| 1. |
- Allin, K. H., et al.
(författare)
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Aberrant intestinal microbiota in individuals with prediabetes
- 2018
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 61:4, s. 810-820
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Individuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1-7.0 mmol/l or HbA(1c) of 42-48 mmol/mol [6.0-6.5%]) and a range of clinical biomarkers of poor metabolic health. Methods In the present case-control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age-and sex-matched individuals with normal glucose regulation. Results We found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of Clostridium was decreased (mean log(2) fold change -0.64 (SEM 0.23), p(adj) = 0.0497), whereas the abundances of Dorea, [ Ruminococcus], Sutterella and Streptococcus were increased (mean log(2) fold change 0.51 (SEM 0.12), p(adj) = 5 x 10(-4); 0.51 (SEM 0.11), p(adj) = 1 x 10-4; 0.60 (SEM 0.21), p(adj) = 0.0497; and 0.92 (SEM0.21), padj = 4 x 10(-4), respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and Akkermansia muciniphila, which both displayed lower abundance among individuals with prediabetes (mean log(2) fold change -1.74 (SEM0.41), p(adj) = 2 x 10(-3) and -1.65 (SEM0.34), p(adj) = 4 x 10(-4), respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice. Conclusions/interpretation Collectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus Clostridium and the mucin-degrading bacterium A. muciniphila. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.
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| 2. |
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| 3. |
- Belda, E., et al.
(författare)
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Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism
- 2022
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 71:12
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity.
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| 4. |
- Forslund, Sofia K., et al.
(författare)
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Combinatorial, additive and dose-dependent drug–microbiome associations
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 600:7889, s. 500-505
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Tidskriftsartikel (refereegranskat)abstract
- During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1–5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.
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| 5. |
- Fromentin, S., et al.
(författare)
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Microbiome and metabolome features of the cardiometabolic disease spectrum
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:2, s. 303-314
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Tidskriftsartikel (refereegranskat)abstract
- By studying individuals along a spectrum of cardiometabolic disease and adjusting for effects of lifestyle and medication, this investigation identifies alterations of the metabolome and microbiome from dysmetabolic conditions, such as obesity and type 2 diabetes, to ischemic heart disease. Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.
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| 6. |
- Gebre-Medhin, Samuel, et al.
(författare)
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Recurrent Rearrangement of the PHF1 Gene in Ossifying Fibromyxoid Tumors.
- 2012
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 181:3, s. 1069-1077
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Tidskriftsartikel (refereegranskat)abstract
- Ossifying fibromyxoid tumor (OFMT) is a soft tissue tumor of unknown lineage. Although most cases are histologically and clinically benign, some show malignant morphological features and local recurrences are not uncommon; a few may even metastasize. In the present study, cytogenetic analysis identified different structural rearrangements of chromosome band 6p21 in tumor cells from three cases of OFMT, including one with typical, one with atypical, and one with malignant morphological features. Mapping of the 6p21 breakpoint by fluorescence in situ hybridization (FISH) indicated that the PHF1 gene was rearranged in all three cases. Further FISH, 5'-rapid amplification of cDNA ends, and RT-PCR analyses disclosed an EP400/PHF1 fusion transcript in one of the cases. Interphase FISH on tumor sections from 13 additional cases of OFMT showed rearrangement of the PHF1 locus in four of four typical, two of three atypical, and one of six malignant lesions. Thus, the PHF1 gene, previously shown to be the 3'-partner of fusion genes in endometrial stromal tumors, is also recurrently involved in the pathogenesis of OFMTs, irrespective of whether they are diagnosed as typical, atypical, or malignant lesions. The PHF1 protein interacts with the polycomb-repressive complex 2 (PRC2), which, in turn, regulates the expression of a variety of developmental genes. Thus, the results indicate that deregulation of PRC2 target genes is crucial for OFMT development.
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| 7. |
- Hansén Nord, Karolin, et al.
(författare)
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Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation.
- 2008
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 98:2, s. 434-442
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Tidskriftsartikel (refereegranskat)abstract
- The initiating somatic genetic events in chordoma development have not yet been identified. Most cytogenetically investigated chordomas have displayed near-diploid or moderately hypodiploid karyotypes, with several numerical and structural rearrangements. However, no consistent structural chromosome aberration has been reported. This is the first array-based study characterising DNA copy number changes in chordoma. Array comparative genomic hybridisation (aCGH) identified copy number alterations in all samples and imbalances affecting 5 or more out of the 21 investigated tumours were seen on all chromosomes. In general, deletions were more common than gains and no high-level amplification was found, supporting previous findings of primarily losses of large chromosomal regions as an important mechanism in chordoma development. Although small imbalances were commonly found, the vast majority of these were detected in single cases; no small deletion affecting all tumours could be discerned. However, the CDKN2A and CDKN2B loci in 9p21 were homo- or heterozygously lost in 70% of the tumours, a finding corroborated by fluorescence in situ hybridisation, suggesting that inactivation of these genes constitute an important step in chordoma development.British Journal of Cancer (2008) 98, 434-442. doi:10.1038/sj.bjc.6604130 www.bjcancer.com Published online 11 December 2007.
