Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease

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Abstract

Studies of inflammatory bowel disease (IBD) have been inconclusive in relating microbiota with distribution of inflammation. We report microbiota, host transcriptomics, epigenomics and genetics from matched inflamed and non-inflamed colonic mucosa [50 Crohn’s disease (CD); 80 ulcerative colitis (UC); 31 controls]. Changes in community-wide and within-patient microbiota are linked with inflammation, but we find no evidence for a distinct microbial diagnostic signature, probably due to heterogeneous host-microbe interactions, and show only marginal microbiota associations with habitual diet. Epithelial DNA methylation improves disease classification and is associated with both inflammation and microbiota composition. Microbiota sub-groups are driven by dominant Enterbacteriaceae and Bacteroides species, representative strains of which are pro-inflammatory in vitro, are also associated with immune-related epigenetic markers. In conclusion, inflamed and non-inflamed colonic segments in both CD and UC differ in microbiota composition and epigenetic profiles.

Abstract

Inflammatory bowel disease (IBD) has been linked to host-microbiota interactions. Here, the authors investigate mucosa-associated microbiota using endoscopically-targeted biopsies from inflamed and non-inflamed colon in patients with Crohn’s disease and ulcerative colitis, finding associations with inflammation and host epigenomic alterations.

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Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease.

J.-P. Segain (2000)

Proinflammatory cytokines are key factors in the pathogenesis of Crohn's disease (CD). Activation of nuclear factor kappa B (NFkappaB), which is involved in their gene transcription, is increased in the intestinal mucosa of CD patients. As butyrate enemas may be beneficial in treating colonic inflammation, we investigated if butyrate promotes this effect by acting on proinflammatory cytokine expression. Intestinal biopsy specimens, isolated lamina propria cells (LPMC), and peripheral blood mononuclear cells (PBMC) were cultured with or without butyrate for assessment of secretion of tumour necrosis factor (TNF) and mRNA levels. NFkappaB p65 activation was determined by immunofluorescence and gene reporter experiments. Levels of NFkappaB inhibitory protein (IkappaBalpha) were analysed by western blotting. The in vivo efficacy of butyrate was assessed in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis. Butyrate decreased TNF production and proinflammatory cytokine mRNA expression by intestinal biopsies and LPMC from CD patients. Butyrate abolished lipopolysaccharide (LPS) induced expression of cytokines by PBMC and transmigration of NFkappaB from the cytoplasm to the nucleus. LPS induced NFkappaB transcriptional activity was decreased by butyrate while IkappaBalpha levels were stable. Butyrate treatment also improved TNBS induced colitis. Butyrate decreases proinflammatory cytokine expression via inhibition of NFkappaB activation and IkappaBalpha degradation. These anti-inflammatory properties provide a rationale for assessing butyrate in the treatment of CD.

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Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota.

Lindsey G Albenberg, Tatiana V. Esipova, Colleen P. Judge … (2014)

The gut microbiota is a complex and densely populated community in a dynamic environment determined by host physiology. We investigated how intestinal oxygen levels affect the composition of the fecal and mucosally adherent microbiota. We used the phosphorescence quenching method and a specially designed intraluminal oxygen probe to dynamically quantify gut luminal oxygen levels in mice. 16S ribosomal RNA gene sequencing was used to characterize the microbiota in intestines of mice exposed to hyperbaric oxygen, human rectal biopsy and mucosal swab samples, and paired human stool samples. Average Po2 values in the lumen of the cecum were extremely low (<1 mm Hg). In altering oxygenation of mouse intestines, we observed that oxygen diffused from intestinal tissue and established a radial gradient that extended from the tissue interface into the lumen. Increasing tissue oxygenation with hyperbaric oxygen altered the composition of the gut microbiota in mice. In human beings, 16S ribosomal RNA gene analyses showed an increased proportion of oxygen-tolerant organisms of the Proteobacteria and Actinobacteria phyla associated with rectal mucosa, compared with feces. A consortium of asaccharolytic bacteria of the Firmicute and Bacteroidetes phyla, which primarily metabolize peptones and amino acids, was associated primarily with mucus. This could be owing to the presence of proteinaceous substrates provided by mucus and the shedding of the intestinal epithelium. In an analysis of intestinal microbiota of mice and human beings, we observed a radial gradient of microbes linked to the distribution of oxygen and nutrients provided by host tissue. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

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High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease

Alan W. Walker, Jeremy Sanderson, Carol Churcher … (2011)

