ABSTRACT
Cow milk consumption (CMC) and downstream alterations of serum metabolites are commonly considered important factors regulating human health status. Foods may lead to metabolic changes directly or indirectly through remodelling gut microbiota (GM). We sought to identify the metabolic alterations in Chinese Peri-/Postmenopausal women with habitual CMC and explore if the GM mediates the CMC-metabolite associations. 346 Chinese Peri-/Postmenopausal women participants were recruited in this study. Fixed effects regression and partial least squares discriminant analysis (PLS-DA) were applied to reveal alterations of serum metabolic features in different CMC groups. Spearman correlation coefficient was computed to detect metabolome-metagenome association. 36 CMC-associated metabolites including palmitic acid (FA(16:0)), 7alpha-hydroxy-4-cholesterin-3-one (7alphaC4), citrulline were identified by both fixed effects regression (FDR < 0.05) and PLS-DA (VIP score > 2). Some significant metabolite-GM associations were observed, including FA(16:0) with gut species Bacteroides ovatus, Bacteroides sp.D2. These findings would further prompt our understanding of the effect of cow milk on human health.
Subject(s)
Gastrointestinal Microbiome , Milk , Postmenopause , Humans , Female , Animals , Middle Aged , Postmenopause/blood , China , Cattle , Citrulline/blood , Aged , Diet , Metabolome , Bacteroides , East Asian PeopleABSTRACT
OBJECTIVE: To elucidate an etiology in a case with persistent oligohydramnios by prenatal diagnosis and actively treat the case to achieve good prognosis. METHODS: We performed whole exome sequencing (WES) of DNA from the fetus and parents. Serial amnioinfusions were conducted until birth. Pressors were required to maintain normal blood pressure. The infant angiotensin-converting enzyme (ACE) activity, angiotensin II (Ang II, a downstream product of ACE), and compensatory enzymes (CEs) activities were measured. Compensatory enzyme activities in plasma from age-matched healthy controls were also detected. RESULTS: We identified a fetus with a severe ACE mutation prenatally. The infant was born prematurely without pulmonary dysplasia. Hypotension and anuria resolved spontaneously. He had almost no ACE activity, but his Ang II level and CE activity exceeded the upper limit of the normal range and the upper limit of the 95% confidence interval of controls, respectively. His renal function also largely recovered. CONCLUSION: Fetuses with ACE mutations can be diagnosed prenatally through WES. Serial amnioinfusion permits the continuation of pregnancy in fetal ACE deficiency. Compensatory enzymes for defective ACE appeared postnatally. Renal function may be spared by preterm delivery; furthermore, for postnatal vasopressor therapy to begin, improving renal perfusion pressure before nephrogenesis has been completed.
Subject(s)
Oligohydramnios , Peptidyl-Dipeptidase A , Pregnancy , Infant, Newborn , Male , Female , Humans , Peptidyl-Dipeptidase A/genetics , Prenatal Diagnosis , Fetus , Oligohydramnios/diagnostic imaging , Oligohydramnios/therapy , Delivery, ObstetricABSTRACT
Introduction: The number of primordial follicles (PFs) in mammals determines the ovarian reserve, and impairment of primordial follicle formation (PFF) will cause premature ovarian insufficiency (POI). Methods: By analyzing public single-cell RNA sequencing performed during PFF on mice and human ovaries, we identified novel functional genes and novel ligand-receptor interaction during PFF. Based on immunofluorescence and in vitro ovarian culture, we confirmed mechanisms of genes and ligand-receptor interaction in PFF. We also applied whole exome sequencing (WES) in 93 cases with POI and whole genome sequencing (WGS) in 465 controls. Variants in POI patients were further investigated by in silico analysis and functional verification. Results: We revealed ANXA7 (annexin A7) and GTF2F1 (general transcription factor IIF subunit 1) in germ cells to be novel potentially genes in promoting PFF. Ligand Mdk (midkine) in germ cells and its receptor Sdc1 (syndecan 1) in granulosa cells are novel interaction crucial for PFF. Based on immunofluorescence, we confirmed significant up-regulation of ANXA7 in PFs compared with germline cysts, and uniform expression of GTF2F1, MDK and SDC1 during PFF, in 25 weeks human fetal ovary. In vitro investigation indicated that Anxa7 and Gtf2f1 are vital for mice PFF by regulating Jak/Stat3 and Jnk signaling pathways, respectively. Ligand-receptor (Mdk-Sdc1) are crucial for PFF by regulating Pi3k-akt signaling pathway. Two heterozygous variants in GTF2F1, and one heterozygous variants in SDC1 were identified in cases, but no variant were identified in controls. The protein level of GTF2F1 or SDC1 in POI cases are significantly lower than that of controls, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent. Discussion: Our study identified novel genes and novel ligand-receptor interaction during PFF, and further expanding the genetic architecture of POI.
