The DNA methylome of inflammatory bowel disease (IBD) reflects intrinsic and extrinsic factors in intestinal mucosal cells

Agliata, Iolanda; Fernández-Jiménez, Nora; Goldsmith, Chloe D.; Marie, Julien C.; Bilbao, José Ramón; Dante, Robert; Hernandez-Vargas, Héctor

doi:10.1080/15592294.2020.1748916

Cited by 23 publications

(12 citation statements)

References 61 publications

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“…Interestingly, many of the publications we examined did not even mention leukocyte infiltration as a confounding factor in their quest to find disease biomarkers, despite examining inflammatory diseases [21,26,[29][30][31]. Others mentioned leukocyte infiltration as a possibility or discussed cellular heterogeneity [22,23,28,32,34] but did not control for this variability. In some cases, this occurred in meta-analyses where the authors examined previously collected data and conducting additional experimental controls was not possible [22,23,34].…”

Section: Independent Validation Of Ls-dmps In Inflammatory Diseasementioning

confidence: 98%

“…cn/ ewas/ atlas) [20], we discovered 28 associated traits from 35 publications (Table S2) that were associated with our ls-DMPs. The top three traits with the highest number overlapping CpG sites were psoriasis (33 DMPs identified by Chandra et al [21]), inflammatory bowel disease (IBD) (12 DMPs identified by Agliata et al [22]), and Alzheimer disease (AD) (12 DMPs identified over three publications [23][24][25]).…”

Section: Independent Validation Of Ls-dmps In Inflammatory Diseasementioning

confidence: 99%

“…Others mentioned leukocyte infiltration as a possibility or discussed cellular heterogeneity [22,23,28,32,34] but did not control for this variability. In some cases, this occurred in meta-analyses where the authors examined previously collected data and conducting additional experimental controls was not possible [22,23,34]. Only one publication investigated the proportion of leukocytes in their samples; however, these data were not shown [27].…”

Section: Independent Validation Of Ls-dmps In Inflammatory Diseasementioning

confidence: 99%

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Leukocyte-specific DNA methylation biomarkers and their implication for pathological epigenetic analysis

Dunnet

Ortega‐Recalde

Waters

et al. 2022

Epigenetics Commun.

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Background Distinct cell types can be identified by their DNA methylation patterns. Much research over the last decade has focused on DNA methylation changes in cancer or the use of cell-free circulating DNA in plasma to identify damaged tissue in cases of trauma or organ transplantation. However, there has been little research into the differential methylation patterns between leukocytes and other tissues and how they can be used as a detection tool for immune activity in a range of contexts. Results We have identified several loci that are fully methylated in leukocytes but virtually devoid of methylation in a range of other mesoderm-, ectoderm-, and endoderm-derived tissues. We validated these biomarkers using amplicon-bisulphite-sequencing on saliva and in vitro mixing of peripheral blood mononuclear cells and intestinal organoid cells combined at a defined range of ratios. Interestingly, these methylation biomarkers have previously been identified as altered in various inflammatory diseases, including Alzheimer disease, inflammatory bowel disease, and psoriasis. We hypothesise this is due to leukocyte infiltration rather than being a feature of the diseased cells themselves. Moreover, we show a positive linear relationship between infiltrating leukocytes and DNA methylation levels at the HOXA3 locus in six cancer types, indicative of further immune cell infiltration. Conclusions Our data emphasise the importance of considering cellular composition when undertaking DNA methylation analysis and demonstrate the feasibility of developing new diagnostic tests to detect inflammation and immune cell infiltration.

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Section: Independent Validation Of Ls-dmps In Inflammatory Diseasementioning

confidence: 98%

Section: Independent Validation Of Ls-dmps In Inflammatory Diseasementioning

confidence: 99%

Section: Independent Validation Of Ls-dmps In Inflammatory Diseasementioning

confidence: 99%

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Leukocyte-specific DNA methylation biomarkers and their implication for pathological epigenetic analysis

Dunnet

Ortega‐Recalde

Waters

et al. 2022

Epigenetics Commun.

