receptor, membrane receptor, FA transmembrane transporter, and BA transporter protein in mice were measured by western blot. RESULTS: NAFLD mice combined with cholestasis developed more severe cholestasis and dysregulated BA and FA metabolism. Meanwhile, the expression of FXR protein was decreased in NAFLD mice combined with cholestasis compared to the controls. Fxr-/- mice showed liver injury. HFD aggravated the liver injury with decreased BSEP expression, increased expression of NTCP, LXRα, SREBP-1c, FAS, ACC1, and CD36, and significantly increased BA and FA accumulation. CONCLUSION: All the results suggested that FXR plays a key role in both FA and BA metabolism in NAFLD combined with cholestasis and thus may be a potential target for the treatment of disorders of BA and FA metabolism in NAFLD combined with cholestasis.

Convergent Genomic Signatures of Cashmere Traits: Evidence for Natural and Artificial Selection.

Convergent evolution provides powerful opportunities to investigate the genetic basis of complex traits. The Tibetan antelope (Pantholops hodgsonii) and Siberian ibex (Capra sibirica) belong to different subfamilies in Bovidae, but both have evolved similar superfine cashmere characteristics to meet the cold temperature in plateau environments. The cashmere traits of cashmere goats underwent strong artificial selection, and some traces of domestication also remained in the genome. Hence, we investigated the convergent genomic signatures of cashmere traits between natural and artificial selection. We compared the patterns of convergent molecular evolution between Tibetan antelope and Siberian ibex by testing positively selected genes, rapidly evolving genes and convergent amino acid substitutions. In addition, we analyzed the selected genomic features of cashmere goats under artificial selection using whole-genome resequencing data, and skin transcriptome data of cashmere goats were also used to focus on the genes involved in regulating cashmere traits. We found that molecular convergent events were very rare, but natural and artificial selection genes were convergent enriched in similar functional pathways (e.g., ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway) in a variety of gene sets. Type IV collagen family genes (COL4A2, COL4A4, COL4A5, COL6A5, COL6A6) and integrin family genes (ITGA2, ITGA4, ITGA9, ITGB8) may be important candidate genes for cashmere formation and development. Our results provide a comprehensive approach and perspective for exploring cashmere traits and offer a valuable reference for subsequent in-depth research on the molecular mechanisms regulating cashmere development and fineness.

Altered bile acid glycine : taurine ratio in the progression of chronic liver disease.

BACKGROUND AND AIM: The onset and progression of chronic liver disease (CLD) is a multistage process spanning years or several decades. Some bile acid (BA) features are identified as indicators for CLD progression. However, BAs are highly influenced by various factors and are stage and/or population specific. Emerging evidences demonstrated the association of structure of conjugated BAs and CLD progression. Here, we aimed to investigate the alteration of conjugated BAs and identify new features for CLD progression. METHODS: Based on liquid chromatography-mass spectrometry platform, 15 BAs were quantified in 1883 participants including healthy controls and CLD patients (non-alcoholic fatty liver [NAFL], non-alcoholic steatohepatitis [NASH], fibrosis, cirrhosis, and three types of liver cancer). Logistic regression was used to construct diagnostic models. Model performances were evaluated in discovery and test sets by area under the receiver operating characteristic curve, sensitivity, specificity, accuracy, and kappa index. RESULTS: Five BA glycine : taurine ratios were calculated, and glycocholic acid/taurocholic acid, glycodeoxycholic acid/taurodeoxycholic acid, and glycochenodeoxycholic acid/taurochenocholic acid were identified as candidates. Three diagnostic models were constructed for the differentiation of healthy control and early CLD (NAFL + NASH), early and advanced CLD (fibrosis + cirrhosis + liver cancer), and NAFL and NASH, respectively. The areas under the receiver operating characteristic curve of the models ranged from 0.91 to 0.97. The addition of age and gender improved model performances further. The alterations of the candidates and the performances of the diagnostic models were successfully validated by independent test sets (n = 291). CONCLUSIONS: Our findings revealed stage-specific BA perturbation patterns and provided new biomarkers and tools for the monitoring of liver disease progression.

Bile Acid Profiles Are Distinct among Patients with Different Etiologies of Chronic Liver Disease.