Subject(s)
Menopause, Premature , Primary Ovarian Insufficiency , Female , Humans , Animals , Mice , Exome Sequencing , Phosphatidylinositol 3-Kinases/metabolism , Ligands , Single-Cell Gene Expression Analysis , Ovarian Follicle/metabolism , Primary Ovarian Insufficiency/genetics , Mammals/geneticsABSTRACT
Endometriosis is a benign high prevalent disease exhibiting malignant features. However, the underlying pathogenesis and key molecules of endometriosis remain unclear. By integrating and analysis of existing expression profile datasets, we identified coxsackie and adenovirus receptor (CXADR), as a novel key gene in endometriosis. Based on the results of immunohistochemistry (IHC), we confirmed significant down-regulation of CXADR in ectopic endometrial tissues obtained from women with endometriosis compared with healthy controls. Further in vitro investigation indicated that CXADR regulated the stability and function of the phosphatases and AKT inhibitors PHLPP2 (pleckstrin homology domain and leucine-rich repeat protein phosphatase 2) and PTEN (phosphatase and tensin homolog). Loss of CXADR led to phosphorylation of AKT and glycogen synthase kinase-3ß (GSK-3ß), which resulted in stabilization of an epithelial-mesenchymal transition (EMT) factor, SNAIL1 (snail family transcriptional repressor 1). Therefore, EMT processs was induced, and the proliferation, migration and invasion of Ishikawa cells were enhanced. Over-expression of CXADR showed opposite effects. These findings suggest a previously undefined role of AKT/GSK-3ß signaling axis in regulating EMT and reveal the involvement of a CXADR-induced EMT, in pathogenic progression of endometriosis.
Subject(s)
Endometriosis , Proto-Oncogene Proteins c-akt , Female , Humans , Cell Adhesion Molecules , Cell Line, Tumor , Cell Movement , Endometriosis/genetics , Epithelial-Mesenchymal Transition , Glycogen Synthase Kinase 3 beta , Phosphoprotein Phosphatases/pharmacology , Phosphoric Monoester Hydrolases , Proto-Oncogene Proteins c-akt/metabolism , Snail Family Transcription Factors/genetics , Snail Family Transcription Factors/metabolismABSTRACT
Although the gut microbiota has been reported to influence osteoporosis risk, the individual species involved, and underlying mechanisms, remain largely unknown. We performed integrative analyses in a Chinese cohort of peri-/post-menopausal women with metagenomics/targeted metabolomics/whole-genome sequencing to identify novel microbiome-related biomarkers for bone health. Bacteroides vulgatus was found to be negatively associated with bone mineral density (BMD), which was validated in US white people. Serum valeric acid (VA), a microbiota derived metabolite, was positively associated with BMD and causally downregulated by B. vulgatus. Ovariectomized mice fed B. vulgatus demonstrated increased bone resorption and poorer bone micro-structure, while those fed VA demonstrated reduced bone resorption and better bone micro-structure. VA suppressed RELA protein production (pro-inflammatory), and enhanced IL10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells and enhanced maturation of osteoblasts in vitro. The findings suggest that B. vulgatus and VA may represent promising targets for osteoporosis prevention/treatment.
