| 1. |
- Lu, Hongzhong, 1987, et al.
(författare)
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A consensus S. cerevisiae metabolic model Yeast8 and its ecosystem for comprehensively probing cellular metabolism
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-scale metabolic models (GEMs) represent extensive knowledgebases that provide a platform for model simulations and integrative analysis of omics data. This study introduces Yeast8 and an associated ecosystem of models that represent a comprehensive computational resource for performing simulations of the metabolism of Saccharomyces cerevisiae––an important model organism and widely used cell-factory. Yeast8 tracks community development with version control, setting a standard for how GEMs can be continuously updated in a simple and reproducible way. We use Yeast8 to develop the derived models panYeast8 and coreYeast8, which in turn enable the reconstruction of GEMs for 1,011 different yeast strains. Through integration with enzyme constraints (ecYeast8) and protein 3D structures (proYeast8DB), Yeast8 further facilitates the exploration of yeast metabolism at a multi-scale level, enabling prediction of how single nucleotide variations translate to phenotypic traits.
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| 2. |
- Li, Peishun, 1988, et al.
(författare)
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Metabolic Alterations in Older Women With Low Bone Mineral Density Supplemented With Lactobacillus reuteri
- 2021
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Ingår i: JBMR Plus. - : Wiley. - 2473-4039. ; 5:4
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Tidskriftsartikel (refereegranskat)abstract
- JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. Osteoporosis and its associated fractures are highly prevalent in older women. Recent studies have shown that gut microbiota play important roles in regulating bone metabolism. A previous randomized controlled trial (RCT) found that supplementation with Lactobacillus reuteri ATCC PTA 6475 (L.reuteri) led to substantially reduced bone loss in older women with low BMD. However, the total metabolic effects of L. reuteri supplementation on older women are still not clear. In this study, a post hoc analysis (not predefined) of serum metabolomic profiles of older women from the previous RCT was performed to investigate the metabolic dynamics over 1 year and to evaluate the effects of L. reuteri supplementation on human metabolism. Distinct segregation of the L. reuteri and placebo groups in response to the treatment was revealed by partial least squares-discriminant analysis. Although no individual metabolite was differentially and significantly associated with treatment after correction for multiple testing, 97 metabolites responded differentially at any one time point between L. reuteri and placebo groups (variable importance in projection score >1 and p value <0.05). These metabolites were involved in multiple processes, including amino acid, peptide, and lipid metabolism. Butyrylcarnitine was particularly increased at all investigated time points in the L. reuteri group compared with placebo, indicating that the effects of L. reuteri on bone loss are mediated through butyrate signaling. Furthermore, the metabolomic profiles in a case (low BMD) and control population (high BMD) of elderly women were analyzed to confirm the associations between BMD and the identified metabolites regulated by L. reuteri supplementation. The amino acids, especially branched-chain amino acids, showed association with L. reuteri treatment and with low BMD in older women, and may serve as potential therapeutic targets. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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| 3. |
- Guman, M. S.S., et al.
(författare)
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Adipose Tissue, Bile Acids, and Gut Microbiome Species Associated With Gallstones After Bariatric Surgery
- 2022
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Ingår i: Journal of Lipid Research. - : Elsevier BV. - 0022-2275 .- 1539-7262. ; 63:11, s. 100280-
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Tidskriftsartikel (refereegranskat)abstract
- Several risk factors are associated with gallstone disease after bariatric surgery, but the underlying pathophysiological mechanisms of gallstone formation are unclear. We hypothesize that gallstone formation after bariatric surgery is induced by different pathways compared with gallstone formation in the general population, since postoperative formation occurs rapidly in patients who did not develop gallstones in preceding years. To identify both pathophysiological and potentially protective mechanisms against postoperative gallstone formation, we compared the preoperative fasting metabolome, fecal microbiome, and liver and adipose tissue transcriptome obtained before or during bariatric surgery of obese patients with and without postoperative gallstones. In total, 88 patients were selected from the BARIA longitudinal cohort study. Within this group, 32 patients had postoperative gallstones within 2 years. Gut microbiota metagenomic analyses showed group differences in abundance of 41 bacterial species, particularly abundance of Lactobacillaceae and Enterobacteriaceae in patients without gallstones. Subcutaneous adipose tissue transcriptomic analyses revealed four genes that were suppressed in gallstone patients compared with patients without gallstones. These baseline gene expression and gut microbiota composition differences might relate to protective mechanisms against gallstone formation after bariatric surgery. Moreover, baseline fasting blood samples of patients with postoperative gallstones showed increased levels of several bile acids. Overall, we revealed different genes and bacteria associated with gallstones than those previously reported in the general population, supporting the hypothesis that gallstone formation after bariatric surgery follows a different trajectory. Further research is necessary to confirm the involvement of the bile acids, adipose tissue activity, and microbial species observed here.
