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Hyötyläinen, T., McGlinchey, A. J., Salihovic, S., Schubert, A., Douglas, A., Hay, D. C., . . . Oresic, M. (2024). In utero exposures to perfluoroalkyl substances and the human fetal liver metabolome in Scotland: a cross-sectional study. The Lancet Planetary Health, 8(1), e5-e17
Open this publication in new window or tab >>In utero exposures to perfluoroalkyl substances and the human fetal liver metabolome in Scotland: a cross-sectional study
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2024 (English)In: The Lancet Planetary Health, E-ISSN 2542-5196, Vol. 8, no 1, p. e5-e17Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances are classed as endocrine disrupting compounds but continue to be used in many products such as firefighting foams, flame retardants, utensil coatings, and waterproofing of food packaging. Perfluoroalkyl exposure aberrantly modulates lipid, metabolite, and bile acid levels, increasing susceptibility to onset and severity of metabolic diseases, such as diabetes and metabolic dysfunction-associated steatotic liver disease. To date, most studies in humans have focused on perfluoroalkyl-exposure effects in adults. In this study we aimed to show if perfluoroalkyls are present in the human fetal liver and if they have metabolic consequences for the human fetus.

METHODS: In this cross-sectional study, human fetal livers from elective termination of pregnancies at the Aberdeen Pregnancy Counselling Service, Aberdeen, UK, were analysed by both targeted (bile acids and perfluoroalkyl substances) and combined targeted and untargeted (lipids and polar metabolites) mass spectrometry based metabolomic analyses, as well as with RNA-Seq. Only fetuses from normally progressing pregnancies (determined at ultrasound scan before termination), terminated for non-medical reasons, from women older than 16 years, fluent in English, and between 11 and 21 weeks of gestation were collected. Women exhibiting considerable emotional distress or whose fetuses had anomalies identified at ultrasound scan were excluded. Stringent bioinformatic and statistical methods such as partial correlation network analysis, linear regression, and pathway analysis were applied to this data to investigate the association of perfluoroalkyl exposure with hepatic metabolic pathways.

FINDINGS: Fetuses included in this study were collected between Dec 2, 2004, and Oct 27, 2014. 78 fetuses were included in the study: all 78 fetuses were included in the metabolomics analysis (40 female and 38 male) and 57 fetuses were included in the RNA-Seq analysis (28 female and 29 male). Metabolites associated with perfluoroalkyl were identified in the fetal liver and these varied with gestational age. Conjugated bile acids were markedly positively associated with fetal age. 23 amino acids, fatty acids, and sugar derivatives in fetal livers were inversely associated with perfluoroalkyl exposure, and the bile acid glycolithocholic acid was markedly positively associated with all quantified perfluoroalkyl. Furthermore, 7α-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis rate, was strongly positively associated with perfluoroalkyl levels and was detectable as early as gestational week 12.

INTERPRETATION: Our study shows direct evidence for the in utero effects of perfluoroalkyl exposure on specific key hepatic products. Our results provide evidence that perfluoroalkyl exposure, with potential future consequences, manifests in the human fetus as early as the first trimester of gestation. Furthermore, the profiles of metabolic changes resemble those observed in perinatal perfluoroalkyl exposures. Such exposures are already linked with susceptibility, initiation, progression, and exacerbation of a wide range of metabolic diseases.

Place, publisher, year, edition, pages
Elsevier, 2024
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:oru:diva-110658 (URN)10.1016/S2542-5196(23)00257-7 (DOI)001158718400001 ()38199723 (PubMedID)2-s2.0-85181938990 (Scopus ID)
Funder
EU, Horizon EuropeEU, FP7, Seventh Framework ProgrammeSwedish Research CouncilSwedish Research Council FormasNovo Nordisk FoundationAcademy of Finland
Note

FUNDING: UK Medical Research Council, Horizon Europe Program of the European Union, Seventh Framework Programme of the European Union, NHS Grampian Endowments grants, European Partnership for the Assessment of Risks from Chemicals, Swedish Research Council, Formas, Novo Nordisk Foundation, and the Academy of Finland.

Available from: 2024-01-11 Created: 2024-01-11 Last updated: 2024-02-20Bibliographically approved
Sen, P., Qadri, S., Luukkonen, P. K., Ragnarsdottir, O., McGlinchey, A. J., Jäntti, S., . . . Hyötyläinen, T. (2022). Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease. Journal of Hepatology, 76(2), 283-293
Open this publication in new window or tab >>Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease
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2022 (English)In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 76, no 2, p. 283-293Article in journal (Refereed) Published
Abstract [en]

Background & aims: Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism.