Subject(s)
Bone Resorption , Gastrointestinal Microbiome , Osteoporosis , Humans , Female , Mice , AnimalsABSTRACT
BACKGROUND: Intellectual disability (ID) is characterized by an IQ < 70, which implies below-average intellectual function and a lack of skills necessary for daily living. ID may occur due to multiple causes, such as metabolic, infectious, and chromosomal causes. ID affects approximately 1-3% of the population; however, the cause can be identified in only 25% of clinical patients. METHODS: To find the cause of genetic ID in a family, we performed whole-exome sequencing and Sanger sequencing to confirm the presence of a SETBP1 variant and real-time quantitative polymerase chain reaction to detect SETBP1 expression in the proband and normal controls. RESULTS: A novel variant, c.942_943insGT (p. Asp316TrpfsTer28), was found in SETBP1. Furthermore, we observed that SETBP1 expression in patients was only 20% that of normal controls (P < 0.05). CONCLUSION: A heterozygous variant in SETBP1 associated with ID was found. This report provides further evidence for its genetic basis and support for clinical genetic diagnosis.
Subject(s)
Intellectual Disability , Humans , Intellectual Disability/genetics , East Asian People , Family , Asian People/genetics , Pedigree , Mutation , Carrier Proteins/genetics , Nuclear Proteins/geneticsABSTRACT
Background: Lipid pathways have been implicated in the pathogenesis of osteoporosis (OP). Lipid-lowering drugs may be used to prevent and treat OP. However, the causal interpretation of results from traditional observational designs is controversial by confounding. We aimed to investigate the causal association between genetically proxied lipid-lowering drugs and OP risk. Methods: We conducted two-step Mendelian randomization (MR) analyses to investigate the causal association of genetically proxied lipid-lowering drugs on the risk of OP. The first step MR was used to estimate the associations of drug target genes expression with low-density lipoprotein cholesterol (LDL-C) levels. The significant SNPs in the first step MR were used as instrumental variables in the second step MR to estimate the associations of LDL-C levels with forearm bone mineral density (FA-BMD), femoral neck BMD (FN-BMD), lumbar spine BMD (LS-BMD) and fracture. The significant lipid-lowering drugs after MR analyses were further evaluated for their effects on bone mineralization using a dexamethasone-induced OP zebrafish model. Results: The first step MR analysis found that the higher expression of four genes (HMGCR, NPC1L1, PCSK9 and PPARG) was significantly associated with a lower LDL-C level. The genetically decreased LDL-C level mediated by the PPARG was significantly associated with increased FN-BMD (BETA = -1.38, p = 0.001) and LS-BMD (BETA = -2.07, p = 3.35 × 10-5) and was marginally significantly associated with FA-BMD (BETA = -2.36, p = 0.008) and reduced fracture risk (OR = 3.47, p = 0.008). Bezafibrate (BZF) and Fenofibric acid (FBA) act as PPARG agonists. Therefore genetically proxied BZF and FBA had significant protective effects on OP. The dexamethasone-induced OP zebrafish treated with BZF and FBA showed increased bone mineralization area and integrated optical density (IOD) with alizarin red staining. Conclusion: The present study provided evidence that BZF and FBA can increase BMD, suggesting their potential effects in preventing and treating OP. These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of OP.