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“…IBD consist of multifactorial diseases, whose pathophysiological architecture is based on predisposing genetic factors added to environmental factors and the intestinal microbiota, as illustrated in (Figure 2). However, studies still seek to elucidate better these elements and how they participate in the development of an exacerbated and extremely harmful inflammatory response [22][23][24].…”

Section: Inflammatory Bowel Disease: Pathophysiologymentioning

confidence: 99%

The Role of Prebiotics on Inflammatory Bowel Disease: A Systematic Review

Vm¹,

Barbalho²,

Jn³

et al. 2021

JJGH

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1.1. Background: Inflammatory Bowel Diseases (IBD) are a set of disorders of idiopathic and multifactorial etiology, composed of two main entities: Ulcerative Colitis (UC) and Crohn's Disease (CD). The pathophysiology relies on inflammatory responses of the intestinal wall. Modern western dietary habits lack fibers and short-chain fatty acids (SCFAs), contributing to dysbiosis and malnutrition. Prebiotics are non-digestible oligosaccharides present in foods with a high amount of fiber and depend on microorganisms' action to be metabolized. This paper aimed to build a systematic review of the effects of IBD. Methods:This review included studies available in MEDLINE-PubMed, EMBASE, and Cochrane databases, and the final selection included ten studies performed in humans. Our results show that ten studies investigated the use of prebiotics in humans. Therapies with prebiotics could improve and correct the microbiome imbalance caused by gut diseases, dietary habits, and drug administration. Thus, they could be considered as adjuvant therapy for IBD. However, the included studies were performed with a low number of patients, with different doses, different types of prebiotics, and therapy duration. Conclusion:We suggest that more clinical trials are needed to elucidate the correct doses, types of prebiotics, and treatment duration to reach beneficial results for IBD patients.

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“…DNA methylation (DNAm) is one of the main epigenetic mechanisms known to play a key role in regulating cellular function of human cells including the intestinal epithelium 7,8,[15][16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

Culture Associated DNA Methylation Changes Impact on Cellular Function of Human Intestinal Organoids

Edgar

Perrone

Foster

et al. 2022

Preprint

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Background & AimsHuman intestinal epithelial organoids (IEO) are a powerful tool to model major aspects of intestinal development, health and diseases, as patient derived cultures retain many features found in-vivo. A necessary aspect of the organoid model is the requirement to expand cultures in-vitro through several rounds of passaging. This is of concern, as the passaging of cells has been shown to affect cell morphology, ploidy, and function. In this study, we address concerns around long term passaging of IEO to better characterise and define effects on cell morphology and function.MethodsHere we have analysed 173 human IEO from two sampling sites, terminal ileum and sigmoid colon and examined the effect of culture duration on DNA methylation (DNAm), gene expression and cellular function including their response to proinflammatory cytokines and in-vitro cell differentiation.ResultsOur analyses revealed a major effect of culture duration on DNAm, leading to significant changes at 61,337 loci representing approximately 8% of all CpGs tested. Although global cellular functions such as gut segment-specific gene expression remained stable, a subset of methylation changes correlated with altered gene expression at baseline as well as in response to inflammatory cytokine exposure and in-vitro differentiation. Importantly, epigenetic changes were found to be enriched in genomic regions associated with colonic cancer and distant to the site of replication indicating similarities to malignant transformation.ConclusionsOur study reveals culture-associated epigenetic, transcriptomic and functional changes in human mucosa derived IEO and highlights the importance of considering passage number as a potentially confounding factor.SynopsisThis work describes cell culture induced changes to DNA methylation, gene expression and cellular function in human IEO. Globally organoids lost DNA methylation with time in culture while DNA methylation also became generally more variable. This work suggests a shifted epigenetic profile in organoids cultured long-term.

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The DNA methylome of inflammatory bowel disease (IBD) reflects intrinsic and extrinsic factors in intestinal mucosal cells

Cited by 23 publications

References 61 publications

Leukocyte-specific DNA methylation biomarkers and their implication for pathological epigenetic analysis

Leukocyte-specific DNA methylation biomarkers and their implication for pathological epigenetic analysis

The Role of Prebiotics on Inflammatory Bowel Disease: A Systematic Review

Culture Associated DNA Methylation Changes Impact on Cellular Function of Human Intestinal Organoids

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