Methods: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using 4 mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARa-humanized mouse model.

Results: PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly those related to bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in females than males. Specifically, we observed PFAS-associated upregulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-à-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes.

Conclusions: Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism.

Lay summary: There is increasing evidence that specific environmental contaminants, such as perfluorinated alkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts metabolic processes associated with NAFLD, and that the effect is different in females and males.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
chemical exposure, exposome, perfluorinated alkyl substance, non- alcoholic steatohepatitis, fibrosis, bile acid, lipidome, metabolome, metabolic pathway
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:oru:diva-94873 (URN)10.1016/j.jhep.2021.09.039 (DOI)000752560300006 ()34627976 (PubMedID)2-s2.0-85120349915 (Scopus ID)
Funder
Novo Nordisk, NNF20OC0063971Academy of Finland, 333981 309263Swedish Research Council, 2016-05176EU, Horizon 2020, 634413
Note

Funding agencies:

Juselius Foundation

United States Department of Health & Human Services

National Institutes of Health (NIH) - USA

NIH National Institute of Environmental Health Sciences (NIEHS) P42 ES007381 R01 ES027813

Available from: 2021-10-11 Created: 2021-10-11 Last updated: 2022-03-03Bibliographically approved
McGlinchey, A. J., Govaere, O., Geng, D., Ratziu, V., Allison, M., Bousier, J., . . . Oresic, M. (2022). Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease. JHEP Reports, 4(5), Article ID 100477.
Open this publication in new window or tab >>Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease
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2022 (English)In: JHEP Reports, E-ISSN 2589-5559, Vol. 4, no 5, article id 100477Article in journal (Refereed) Published
Abstract [en]

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis).

Methods: We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis.

Results: Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered.

Conclusions: Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress.

Clinical Trials registration: The study is registered at Clinicaltrials.gov (NCT04442334).

Lay summary: Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic 'watershed' in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Fibrosis, Lipidomics, Mass spectrometry, Metabolomics, Non-alcoholic steatohepatitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-98643 (URN)10.1016/j.jhepr.2022.100477 (DOI)000795853800009 ()35434590 (PubMedID)2-s2.0-85127766899 (Scopus ID)
Funder
EU, Horizon 2020
Note

Funding agencies:

Elucidating Pathways of Steatohepatitis (EPoS) consortium - Horizon 2020634413

Innovative Medicines Initiative (IMI2) Program of the European Union 777377

EFPIA

Newcastle NIHR Biomedical Research Centre

European NAFLD Registry

Available from: 2022-04-21 Created: 2022-04-21 Last updated: 2024-06-24Bibliographically approved
Sen, P., Govaere, O., Sinioja, T., McGlinchey, A. J., Geng, D., Ratziu, V., . . . Oresic, M. (2022). Quantitative modeling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease. iScience, 25(9), Article ID 104949.
Open this publication in new window or tab >>Quantitative modeling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease
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2022 (English)In: iScience, E-ISSN 2589-0042 , Vol. 25, no 9, article id 104949Article in journal (Refereed) Published
Abstract [en]

Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent disease that is associated with multiple metabolic disturbances, yet the metabolic pathways underlying its progression are poorly understood. Here, we studied metabolic pathways of the human liver across the full histological spectrum of NAFLD. We analyzed whole liver tissue transcriptomics and serum metabolomics data obtained from a large, prospectively enrolled cohort of 206 histologically characterized patients derived from the European NAFLD Registry and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. We identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids, and their link with complex glycosaminoglycans in advanced fibrosis. Furthermore, we derived GEMs and identified metabolic signatures of three common NAFLD-associated gene variants (PNPLA3, TM6SF2, and HSD17B13). The study demonstrates dysregulated liver metabolic pathways which may contribute to the progression of NAFLD.