ABSTRACT
Obesity is associated with various adverse health outcomes. Body fat (BF) distribution is recognized as an important factor of negative health consequences of obesity. Although metabolomics studies, mainly focused on body mass index (BMI) and waist circumference, have explored the biological mechanisms involved in the development of obesity, these proxy composite measures are not accurate and cannot reflect BF distribution, and thus may hinder accurate assessment of metabolic alterations and differential risk of metabolic disorders among individuals presenting adiposity differently throughout the body. Thus, the exact relations between metabolites and BF remain to be elucidated. Here, we aim to examine the associations of metabolites and metabolic pathways with BF traits which reflect BF distribution. We performed systematic untargeted serum metabolite profiling and dual-energy X-ray absorptiometry (DXA) whole body fat scan for 517 Chinese women. We jointly analyzed DXA-derived four BF phenotypes to detect cross-phenotype metabolite associations and to prioritize important metabolomic factors. Topology-based pathway analysis was used to identify important BF-related biological processes. Finally, we explored the relationships of the identified BF-related candidate metabolites with BF traits in different sex and ethnicity through two independent cohorts. Acetylglycine, the top distinguished finding, was validated for its obesity resistance effect through in vivo studies of various diet-induced obese (DIO) mice. Eighteen metabolites and fourteen pathways were discovered to be associated with BF phenotypes. Six of the metabolites were validated in varying sex and ethnicity. The obesity-resistant effects of acetylglycine were observed to be highly robust and generalizable in both human and DIO mice. These findings demonstrate the importance of metabolites associated with BF distribution patterns and several biological pathways that may contribute to obesity and obesity-related disease etiology, prevention, and intervention. Acetylglycine is highlighted as a potential therapeutic candidate for preventing excessive adiposity in future studies.
ABSTRACT
Functional constipation (FC) is a high morbidity gastrointestinal disease for which dysfunction in the enteric nervous system is a major pathogenesis mechanism. To enhance our understanding of the involvement of intestinal microbiota and its metabolites in the pathogenesis of FC, we conducted a shotgun metagenomic sequencing analysis of gut microbiota and serum short-chain fatty acids (SCFAs) analysis in 460 Chinese women with different defecation frequencies. We observed that the abundance ofFusobacterium_varium, a butyric acid-producing bacterium, was positively correlated (P = 0.0096) with the frequency of defecation; however, the concentrations of serum butyric acid was negatively correlated (P = 3.51E-05) with defecation frequency. These results were verified in an independent cohort (6 patients with FC and 6 controls). To further study the effects of butyric acid on intestinal nerve cells, we treated mouse intestinal neurons in vitro with various concentrations of butyrate (0.1, 0.5, 1, and 2.5 mM). We found that intestinal neurons treated with 0.5 mM butyrate proliferated better than those in the other treatment groups, with significant differences in cell cycle and oxidative phosphorylation signal pathways. We suggest that the decreased butyrate production resulting from the reduced abundance of Fusobacterium in gut microbiota affects the proliferation of intestinal neurons and the energy supply of intestinal cells. However, with FC disease advancing, the consumption and excretion of butyric acid reduce, leading to its accumulation in the intestine. Moreover, the accumulation of an excessively high amount of butyric acid inhibits the proliferation of nerve cells and subsequently exacerbates the disease.
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Background and Objectives: Osteoblasts are derived from bone marrow mesenchymal stem cells (BMMSCs) and play important role in bone remodeling. While our previous studies have investigated the cell subtypes and heterogeneity in osteoblasts and BMMSCs separately, cell-to-cell communications between osteoblasts and BMMSCs in vivo in humans have not been characterized. The aim of this study was to investigate the cellular communication between human primary osteoblasts and bone marrow mesenchymal stem cells. Methods and Results: To investigate the cell-to-cell communications between osteoblasts and BMMSCs and identify new cell subtypes, we performed a systematic integration analysis with our single-cell RNA sequencing (scRNA-seq) transcriptomes data from BMMSCs and osteoblasts. We successfully identified a novel preosteoblasts subtype which highly expressed ATF3, CCL2, CXCL2 and IRF1. Biological functional annotations of the transcriptomes suggested that the novel preosteoblasts subtype may inhibit osteoblasts differentiation, maintain cells to a less differentiated status and recruit osteoclasts. Ligand-receptor interaction analysis showed strong interaction between mature osteoblasts and BMMSCs. Meanwhile, we found FZD1 was highly expressed in BMMSCs of osteogenic differentiation direction. WIF1 and SFRP4, which were highly expressed in mature osteoblasts were reported to inhibit osteogenic differentiation. We speculated that WIF1 and sFRP4 expressed in mature osteoblasts inhibited the binding of FZD1 to Wnt ligand in BMMSCs, thereby further inhibiting osteogenic differentiation of BMMSCs. Conclusions: Our study provided a more systematic and comprehensive understanding of the heterogeneity of osteogenic cells. At the single cell level, this study provided insights into the cell-to-cell communications between BMMSCs and osteoblasts and mature osteoblasts may mediate negative feedback regulation of osteogenesis process.