A significant increase of bile acid (BA) levels has been recognized as a general metabolic phenotype of diverse liver diseases. Monitoring of BA profiles has been proposed for etiology differentiation on liver injury. Here, we quantitatively profiled serum BAs of healthy controls and 719 patients with chronic liver disease of five etiologies, hepatitis B virus (HBV), hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH), alcohol-induced liver disease (ALD), and primary biliary cirrhosis (PBC), and investigated the generality and specificity of different etiologies. The raw data have been deposited into MetaboLights (ID: MTBLS2459). We found that patients with HBV, HCV, and NASH appeared to be more similar, and ALD and PBC patients clustered together. BA profiles, consisting of a total concentration of the 21 quantified BAs [total BAs (TBAs)], 21 BA proportions, and 24 BA relevant variables, were highly different among the etiologies. Specifically, the total BAs was higher in ALD and PBC patients compared with the other three groups. The proportion of conjugated deoxycholates was the highest in HBV-infected patients. The ratio of 12α-hydroxylated (12α-OH) to non-12α-OH BAs was the highest in NASH patients. The proportion of taurine-conjugated BAs was the highest in ALD patients. For PBC patients, the proportion of ursodeoxycholate species was the highest, and the ratio of primary to secondary BAs was the lowest. Comparatively, the difference of BA profiles among cirrhosis patients was consistent but weaker than that of all patients. The correlations between BA profiles and clinical indices were also quite different in different pathological groups, both in all patients and in patients with cirrhosis. Overall, our findings suggested that BA compositions are distinct among patients with different etiologies of chronic liver disease, and some BA-relevant variables are of clinical potentials for liver injury type differentiation, although further validations on more etiologies and populations are needed.

A Metabolite Array Technology for Precision Medicine.

The application of metabolomics in translational research suffers from several technological bottlenecks, such as data reproducibility issues and the lack of standardization of sample profiling procedures. Here, we report an automated high-throughput metabolite array technology that can rapidly and quantitatively determine 324 metabolites including fatty acids, amino acids, organic acids, carbohydrates, and bile acids. Metabolite identification and quantification is achieved using the Targeted Metabolome Batch Quantification (TMBQ) software, the first cross-vendor data processing pipeline. A test of this metabolite array was performed by analyzing serum samples from patients with chronic liver disease (N = 1234). With high detection efficiency and sensitivity in serum, urine, feces, cell lysates, and liver tissue samples and suitable for different mass spectrometry systems, this metabolite array technology holds great potential for biomarker discovery and high throughput clinical testing. Additionally, data generated from such standardized procedures can be used to generate a clinical metabolomics database suitable for precision medicine in next-generation healthcare.

IP4M: an integrated platform for mass spectrometry-based metabolomics data mining.

BACKGROUND: Metabolomics data analyses rely on the use of bioinformatics tools. Many integrated multi-functional tools have been developed for untargeted metabolomics data processing and have been widely used. More alternative platforms are expected for both basic and advanced users. RESULTS: Integrated mass spectrometry-based untargeted metabolomics data mining (IP4M) software was designed and developed. The IP4M, has 62 functions categorized into 8 modules, covering all the steps of metabolomics data mining, including raw data preprocessing (alignment, peak de-convolution, peak picking, and isotope filtering), peak annotation, peak table preprocessing, basic statistical description, classification and biomarker detection, correlation analysis, cluster and sub-cluster analysis, regression analysis, ROC analysis, pathway and enrichment analysis, and sample size and power analysis. Additionally, a KEGG-derived metabolic reaction database was embedded and a series of ratio variables (product/substrate) can be generated with enlarged information on enzyme activity. A new method, GRaMM, for correlation analysis between metabolome and microbiome data was also provided. IP4M provides both a number of parameters for customized and refined analysis (for expert users), as well as 4 simplified workflows with few key parameters (for beginners who are unfamiliar with computational metabolomics). The performance of IP4M was evaluated and compared with existing computational platforms using 2 data sets derived from standards mixture and 2 data sets derived from serum samples, from GC-MS and LC-MS respectively. CONCLUSION: IP4M is powerful, modularized, customizable and easy-to-use. It is a good choice for metabolomics data processing and analysis. Free versions for Windows, MAC OS, and Linux systems are provided.

Prepregnant Obesity of Mothers in a Multiethnic Cohort Is Associated with Cord Blood Metabolomic Changes in Offspring.