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| 4. |
- Kumar, Manish, 1982, et al.
(författare)
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Gut microbiota dysbiosis is associated with malnutrition and reduced plasma amino acid levels: Lessons from genome-scale metabolic modeling
- 2018
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Ingår i: Metabolic Engineering. - : Elsevier BV. - 1096-7176 .- 1096-7184. ; 49, s. 128-142
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Tidskriftsartikel (refereegranskat)abstract
- Malnutrition is a severe non-communicable disease, which is prevalent in children from low-income countries. Recently, a number of metagenomics studies have illustrated associations between the altered gut microbiota and child malnutrition. However, these studies did not examine metabolic functions and interactions between individual species in the gut microbiota during health and malnutrition. Here, we applied genome-scale metabolic modeling to model the gut microbial species, which were selected from healthy and malnourished children from three countries. Our analysis showed reduced metabolite production capabilities in children from two lowincome countries compared with a high-income country. Additionally, the models were also used to predict the community-level metabolic potentials of gut microbes and the patterns of pairwise interactions among species. Hereby we found that due to bacterial interactions there may be reduced production of certain amino acids in malnourished children compared with healthy children from the same communities. To gain insight into alterations in the metabolism of malnourished (stunted) children, we also performed targeted plasma metabolic profiling in the first 2 years of life of 25 healthy and 25 stunted children. Plasma metabolic profiling further revealed that stunted children had reduced plasma levels of essential amino acids compared to healthy controls. Our analyses provide a framework for future efforts towards further characterization of gut microbial metabolic capabilities and their contribution to malnutrition.
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| 5. |
- Lappa, Dimitra, 1988, et al.
(författare)
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Self-organized metabotyping of obese individuals identifies clusters responding differently to bariatric surgery
- 2023
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 18:3, s. e0279335-
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Tidskriftsartikel (refereegranskat)abstract
- Weight loss through bariatric surgery is efficient for treatment or prevention of obesity related diseases such as type 2 diabetes and cardiovascular disease. Long term weight loss response does, however, vary among patients undergoing surgery. Thus, it is difficult to identify predictive markers while most obese individuals have one or more comorbidities. To overcome such challenges, an in-depth multiple omics analyses including fasting peripheral plasma metabolome, fecal metagenome as well as liver, jejunum, and adipose tissue transcriptome were performed for 106 individuals undergoing bariatric surgery. Machine leaning was applied to explore the metabolic differences in individuals and evaluate if metabolism-based patients' stratification is related to their weight loss responses to bariatric surgery. Using Self-Organizing Maps (SOMs) to analyze the plasma metabolome, we identified five distinct metabotypes, which were differentially enriched for KEGG pathways related to immune functions, fatty acid metabolism, protein-signaling, and obesity pathogenesis. The gut metagenome of the most heavily medicated metabotypes, treated simultaneously for multiple cardiometabolic comorbidities, was significantly enriched in Prevotella and Lactobacillus species. This unbiased stratification into SOM-defined metabotypes identified signatures for each metabolic phenotype and we found that the different metabotypes respond differently to bariatric surgery in terms of weight loss after 12 months. An integrative framework that utilizes SOMs and omics integration was developed for stratifying a heterogeneous bariatric surgery cohort. The multiple omics datasets described in this study reveal that the metabotypes are characterized by a concrete metabolic status and different responses in weight loss and adipose tissue reduction over time. Our study thus opens a path to enable patient stratification and hereby allow for improved clinical treatments.