Place, publisher, year, edition, pages
Cell Press, 2022
Keywords
Health sciences, Metabolomics, Omics, Systems biology
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-101123 (URN)10.1016/j.isci.2022.104949 (DOI)000861134500001 ()36065182 (PubMedID)2-s2.0-85136475793 (Scopus ID)
Funder
European CommissionNovo Nordisk, NNF20OC0063971Academy of Finland
Note

Funding agencies:

EPOS (Elucidating Pathways of Steatohepatitis) - Horizon 2020 Framework Program of the European Union 634413

Innovative Medicines Initiative 2 Joint Undertaking 777377

EFPIA

UK Research & Innovation (UKRI)

Medical Research Council UK (MRC)

  

Available from: 2022-09-07 Created: 2022-09-07 Last updated: 2022-12-19Bibliographically approved
Sen, P., Lamichhane, S., Mathema, V. B., McGlinchey, A. J., Dickens, A. M., Khoomrung, S. & Oresic, M. (2021). Deep learning meets metabolomics: a methodological perspective. Briefings in Bioinformatics, 22(2), 1531-1542
Open this publication in new window or tab >>Deep learning meets metabolomics: a methodological perspective
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2021 (English)In: Briefings in Bioinformatics, ISSN 1467-5463, E-ISSN 1477-4054, Vol. 22, no 2, p. 1531-1542Article, review/survey (Refereed) Published
Abstract [en]

Deep learning (DL), an emerging area of investigation in the fields of machine learning and artificial intelligence, has markedly advanced over the past years. DL techniques are being applied to assist medical professionals and researchers in improving clinical diagnosis, disease prediction and drug discovery. It is expected that DL will help to provide actionable knowledge from a variety of 'big data', including metabolomics data. In this review, we discuss the applicability of DL to metabolomics, while presenting and discussing several examples from recent research. We emphasize the use of DL in tackling bottlenecks in metabolomics data acquisition, processing, metabolite identification, as well as in metabolic phenotyping and biomarker discovery. Finally, we discuss how DL is used in genome-scale metabolic modelling and in interpretation of metabolomics data. The DL-based approaches discussed here may assist computational biologists with the integration, prediction and drawing of statistical inference about biological outcomes, based on metabolomics data.

Place, publisher, year, edition, pages
Oxford University Press, 2021
Keywords
Artificial intelligence, deep learning, genome-scale metabolic modelling, lipidomics, machine learning, metabolism, metabolomics
National Category
Bioinformatics and Computational Biology
Identifiers
urn:nbn:se:oru:diva-85810 (URN)10.1093/bib/bbaa204 (DOI)000642298000075 ()32940335 (PubMedID)2-s2.0-85103474602 (Scopus ID)
Available from: 2020-09-18 Created: 2020-09-18 Last updated: 2025-02-07Bibliographically approved
Selvaraj, E. A., Mózes, F. E., Ajmer Jayaswal, A. N., Zafarmand, M. H., Vali, Y., Lee, J. A., . . . Pavlides, M. (2021). Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: a systematic review and meta-analysis. Journal of Hepatology, 75(4), 770-785
Open this publication in new window or tab >>Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: a systematic review and meta-analysis
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2021 (English)In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 75, no 4, p. 770-785Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), two-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) are proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH).

METHODS: PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model.

RESULTS: We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and four 2DSWE studies, and for diagnosing NASH in four MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs.

CONCLUSIONS: When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking.

LAY SUMMARY: Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy in assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Biomarkers, Diffusion weighted imaging, Iron-corrected T1, Liver fibrosis, Magnetic resonance elastography, Magnetic resonance imaging, NASH-MRI, Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Shear wave elastography, Transient elastography, deMILI, fibro-MRI
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-91805 (URN)10.1016/j.jhep.2021.04.044 (DOI)000701809900006 ()33991635 (PubMedID)2-s2.0-85108940286 (Scopus ID)
Funder
EU, Horizon 2020
Note

Review

Funding agencies:

Innovative Medicines Initiative 2 Joint Undertaking 777377

Europen Federation of Pharmaceutical Industries and Associations (efpia.eu)

Available from: 2021-05-17 Created: 2021-05-17 Last updated: 2024-09-03Bibliographically approved
Sen, P., Govaere, O., Sinioja, T., McGlinchey, A. J., Geng, D., Ratziu, V., . . . Oresic, M. (2021). Genome-scale metabolic modeling of human hepatocytes reveals dysregulation of glycosphingolipid pathways in progressive non-alcoholic fatty liver disease. Paper presented at The International Liver Congress, (Digital congress), June 23–26, 2021. Journal of Hepatology, 75(Suppl. 2), S256-S256
Open this publication in new window or tab >>Genome-scale metabolic modeling of human hepatocytes reveals dysregulation of glycosphingolipid pathways in progressive non-alcoholic fatty liver disease
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2021 (English)In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 75, no Suppl. 2, p. S256-S256Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background and aims: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver diseases intertwined with the metabolic disorders. The prevalence of NAFLD is rapidly increasing worldwide, while the pathologyand the underlying mechanism driving NAFLD is not fully understood. In NAFLD, a series of metabolic changes takes place in the liver. However, the alteration of the metabolic pathways in the human liver along the progression of NAFLD,i.e., transition from non-alcoholic steatosis (NAFL) to steatohepatitis (NASH) through cirrhosis remains to be discovered. Here, we sought to examine the metabolic pathways of the human liver across the full histological spectrum of NAFLD.