Maternal obesity has become a growing global health concern that may predispose the offspring to medical conditions later in life. However, the metabolic link between maternal prepregnant obesity and healthy offspring has not yet been fully elucidated. In this study, we conducted a case-control study using a coupled untargeted and targeted metabolomic approach from the newborn cord blood metabolomes associated with a matched maternal prepregnant obesity cohort of 28 cases and 29 controls. The subjects were recruited from multiethnic populations in Hawaii, including rarely reported Native Hawaiian and other Pacific Islanders (NHPI). We found that maternal obesity was the most important factor contributing to differences in cord blood metabolomics. Using an elastic net regularization-based logistic regression model, we identified 29 metabolites as potential early-life biomarkers manifesting intrauterine effect of maternal obesity, with accuracy as high as 0.947 after adjusting for clinical confounding (maternal and paternal age, ethnicity, parity, and gravidity). We validated the model results in a subsequent set of samples (N = 30) with an accuracy of 0.822. Among the metabolites, six metabolites (galactonic acid, butenylcarnitine, 2-hydroxy-3-methylbutyric acid, phosphatidylcholine diacyl C40:3, 1,5-anhydrosorbitol, and phosphatidylcholine acyl-alkyl 40:3) were individually and significantly different between the maternal obese and normal-weight groups. Interestingly, hydroxy-3-methylbutyric acid showed significantly higher levels in cord blood from the NHPI group compared to that from Asian and Caucasian groups. In summary, significant associations were observed between maternal prepregnant obesity and offspring metabolomic alternation at birth, revealing the intergenerational impact of maternal obesity.

Serum metabolite profiles are associated with the presence of advanced liver fibrosis in Chinese patients with chronic hepatitis B viral infection.

BACKGROUND: Accurate and noninvasive diagnosis and staging of liver fibrosis are essential for effective clinical management of chronic liver disease (CLD). We aimed to identify serum metabolite markers that reliably predict the stage of fibrosis in CLD patients. METHODS: We quantitatively profiled serum metabolites of participants in 2 independent cohorts. Based on the metabolomics data from cohort 1 (504 HBV associated liver fibrosis patients and 502 normal controls, NC), we selected a panel of 4 predictive metabolite markers. Consequently, we constructed 3 machine learning models with the 4 metabolite markers using random forest (RF), to differentiate CLD patients from normal controls (NC), to differentiate cirrhosis patients from fibrosis patients, and to differentiate advanced fibrosis from early fibrosis, respectively. RESULTS: The panel of 4 metabolite markers consisted of taurocholate, tyrosine, valine, and linoelaidic acid. The RF models of the metabolite panel demonstrated the strongest stratification ability in cohort 1 to diagnose CLD patients from NC (area under the receiver operating characteristic curve (AUROC) = 0.997 and the precision-recall curve (AUPR) = 0.994), to differentiate fibrosis from cirrhosis (0.941, 0.870), and to stage liver fibrosis (0.918, 0.892). The diagnostic accuracy of the models was further validated in an independent cohort 2 consisting of 300 CLD patients with chronic HBV infection and 90 NC. The AUCs of the models were consistently higher than APRI, FIB-4, and AST/ALT ratio, with both greater sensitivity and specificity. CONCLUSIONS: Our study showed that this 4-metabolite panel has potential usefulness in clinical assessments of CLD progression in patients with chronic hepatitis B virus infection.

polyPK: an R package for pharmacokinetic analysis of multi-component drugs using a metabolomics approach.

Summary: Pharmacokinetics (PK) is a long-standing bottleneck for botanical drug and traditional medicine research. By using an integrated phytochemical and metabolomics approach coupled with multivariate statistical analysis, we propose a new strategy, Poly-PK, to simultaneously monitor the performance of drug constituents and endogenous metabolites, taking into account both the diversity of the drug's chemical composition and its complex effects on the mammalian metabolic pathways. Poly-PK is independent of specific measurement platforms and has been successfully applied in the PK studies of Puerh tea, a traditional Chinese medicine Huangqi decoction and many other multi-component drugs. Here, we introduce an R package, polyPK, the first and only automation of the data analysis pipeline of Poly-PK strategy. polyPK provides 10 functions for data pre-processing, differential compound identification and grouping, traditional PK parameters calculation, multivariate statistical analysis, correlations, cluster analyses and resulting visualization. It may serve a wide range of users, including pharmacologists, biologists and doctors, in understanding the metabolic fate of multi-component drugs. Availability and implementation: polyPK package is freely available from the R archive CRAN (https://CRAN.R-project.org/package=polyPK). Contact: wjia@cc.hawaii.edu or chentianlu@sjtu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online.

Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers.

INTRODUCTION: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-ß deposition. METHOD: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aß1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION: This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.

Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome.

INTRODUCTION: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). METHODS: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. RESULTS: In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles. DISCUSSION: We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.

[Prevalence and epidemic characteristics of metabolic syndrome among adult residents in Nanjing City in 2010-2013].

OBJECTIVE: To understand the prevalence and epidemic characteristics of metabolic syndrome(MS) among adult residents in Nanjing City. METHODS: In 2010-2013, a total of 4918 adult residents in Nanjing City were surveyed using a multi-stage stratification and population proportional clustering random sampling method. Questionnaires, physical examinations and laboratory examinations were conducted to collect the basic conditions, health history of the subjects and related indicators including height, weight, waist circumference, blood pressure, fasting blood glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol, etc. The 2009 International Joint Interim Statement(JIS) was used to filter patients with metabolic syndrome. RESULTS: Among the 4918 surveyed subjects, 1627 were MS, with a crude prevalence rate of 33. 1% and an age-standardized prevalence rate of 26. 3%, the standardized prevalence rate of MS was 29. 0% in males and 24. 8% in females. Age-standardized prevalence rates between different genders had no significant statistical difference(χ~2=1. 352, P=0. 245). There were significant statistical differences between the crude prevalence rate of MS among subjects of different ages(χ~2=132. 557, P<0. 001), occupations(χ~2=87. 572, P<0. 001)and educational level(χ~2=26. 077, P<0. 001). Patients with a family history of hypertension(χ~2=26. 582, P<0. 001) and a family history of diabetes(χ~2=16. 013, P<0. 001)had a higher prevalence of MS. CONCLUSION: The prevalence of metabolic syndrome in adult residents in Nanjing City in 2010-2013 was relatively high.

Strategy for an Association Study of the Intestinal Microbiome and Brain Metabolome Across the Lifespan of Rats.

There is increased appreciation for the diverse roles of the microbiome-gut-brain axis on mammalian growth and health throughout the lifespan. Numerous studies have demonstrated that the gut microbiome and their metabolites are extensively involved in the communication between brain and gut. Association study of brain metabolome and gut microbiome is an active field offering large amounts of information on the interaction of microbiome, brain and gut but data size and complicated hierarchical relationships were found to be major obstacles to the formation of significant, reproducible conclusions. This study addressed a two-level strategy of brain metabolome and gut microbiome association analysis of male Wistar rats in the process of growth, employing several analytical platforms and various bioinformatics methods. Trajectory analysis showed that the age-related brain metabolome and gut microbiome had similarity in overall alteration patterns. Four high taxonomical level correlated pairs of "metabolite type-bacterial phylum", including "lipids-Spirochaetes", "free fatty acids (FFAs)-Firmicutes", "bile acids (BAs)-Firmicutes", and "Neurotransmitters-Bacteroidetes", were screened out based on unit- and multivariant correlation analysis and function analysis. Four groups of specific "metabolite-bacterium" association pairs from within the above high level key pairs were further identified. The key correlation pairs were validated by an independent animal study. This two-level strategy is effective in identifying principal correlations in big data sets obtained from the systematic multiomics study, furthering our understanding on the lifelong connection between brain and gut.

The ratio of dihomo-γ-linolenic acid to deoxycholic acid species is a potential biomarker for the metabolic abnormalities in obesity.