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| 6. |
- Lappa, Dimitra, 1988
(författare)
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The Dark side of Obesity: Multi-omics analysis of the dysmetabolic morbidities spectrum
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity is one of the most prevalent clinical conditions worldwide and is associated with a wide spectrum of dysmetabolic comorbidities. Complex cardio-metabolic disease cohorts, such as obesity cohorts are characterised by population heterogeneity, multiple underlying diseases status and different comorbidities’ treatment regiments. The systematic collection of multiple types of clinical and biological data from such cohorts and the data-analysis in an integrative manner is a challenging task due to the variables’ dimensionality and the lack of standardised know-how of post-processing. The main resource of this thesis has been the BARIA cohort, a detailed collection over time of multiple omics and demographic data from participants in bariatric surgery. BARIA datasets included plasma metabolites, RNA from hepatic, jejunal, mesenteric and subcutaneous adipose tissues and gut microbial metagenome, besides biometric data. The work presented in this thesis included the development of a systems biology integrative framework based on BARIA that (i) utilised unsupervised machine learning algorithms, self-organizing maps in particular, and multi-omics integrative frameworks, the DIABLO library, in order to stratify the BARIA heterogeneous obesity cohort and predict the bariatric surgery’s outcome. The thesis covered how BARIA can be the onset for (ii) studying molecular mechanisms related to type 2 diabetes (T2D) and G-protein coupled receptors (GPCRs) and for identifying a minimal set of biomarkers for obesity’s comorbidities such as (iii) non-alcoholic fatty liver disease (NAFL) and (iv) gallstones formation after bariatric surgery. The results indicated that the metabotypes comprising a bariatric surgery cohort exhibited a concrete metabolic status and different responses over time after the bariatric surgery. It has been demonstrated how obesity and T2D associated metabolites, such as 3-hydroxydecanoate, can increase inflammatory responses via GPCRs molecular activation and signalling. Last but not least, minimal sets of both evasive and non-evasive multi-omic discriminatory biomarkers for obesity’s dysmetabolic morbidities (NAFLD and gallstones after bariatric surgery) were obtained. Taking into consideration all the findings, this thesis presented how data-driven approaches can be used for studying in-depth heterogeneous cohorts, hereby facilitating early diagnosis and enabling potential preventive actions.
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| 7. |
- Meijnikman, A. S., et al.
(författare)
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A systems biology approach to study non-alcoholic fatty liver (NAFL) in women with obesity
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:8
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) is now the most frequent global chronic liver disease. Individuals with NAFLD exhibited an increased risk of all-cause mortality driven by extrahepatic cancers and liver and cardiovascular disease. Once the disease is established, women have a higher risk of disease progression and worse outcome. It is therefore critical to deepen the current knowledge on the pathophysiology of NAFLD in women. Here, we used a systems biology approach to investigate the contribution of different organs to this disease. We analyzed transcriptomics profiles of liver and adipose tissues, fecal metagenomes, and plasma metabolomes of 55 women with and without NAFLD. We observed differences in metabolites, expression of human genes, and gut microbial features between the groups and revealed that there is substantial crosstalk between these different omics sets. Multi-omics analysis of individuals with NAFLD may provide novel strategies to study the pathophysiology of NAFLD in humans.
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| 8. |
- Meijnikman, A. S., et al.