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Biological control by antagonistic microorganisms are an effective and environmentally friendly approach in postharvest disease management. In order to develop a biocontrol agent for fresh walnut fruit preservation, the potential biocontrol effects of Bacillus amyloliquefaciens RD.006 and Hanseniaspora uvarum FA.006 against the main fungal pathogen of walnuts were evaluated. Botryosphaeria species showed the highest detection, and the JNHT01 strain showed the strongest pathogenicity. Bot. dothidea JNHT01 caused gray mold and brown rot on fresh walnuts, and its incidence rate reached 100% after an 8 days incubation. The growth of this fungal strain can be promoted by lighting, with a maximum growth rate achieved at a pH of 7 and at 28 °C. B. amyloliquefaciens RD.006 and H. uvarum FA.006 supernatants at a concentration of 1-15% v/v showed antifungal activity. The mycelial growth inhibition rates of Bot. dothidea JNHT01 were 23.67-82.61% for B. amyloliquefaciens RD.006 and 1.45-21.74% for H. uvarum FA.006. During Bot. dothidea JNHT01 growth, the biomass, nucleic acid leakage, and malondialdehyde content gradually increased, while the DPPH scavenging capacity and SOD activity decreased. The B. amyloliquefaciens RD.006 and H. uvarum FA.006 strains showed antifungal activity by damaging fungal cell membranes and reducing fungal antioxidant activity. Moreover, the antifungal effect of B. amyloliquefaciens RD.006 was higher than that of H. uvarum FA.006. Hence, the RD.006 strain of B. amyloliquefaciens can be considered a potential biocontrol agent for the management of postharvest walnut diseases caused by Bot. dothidea.
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BACKGROUND: Recently, single-cell RNA sequencing (scRNA-seq) technology was increasingly used to study transcriptomics at a single-cell resolution, scRNA-seq analysis was complicated by the "dropout", where the data only captures a small fraction of the transcriptome. This phenomenon can lead to the fact that the actual expressed transcript may not be detected. We previously performed osteoblast subtypes classification and dissection on freshly isolated human osteoblasts. MATERIALS AND METHODS: Here, we used the scImpute method to impute the missing values of dropout genes from a scRNA-seq dataset generated on freshly isolated human osteoblasts. RESULTS: Based on the imputed gene expression patterns, we discovered three new osteoblast subtypes. Specifically, these newfound osteoblast subtypes are osteoblast progenitors, and two undetermined osteoblasts. Osteoblast progenitors showed significantly high expression of proliferation related genes (FOS, JUN, JUNB and JUND). Analysis of each subtype showed that in addition to bone formation, these undetermined osteoblasts may involve osteoclast and adipocyte differentiation and have the potential function of regulate immune activation. CONCLUSIONS: Our findings provided a new perspective for studying the osteoblast heterogeneity and potential biological functions of these freshly isolated human osteoblasts at the single-cell level, which provides further insight into osteoblasts subtypes under various (pathological) physiological conditions.