Background The gut microbiota is thought to play a key role in the development of the inflammatory bowel diseases Crohn's disease (CD) and ulcerative colitis (UC). Shifts in the composition of resident bacteria have been postulated to drive the chronic inflammation seen in both diseases (the "dysbiosis" hypothesis). We therefore specifically sought to compare the mucosa-associated microbiota from both inflamed and non-inflamed sites of the colon in CD and UC patients to that from non-IBD controls and to detect disease-specific profiles. Results Paired mucosal biopsies of inflamed and non-inflamed intestinal tissue from 6 CD (n = 12) and 6 UC (n = 12) patients were compared to biopsies from 5 healthy controls (n = 5) by in-depth sequencing of over 10,000 near full-length bacterial 16S rRNA genes. The results indicate that mucosal microbial diversity is reduced in IBD, particularly in CD, and that the species composition is disturbed. Firmicutes were reduced in IBD samples and there were concurrent increases in Bacteroidetes, and in CD only, Enterobacteriaceae. There were also significant differences in microbial community structure between inflamed and non-inflamed mucosal sites. However, these differences varied greatly between individuals, meaning there was no obvious bacterial signature that was positively associated with the inflamed gut. Conclusions These results may support the hypothesis that the overall dysbiosis observed in inflammatory bowel disease patients relative to non-IBD controls might to some extent be a result of the disturbed gut environment rather than the direct cause of disease. Nonetheless, the observed shifts in microbiota composition may be important factors in disease maintenance and severity.

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Author and article information

Contributors

M. J. Claesson:

ORCID: http://orcid.org/0000-0002-5712-0623

m.claesson@ucc.ie

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 23 March 2020

Publication date PMC-release: 23 March 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 1512

Affiliations

[1 ]ISNI 0000000123318773, GRID grid.7872.a, School of Microbiology, , University College Cork, ; Cork, Ireland

[2 ]ISNI 0000000123318773, GRID grid.7872.a, APC Microbiome Ireland, , University College Cork, ; Cork, Ireland

[3 ]ISNI 0000 0001 0693 825X, GRID grid.47244.31, Department of Biological Sciences Cork Institute of Technology, ; Cork, Ireland

[4 ]GRID grid.452682.f, Second Genome, ; South San Francisco, CA 94080 USA

[5 ]ISNI 0000000123318773, GRID grid.7872.a, Department of Medicine, , University College Cork, ; Cork, Ireland

[6 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Radboud University Medical Center, Laboratory of Pediatric Infectious Diseases, ; Nijmegen, The Netherlands

[7 ]ISNI 0000000123318773, GRID grid.7872.a, School of Food and Nutritional Sciences, , University College Cork, ; Cork, Ireland

[8 ]ISNI 0000000123318773, GRID grid.7872.a, Irish Centre for Fetal and Neonatal Translational Research, Department of Electrical and Electronic Engineering, , University College Cork, ; Cork, Ireland

[9 ]ISNI 0000 0004 0389 5639, GRID grid.460892.1, Bon Secours Hospital, ; Cork, Ireland

[10 ]ISNI 0000000123318773, GRID grid.7872.a, School of Biochemistry and Cell Biology, , University College Cork, ; Cork, Ireland

[11 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Department of Twin Research and Genetic Epidemiology, , King’s College London, ; London, UK

Author information

F. J. Ryan http://orcid.org/0000-0002-1565-4598

R. S. Fitzgerald http://orcid.org/0000-0002-5569-6311

E. J. Laserna-Mendieta http://orcid.org/0000-0002-9039-7667

P. J. McMurdie http://orcid.org/0000-0001-8879-3954

A. Fanning http://orcid.org/0000-0001-8050-1769

A. Temko http://orcid.org/0000-0001-6548-0971

S. A. Joyce http://orcid.org/0000-0003-4771-3123

J. T. Bell http://orcid.org/0000-0002-3858-5986

F. Shanahan http://orcid.org/0000-0003-0467-0936

M. J. Claesson http://orcid.org/0000-0002-5712-0623

Article

Publisher ID: 15342

DOI: 10.1038/s41467-020-15342-5

PMC ID: 7089947

PubMed ID: 32251296

SO-VID: 5b457b81-3050-4597-8cb8-c977dbb24195

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 15 May 2019

Date accepted : 27 February 2020

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ScienceOpen disciplines: Uncategorized

Keywords: data processing,epigenomics

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ScienceOpen disciplines: Uncategorized

Keywords: data processing, epigenomics

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Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease

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Microbiota and Host

Most cited references 43

Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease.

Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota.

High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease

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Cited by 120

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