(författare)
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Hyperinsulinemia Is Highly Associated With Markers of Hepatocytic Senescence in Two Independent Cohorts
- 2022
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 71:9, s. 1929-1936
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Tidskriftsartikel (refereegranskat)abstract
- Cellular senescence is an essentially irreversible growth arrest that occurs in response to various cellular stressors and may contribute to development of type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD). In this article, we investigated whether chronically elevated insulin levels are associated with cellular senescence in the human liver. In 107 individuals undergoing bariatric surgery, hepatic senescence markers were assessed by immunohistochemistry as well as transcriptomics. A subset of 180 participants from the ongoing Finnish Kuopio OBesity Surgery (KOBS) study was used as validation cohort. We found plasma insulin to be highly associated with various markers of cellular senescence in liver tissue. The liver transcriptome of individuals with high insulin revealed significant upregulation of several genes associated with senescence: p21, TGFβ, PI3K, HLA-G, IL8, p38, Ras, and E2F. Insulin associated with hepatic senescence independently of NAFLD and plasma glucose. By using transcriptomic data from the KOBS study, we could validate the association of insulin with p21 in the liver. Our results support a potential role for hyperinsulinemia in induction of cellular senescence in the liver. These findings suggest possible benefits of lowering insulin levels in obese individuals with insulin resistance.
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| 9. |
- Mikkelsen, Randi Bonke, et al.
(författare)
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Type 2 diabetes is associated with increased circulating levels of 3-hydroxydecanoate activating GPR84 and neutrophil migration
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:12
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Tidskriftsartikel (refereegranskat)abstract
- Obesity and diabetes are associated with inflammation and altered plasma levels of several metabolites, which may be involved in disease progression. Some metabolites can activate G protein-coupled receptors (GPCRs) expressed on immune cells where they can modulate metabolic inflammation. Here, we find that 3-hydroxydecanoate is enriched in the circulation of obese individuals with type 2 diabetes (T2D) compared with nondiabetic controls. Administration of 3-hydroxydecanoate to mice promotes immune cell recruitment to adipose tissue, which was associated with adipose inflammation and increased fasting insulin levels. Furthermore, we demonstrate that 3-hydroxydecanoate stimulates migration of primary human and mouse neutrophils, but not monocytes, through GPR84 and Gαi signaling in vitro. Our findings indicate that 3-hydroxydecanoate is a T2D-associated metabolite that increases inflammatory responses and may contribute to the chronic inflammation observed in diabetes.
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| 10. |
- Van Olden, C. C., et al.
(författare)
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A systems biology approach to understand gut microbiota and host metabolism in morbid obesity: design of the BARIA Longitudinal Cohort Study
- 2021
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 289:3, s. 340-354
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Prevalence of obesity and associated diseases, including type 2 diabetes mellitus, dyslipidaemia and non-alcoholic fatty liver disease (NAFLD), are increasing. Underlying mechanisms, especially in humans, are unclear. Bariatric surgery provides the unique opportunity to obtain biopsies and portal vein blood-samples. Methods The BARIA Study aims to assess how microbiota and their metabolites affect transcription in key tissues and clinical outcome in obese subjects and how baseline anthropometric and metabolic characteristics determine weight loss and glucose homeostasis after bariatric surgery. We phenotype patients undergoing bariatric surgery (predominantly laparoscopic Roux-en-Y gastric bypass), before weight loss, with biometrics, dietary and psychological questionnaires, mixed meal test (MMT) and collect fecal-samples and intra-operative biopsies from liver, adipose tissues and jejunum. We aim to include 1500 patients. A subset (approximately 25%) will undergo intra-operative portal vein blood-sampling. Fecal-samples are analyzed with shotgun metagenomics and targeted metabolomics, fasted and postprandial plasma-samples are subjected to metabolomics, and RNA is extracted from the tissues for RNAseq-analyses. Data will be integrated using state-of-the-art neuronal networks and metabolic modeling. Patient follow-up will be ten years. Results Preoperative MMT of 170 patients were analysed and clear differences were observed in glucose homeostasis between individuals. Repeated MMT in 10 patients showed satisfactory intra-individual reproducibility, with differences in plasma glucose, insulin and triglycerides within 20% of the mean difference. Conclusion The BARIA study can add more understanding in how gut-microbiota affect metabolism, especially with regard to obesity, glucose metabolism and NAFLD. Identification of key factors may provide diagnostic and therapeutic leads to control the obesity-associated disease epidemic.
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