Subject(s)
Osteoblasts , Transcriptome , Humans , RNA-Seq , Osteoblasts/metabolism , Cell Differentiation/genetics , Osteogenesis/genetics , Gene Expression ProfilingABSTRACT
Cow milk consumption (CMC) and alterations of gut bacterial composition are proposed to be closely related to human health and disease. Our research aims to investigate the changes in human gut microbial composition in Chinese peri-/postmenopausal women with different CMC habits. A total of 517 subjects were recruited and questionnaires about their CMC status were collected; 394 subjects were included in the final analyses. Fecal samples were used for studying gut bacterial composition. All the subjects were divided into a control group (n = 248) and a CMC group (n = 146) according to their CMC status. Non-parametric tests and LEfSe at different taxonomic levels were used to reveal differentially abundant taxa and functional categories across different CMC groups. Relative abundance (RA) of one phylum (p_Actinobacteria), three genera (g_Bifidobacterium, g_Anaerostipes, and g_Bacteroides), and 28 species diversified significantly across groups. Specifically, taxa g_Anaerostipes (p < 0.01), g_Bacteroides (p < 0.05), s_Anaerostipes_hadrus (p < 0.01), and s_Bifidobacterium_pseudocatenulatum (p < 0.01) were positively correlated with CMC levels, but p_Actinobacteria (p < 0.01) and g_Bifidobacterium (p < 0.01) were negatively associated with CMC levels. KEGG module analysis revealed 48 gut microbiome functional modules significantly (p < 0.05) associated with CMC, including Vibrio cholerae pathogenicity signature, cholera toxins (p = 9.52e-04), and cephamycin C biosynthesis module (p = 0.0057), among others. In conclusion, CMC was associated with changes in gut microbiome patterns including beta diversity and richness of some gut microbiota. The alterations of certain bacteria including g_Anaerostipes and s_Bifidobacterium_pseudocatenulatum in the CMC group should be important for human health. This study further supports the biological value of habitual cow milk consumption.
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Purpose: The increasing prevalence of sarcopenia remains an ongoing challenge to health care systems worldwide. The lack of treatments encouraged the discovery of human proteomes to find potential therapeutic targets. As one of the major components of the human proteome, plasma proteins are functionally connected with various organs of the body to regulate biological processes and mediate overall homeostasis, which makes it crucial in various complex processes such as aging and chronic diseases. By performing a systematic causal analysis of the plasma proteome, we attempt to reveal the etiological mechanism and discover drug targets for sarcopenia. Methods: By using data from four genome-wide association studies for blood proteins and the UK Biobank data for sarcopenia-related traits, we applied two-sample Mendelian randomization (MR) analysis to evaluate 310 plasma proteins as possible causal mediators of sarcopenia-related traits: appendicular lean mass (ALM) and handgrip strength (right and left). Then we performed a two-sample bidirectional Mendelian randomization analysis for the identified putatively causal proteins to assess potential reverse causality that the trait values may influence protein levels. Finally, we performed phenome-wide MR analysis of the identified putatively causal proteins for 784 diseases to test the possible side effects of these proteins on other diseases. Results: Five plasma proteins were identified as putatively causal mediators of sarcopenia-related traits. Specifically, leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), asporin (ASPN), and contactin-2 (CNTN2) had potential causal effects on appendicular lean mass, and ecto-ADP-ribosyltransferase 4 (ART4) and superoxide dismutase 2 (SOD2) had putative causal effects on the handgrip strength, respectively. None of the five putatively causal proteins had a reverse causality relationship with sarcopenia-related traits, and no side effects on other diseases were identified. Conclusion: We identified five plasma proteins that may serve as putatively potential novel drug targets for sarcopenia. Our study attested to the value of two-sample MR analysis in identifying and prioritizing putatively potential therapeutic targets for complex diseases.
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OBJECTIVE: Many animal experiments and epidemiological studies have shown that the gut microbiota (GM) plays an important role in the development of obesity, but the specific biological mechanism involved in the pathogenesis of disease remain unknown. We aimed to examine the relationships and functional mechanisms of GM on obesity in peri- and post-menopausal women. METHODS: We recruited 499 Chinese peri- and post-menopausal women and performed comprehensive analyses of the gut microbiome, targeted metabolomics for short-chain fatty acids in serum, and host whole-genome sequencing by various association analysis methods. RESULTS: Through constrained linear regression analysis, we found that an elevated abundance of Bacteroides fragilis (B. fragilis) was associated with obesity. We also found that serum levels of acetic acid were negatively associated with obesity, and that B. fragilis was negatively associated with serum acetic acid levels by partial Spearman correlation analysis. Mendelian randomization analysis indicated that B. fragilis increases the risk of obesity and may causally down-regulate acetic acid levels. CONCLUSIONS: We found the gut with B. fragilis may accelerate obesity, in part, by suppressing acetic acid levels. Therefore, B. fragilis and acetic acid may represent important therapeutic targets for obesity intervention in peri- and post-menopausal women.