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| 8. |
- Hansén Nord, Karolin, et al.
(författare)
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Heterogeneous genetic profiles in soft tissue myoepitheliomas
- 2008
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Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 21:11, s. 1311-1319
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Tidskriftsartikel (refereegranskat)abstract
- Myoepithelioma, mixed tumor and parachordoma are uncommon soft tissue tumors thought to represent morphological variants of a single tumor type. The genetic basis of these neoplasms is poorly understood. However, they morphologically resemble mixed tumor of the salivary glands (also known as pleomorphic adenoma), a tumor characterized by deregulated expression of PLAG1 or HMGA2. To evaluate a possible genetic relationship between these soft tissue and salivary gland tumors, PLAG1 expression levels and the genomic status of PLAG1 and HMGA2 were investigated in five soft tissue myoepitheliomas and one pleomorphic adenoma. In addition, all tumors were cytogenetically investigated and whole genome DNA copy number imbalances were studied in five of them. The genetic profiles were heterogeneous and the only aberration common to all soft tissue myoepitheliomas was a minimally deleted region of 3.55 Mb in chromosome band 19p13. Recurrent deletion of CDKN2A suggests that inactivation of this tumor suppressor gene is pathogenetically important in a subset. Furthermore, PLAG1 rearrangement was found in a soft tissue tumor from a patient previously treated for a salivary pleomorphic adenoma, indicating either metastasis of the salivary gland lesion or that some soft tissue tumors develop through the same mechanisms as their salivary gland counterparts.
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| 9. |
- Hansén Nord, Karolin, et al.
(författare)
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Integrative Genome and Transcriptome Analyses Reveal Two Distinct Types of Ring Chromosome in Soft Tissue Sarcomas.
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:4, s. 878-888
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Tidskriftsartikel (refereegranskat)abstract
- Gene amplification is a common phenomenon in malignant neoplasms of all types. One mechanism behind increased gene copy number is the formation of ring chromosomes. Such structures are mitotically unstable and during tumor progression they accumulate material from many different parts of the genome. Hence, their content varies considerably between and within tumors. Partly due to this extensive variation, the genetic content of many ring-containing tumors remains poorly characterized. Ring chromosomes are particularly prevalent in specific subtypes of sarcoma. Here, we have combined fluorescence in situ hybridization, global genomic copy number and gene expression data on ring-containing soft tissue sarcomas and show that they harbor two fundamentally different types of ring chromosome: MDM2-positive and MDM2-negative rings. While the former are often found in an otherwise normal chromosome complement, the latter seem to arise in the context of general chromosomal instability. In line with this, sarcomas with MDM2-negative rings commonly show complete loss of either CDKN2A or RB1-both known to be important for genome integrity. Sarcomas with MDM2-positive rings instead show co-amplification of a variety of potential driver oncogenes. More than one hundred different genes were found to be involved, many of which are known to induce cell growth, promote proliferation or inhibit apoptosis. Several of the amplified and overexpressed genes constitute potential drug targets.
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| 10. |
- Jin, Yuesheng, et al.
(författare)
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Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes.
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 51:5, s. 510-520
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Tidskriftsartikel (refereegranskat)abstract
- Soft tissue angiofibroma is a recently delineated tumor type of unknown cellular origin. Cytogenetic analysis of four cases showed that they shared a t(5;8)(p15;q13). In three of them it was the sole change, underlining its pathogenetic significance. FISH mapping suggested the involvement of the aryl hydrocarbon receptor repressor (AHRR) and nuclear receptor coactivator 2 (NCOA2) genes in 5p15 and 8q13, respectively. RT-PCR revealed in-frame AHRR/NCOA2 and NCOA2/AHHR transcripts in all four cases. Interphase FISH on paraffin-embedded tissue from 10 further cases without cytogenetic data showed that three were positive for fusion of AHRR and NCOA2. While AHRR has never been implicated in gene fusions before, NCOA2 is the 3'-partner in fusions with MYST3 and ETV6 in leukemias and with PAX3 and HEY1 in sarcomas. As in the previously described fusion proteins, NCOA2 contributes with its two activation domains to the AHRR/NCOA2 chimera, substituting for the repressor domain of AHRR. Because the amino terminal part of the transcription factor AHRR, responsible for the recognition of xenobiotic response elements in target genes and for heterodimerization, shows extensive homology with the aryl hydrocarbon receptor (AHR), the fusion is predicted to upregulate the AHR/ARNT signaling pathway. Indeed, global gene expression analysis showed upregulation of CYP1A1 as well as other typical target genes of this pathway, such as those encoding toll-like receptors. Apart from providing a diagnostic marker for soft tissue angiofibroma, the results also suggest that this tumor constitutes an interesting model for evaluating the cellular effects of AHR signaling. © 2012 Wiley Periodicals, Inc.
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