Method: We analyzed the whole liver tissue transcriptomic (RNA-Seq)1 and serum metabolomics data obtained from a large cohort of histologically characterized patients derived from the European NAFLD Registry (n = 206), and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. The integrative approach employed in this study has enabled us to understand the regulation of the metabolic pathways of human liver in NAFL, and with progressive NASH-associated fibrosis (F0-F4).

Results: Our study identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids, and their link with complex glycosaminoglycans in advanced fibrosis. Furthermore, by applying genome-scale metabolic modeling, we were able to identify the metabolic differences among carriers of widely validated genetic variants associated with NAFLD/NASH disease severity in three genes (PNPLA3,TM6SF2andHSD17B13).

Conclusion: The study provides insights into the underlying pathways of the progressive-fibrosing steatohepatitis. Of note, there is a marked dysregulation of the glycosphingolipid metabolism in the liver of the patients with advanced fibrosis.

Place, publisher, year, edition, pages
Elsevier, 2021
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-93394 (URN)000667753800100 ()
Conference
The International Liver Congress, (Digital congress), June 23–26, 2021
Available from: 2021-08-05 Created: 2021-08-05 Last updated: 2021-08-05Bibliographically approved
Fart, F., Salihovic, S., McGlinchey, A. J., Gareau, M. G., Oresic, M., Halfvarson, J., . . . Schoultz, I. (2021). Perfluoroalkyl substances are increased in patients with late-onset ulcerative colitis and induce intestinal barrier defects ex vivo in murine intestinal tissue. Scandinavian Journal of Gastroenterology, 56(11), 1286-1295
Open this publication in new window or tab >>Perfluoroalkyl substances are increased in patients with late-onset ulcerative colitis and induce intestinal barrier defects ex vivo in murine intestinal tissue
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2021 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 56, no 11, p. 1286-1295Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Environmental factors are strongly implicated in late-onset of inflammatory bowel disease. Here, we investigate whether high levels of perfluoroalkyl substances are associated with (1) late-onset inflammatory bowel disease, and (2) disturbances of the bile acid pool. We further explore the effect of the specific perfluoroalkyl substance perfluorooctanoic acid on intestinal barrier function in murine tissue.

METHODS: Serum levels of perfluoroalkyl substances and bile acids were assessed by ultra-performance liquid chromatography coupled to a triple-quadrupole mass spectrometer in matched samples from patients with ulcerative colitis (n = 20) and Crohn's disease (n = 20) diagnosed at the age of ≥55 years. Age and sex-matched blood donors (n = 20), were used as healthy controls. Ex vivo Ussing chamber experiments were performed to assess the effect of perfluorooctanoic acid on ileal and colonic murine tissue (n = 9).

RESULTS: The total amount of perfluoroalkyl substances was significantly increased in patients with ulcerative colitis compared to healthy controls and patients with Crohn's disease (p < .05). Ex vivo exposure to perfluorooctanoic acid induced a significantly altered ileal and colonic barrier function. The distribution of bile acids, as well as the correlation pattern between (1) perfluoroalkyl substances and (2) bile acids, differed between patient and control groups.

DISCUSSION: Our results demonstrate that perfluoroalkyl substances levels are increased in patients with late-onset ulcerative colitis and may contribute to the disease by inducing a dysfunctional intestinal barrier.

Place, publisher, year, edition, pages
Taylor & Francis, 2021
Keywords
PFAS, bile acids, inflammatory bowel disease, intestinal barrier function, ulcerative colitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-93618 (URN)10.1080/00365521.2021.1961306 (DOI)000684451500001 ()34383611 (PubMedID)2-s2.0-85112297285 (Scopus ID)
Funder
Swedish Research Council, 2016-05176European CommissionSwedish Research Council Formas, 2019-00869
Note

Funding Agencies:

Faculty of Medicine and Health, Örebro University ORU2018/04457

Bo Rydin foundation F0514

Örebro Hospital Research Foundation OLL-790011

Available from: 2021-08-16 Created: 2021-08-16 Last updated: 2022-06-16Bibliographically approved
Hylén, U., McGlinchey, A. J., Oresic, M., Bejerot, S., Humble, M. B., Särndahl, E., . . . Eklund, D. (2021). Potential Transdiagnostic Lipid Mediators of Inflammatory Activity in Individuals With Serious Mental Illness. Frontiers in Psychiatry, 12, Article ID 778325.
Open this publication in new window or tab >>Potential Transdiagnostic Lipid Mediators of Inflammatory Activity in Individuals With Serious Mental Illness
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2021 (English)In: Frontiers in Psychiatry, E-ISSN 1664-0640, Vol. 12, article id 778325Article in journal (Refereed) Published
Abstract [en]

Mental disorders are heterogeneous and psychiatric comorbidities are common. Previous studies have suggested a link between inflammation and mental disorders. This link can manifest as increased levels of proinflammatory mediators in circulation and as signs of neuroinflammation. Furthermore, there is strong evidence that individuals suffering from psychiatric disorders have increased risk of developing metabolic comorbidities. Our group has previously shown that, in a cohort of low-functioning individuals with serious mental disorders, there is increased expression of genes associated with the NLRP3 inflammasome, a known sensor of metabolic perturbations, as well as increased levels of IL-1-family cytokines. In the current study, we set out to explore the interplay between disease-specific changes in lipid metabolism and known markers of inflammation. To this end, we performed mass spectrometry-based lipidomic analysis of plasma samples from low-functioning individuals with serious mental disorders (n = 39) and matched healthy controls (n = 39). By identifying non-spurious immune-lipid associations, we derived a partial correlation network of inflammatory markers and molecular lipids. We identified levels of lipids as being altered between individuals with serious mental disorders and controls, showing associations between lipids and inflammatory mediators, e.g., osteopontin and IL-1 receptor antagonist. These results indicate that, in low-functioning individuals with serious mental disorders, changes in specific lipids associate with immune mediators that are known to affect neuroinflammatory diseases.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021
Keywords
mental disorder (disease), schizophrenia, autism spectrum disorder (ASD), obsessive-compulsive disorder, lipidomics, inflammation
National Category
Psychiatry
Identifiers
urn:nbn:se:oru:diva-95923 (URN)10.3389/fpsyt.2021.778325 (DOI)000728838100001 ()34899431 (PubMedID)2-s2.0-85120948410 (Scopus ID)
Available from: 2021-12-13 Created: 2021-12-13 Last updated: 2024-03-18Bibliographically approved
Alves, M. A., Lamichhane, S., Dickens, A., McGlinchey, A. J., Ribeiro, H. C., Sen, P., . . . Oresic, M. (2021). Systems biology approaches to study lipidomes in health and disease. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1866(2), Article ID 158857.
Open this publication in new window or tab >>Systems biology approaches to study lipidomes in health and disease
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2021 (English)In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1866, no 2, article id 158857Article, review/survey (Refereed) Published
Abstract [en]

Lipids have many important biological roles, such as energy storage sources, structural components of plasma membranes and as intermediates in metabolic and signaling pathways. Lipid metabolism is under tight homeostatic control, exhibiting spatial and dynamic complexity at multiple levels. Consequently, lipid-related disturbances play important roles in the pathogenesis of most of the common diseases. Lipidomics, defined as the study of lipidomes in biological systems, has emerged as a rapidly-growing field. Due to the chemical and functional diversity of lipids, the application of a systems biology approach is essential if one is to address lipid functionality at different physiological levels. In parallel with analytical advances to measure lipids in biological matrices, the field of computational lipidomics has been rapidly advancing, enabling modeling of lipidomes in their pathway, spatial and dynamic contexts. This review focuses on recent progress in systems biology approaches to study lipids in health and disease, with specific emphasis on methodological advances and biomedical applications.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Lipidomics, disease biomarkers, genome-scale metabolic modeling, metabolomics, systems biology
National Category
Bioinformatics and Computational Biology
Identifiers
urn:nbn:se:oru:diva-87817 (URN)10.1016/j.bbalip.2020.158857 (DOI)000600665000009 ()33278596 (PubMedID)2-s2.0-85097710331 (Scopus ID)
Funder
Novo Nordisk, NNF19OC0057418Academy of Finland, 323171Swedish Research Council, 2016-05176 201802629
Available from: 2020-12-06 Created: 2020-12-06 Last updated: 2025-02-07Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6682-6030

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