Subject(s)
Bacteroides fragilis , Gastrointestinal Microbiome , Acetic Acid , Bacteroides fragilis/physiology , Female , Humans , Obesity , PostmenopauseABSTRACT
Both sarcopenia and osteoporosis are common geriatric diseases causing huge socioeconomic burdens, and clinically, they often occur simultaneously. Observational studies have found a controversial correlation between sarcopenia and osteoporosis and their causal relationship is not clear. Therefore, we performed a bi-directional two-sample Mendelian randomization (MR) analysis to assess the potential causal relationship between sarcopenia-related traits (hand grip strength, lean mass, walking pace) and osteoporosis. Our analysis was performed by applying genetic variants obtained from the UK Biobank and the GEnetic Factors for OSteoporosis (GEFOS) datasets. We used inverse-variance weighted (IVW) and several sensitivity analyses to estimate and cross-validate the potential causal relationship in this study. We found that bone mineral density (BMD) was causally positively associated with left-hand grip strength (ß = 0.017, p-value = 0.001), fat-free mass (FFM; right leg FFM, ß = 0.014, p-value = 0.003; left arm FFM, ß = 0.014, p-value = 0.005), but not walking pace. Higher hand grip strength was potentially causally associated with increased LS-BMD (right-hand grip strength, ß = 0.318, p-value = 0.001; left-hand grip strength, ß = 0.358, p-value = 3.97 × 10-4). In conclusion, osteoporosis may be a risk factor for sarcopenia-related traits and muscle strength may have a site-specific effect on BMD.
Subject(s)
Osteoporosis , Sarcopenia , Aged , Bone Density/genetics , Hand Strength/physiology , Humans , Mendelian Randomization Analysis , Osteoporosis/complications , Osteoporosis/genetics , Sarcopenia/complications , Sarcopenia/geneticsABSTRACT
While the gut microbiome has been reported to play a role in bone metabolism, the individual species and underlying functional mechanisms have not yet been characterized. We conducted a systematic multi-omics analysis using paired metagenomic and untargeted serum metabolomic profiles from a large sample of 499 peri- and early post-menopausal women to identify the potential crosstalk between these biological factors which may be involved in the regulation of bone mineral density (BMD). Single omics association analyses identified 22 bacteria species and 17 serum metabolites for putative association with BMD. Among the identified bacteria, Bacteroidetes and Fusobacteria were negatively associated, while Firmicutes were positively associated. Several of the identified serum metabolites including 3-phenylpropanoic acid, mainly derived from dietary polyphenols, and glycolithocholic acid, a secondary bile acid, are metabolic byproducts of the microbiota. We further conducted a supervised integrative feature selection with respect to BMD and constructed the inter-omics partial correlation network. Although still requiring replication and validation in future studies, the findings from this exploratory analysis provide novel insights into the interrelationships between the gut microbiome and serum metabolome that may potentially play a role in skeletal remodeling processes.
Subject(s)
Gastrointestinal Microbiome , Microbiota , Biological Factors , Bone Density , Female , Humans , MetabolomeABSTRACT
Concern about rising rates of obesity has prompted searches for obesity-related single nucleotide polymorphisms (SNPs) in genome-wide association studies (GWAS). Identifying plausible regulatory SNPs is very difficult partially because of linkage disequilibrium. We used an unusual epigenomic and transcriptomic analysis of obesity GWAS-derived SNPs in adipose versus heterologous tissues. From 50 GWAS and 121,064 expanded SNPs, we prioritized 47 potential causal regulatory SNPs (Tier-1 SNPs) for 14 gene loci. A detailed examination of seven loci revealed that four (CABLES1, PC, PEMT, and FAM13A) had Tier-1 SNPs positioned so that they could regulate use of alternative transcription start sites, resulting in different polypeptides being generated or different amounts of an intronic microRNA gene being expressed. HOXA11 and long noncoding RNA gene RP11-392O17.1 had Tier-1 SNPs in their 3' or promoter region, respectively, and strong preferences for expression in subcutaneous versus visceral adipose tissue. ZBED3-AS1 had two intragenic Tier-1 SNPs, each of which could contribute to mediating obesity risk through modulating long-distance chromatin interactions. Our approach not only revealed especially credible novel regulatory SNPs, but also helped evaluate previously highlighted obesity GWAS SNPs that were candidates for transcription regulation.