Bile acid (BA) signaling regulates fatty acid metabolism. BA dysregulation plays an important role in the development of metabolic disease. However, BAs in relation to fatty acids have not been fully investigated in obesity-related metabolic disorders. A targeted metabolomic measurement of serum BA and free fatty acid profiles was applied to sera of 381 individuals in 2 independent studies. The results showed that the ratio of dihomo-γ-linolenic acid (DGLA) to deoxycholic acid (DCA) species (DCAS) was significantly increased in obese individuals with type 2 diabetes (T2DM) from a case-control study and decreased in the remission group of obese subjects with T2DM after metabolic surgery. The changes were closely associated with their metabolic status. These results were consistently confirmed in both serum and liver of mice with diet-induced obesity, implying that such a metabolic alteration in circulation reflects changes occurring in the liver. In vitro studies of human liver L-02 cell lines under BA treatment revealed that DCA and its conjugated form, TDCA, significantly inhibited mRNA expression of fatty acid transport protein 5 in the presence of DGLA, which was involved in hepatocyte DGLA uptake. Thus, the DGLA:DCAS ratio may be a promising biomarker for metabolic abnormalities in obesity.-Lei, S., Huang, F., Zhao, A., Chen, T., Chen, W., Xie, G., Zheng, X., Zhang, Y., Yu, H., Zhang, P., Rajani, C., Bao, Y., Jia, W., Jia, W. The ratio of dihomo-γ-linolenic acid to deoxycholic acid species is a potential biomarker for the metabolic abnormalities in obesity.

Serum stearic acid/palmitic acid ratio as a potential predictor of diabetes remission after Roux-en-Y gastric bypass in obesity.

Endogenous fatty acid metabolism that results in elongation and desaturation lipid products is thought to play a role in the development of type 2 diabetes mellitus (T2DM). In this study, we evaluated the potential of estimated elongase and desaturase activities for use as predictive markers for T2DM remission after Roux-en-Y gastric bypass (RYGB). The results of a targeted metabolomics approach from 2 independent studies were used to calculate 24 serum FA concentration ratios (product/precursor). Gene expression data from an open public data set was also analyzed. In a longitudinal study of 38 obese diabetic patients with RYGB, we found higher baseline stearic acid/palmitic acid (S/P) ratio. This ratio reflects an elovl6-encoded elongase enzyme activity that has been found to be associated with greater possibility for diabetes remission after RYGB [odds ratio, 2.16 (95% CI 1.10-4.26)], after adjustment for age, gender, body mass index, diabetes duration, glycosylated hemoglobin A1c, and fasting C-peptide. Our results were validated by examination of postsurgical elovl6 gene expression in morbidly obese patients. The association of S/P with the metabolic status of obese individuals was further validated in a cross-sectional cohort of 381 participants. In summary, higher baseline S/P was associated with greater probability of diabetes remission after RYGB and may serve as a diagnostic marker in preoperative patient assessment. - Zhao, L., Ni, Y., Yu, H., Zhang, P., Zhao, A., Bao, Y., Liu, J., Chen, T., Xie, G., Panee, J., Chen, W., Rajani, C., Wei, R., Su, M., Jia, W., Jia, W. Serum stearic acid/palmitic acid ratio as a potential predictor of diabetes remission after Roux-en-Y gastric bypass in obesity.

Association of dietary sodium:potassium ratio with the metabolic syndrome in Chinese adults.

Several epidemiological studies have investigated that Na or K intakes might be associated with the metabolic syndrome (MetS). However, little evidence has evaluated the association between Na:K ratio and the MetS. In this study, we assessed the association between the dietary Na:K ratio and the MetS. The cross-sectional study was conducted among adults aged 18 years and older in Nanjing, using a multi-stage random sampling method, which resulted in a sample size of 1993 participants. Dietary Na and K intakes were assessed by 3 consecutive days of dietary recollection combined with condiments weighing method. Health-related data were obtained by standardised questionnaires, as well as physical examinations and laboratory assessments. The prevalence rate of the MetS was 36·5 % (728/1993). After adjusting for various lifestyle and dietary factors of the MetS, participants in the highest quartile of dietary Na:K ratio were at a higher risk of developing MetS (OR=1·602; 95 % CI 1·090, 2·353) compared with those in the lowest quartile. Each 1-sd increase in dietary Na:K ratio was associated with a higher risk of prevalent MetS (OR=1·166; 95 % CI: 1·018, 1·336). Among the components of the MetS, dietary Na:K ratio was positively associated with high blood pressure (quartile 3 v. quartile 1: OR=1·656; 95 % CI 1·228, 2·256) and hypertriacylglycerolaemia (quartile 4 v. quartile1: OR=1·305; 95 % CI 1·029, 1·655) in multivariate analysis. These results revealed that higher dietary Na:K ratio significantly increased the risk of the MetS in Chinese adults. Further studies are needed to verify this association.