Subject(s)
Computational Biology/methods , Genome-Wide Association Study/methods , Obesity/genetics , Polymorphism, Single Nucleotide/genetics , Chromatin/genetics , Epigenesis, Genetic/genetics , Epigenomics/methods , Gene Expression/genetics , Gene Expression Profiling/methods , Gene Expression Regulation/genetics , Genetic Predisposition to Disease/genetics , Humans , Linkage Disequilibrium/genetics , Obesity/metabolism , Quantitative Trait Loci/genetics , Transcription Factors/metabolism , Transcriptome/geneticsABSTRACT
Sarcopenia is a systemic disease with progressive and generalized skeletal muscle dysfunction defined by age-related low muscle mass, high content of muscle slow fibers, and low muscle function. Muscle phenotypes and sarcopenia risk are heritable; however, the genetic architecture and molecular mechanisms underlying sarcopenia remain largely unclear. In recent years, significant progress has been made in determining susceptibility loci using genome-wide association studies. In addition, recent advances in omics techniques, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics, offer new opportunities to identify novel targets to help us understand the pathophysiology of sarcopenia. However, each individual technology cannot capture the entire view of the biological complexity of this disorder, while integrative multi-omics analyses may be able to reveal new insights. Here, we review the latest findings of multi-omics studies for sarcopenia and provide an in-depth summary of our current understanding of sarcopenia pathogenesis. Leveraging multi-omics data could give us a holistic understanding of sarcopenia etiology that may lead to new clinical applications. This review offers guidance and recommendations for fundamental research, innovative perspectives, and preventative and therapeutic interventions for sarcopenia.
Subject(s)
Genome-Wide Association Study , Sarcopenia , Genome-Wide Association Study/methods , Genomics/methods , Humans , Metabolomics/methods , Proteomics , Sarcopenia/geneticsABSTRACT
Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stromal cells that have a critical role in the maintenance of skeletal tissues such as bone, cartilage, and the fat in bone marrow. In addition to providing microenvironmental support for hematopoietic processes, BM-MSCs can differentiate into various mesodermal lineages including osteoblast/osteocyte, chondrocyte, and adipocyte that are crucial for bone metabolism. While BM-MSCs have high cell-to-cell heterogeneity in gene expression, the cell subtypes that contribute to this heterogeneity in vivo in humans have not been characterized. To investigate the transcriptional diversity of BM-MSCs, we applied single-cell RNA sequencing (scRNA-seq) on freshly isolated CD271+ BM-derived mononuclear cells (BM-MNCs) from two human subjects. We successfully identified LEPRhiCD45low BM-MSCs within the CD271+ BM-MNC population, and further codified the BM-MSCs into distinct subpopulations corresponding to the osteogenic, chondrogenic, and adipogenic differentiation trajectories, as well as terminal-stage quiescent cells. Biological functional annotations of the transcriptomes suggest that osteoblast precursors induce angiogenesis coupled with osteogenesis, and chondrocyte precursors have the potential to differentiate into myocytes. We also discovered transcripts for several clusters of differentiation (CD) markers that were either highly expressed (e.g., CD167b, CD91, CD130 and CD118) or absent (e.g., CD74, CD217, CD148 and CD68) in BM-MSCs, representing potential novel markers for human BM-MSC purification. This study is the first systematic in vivo dissection of human BM-MSCs cell subtypes at the single-cell resolution, revealing an insight into the extent of their cellular heterogeneity and roles in maintaining bone homeostasis.