The distinct features of microbial ‘dysbiosis’ of Crohn’s disease do not occur to the same extent in their unaffected, genetically-linked kindred

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Abstract

Background/Aims

Studying the gut microbiota in unaffected relatives of people with Crohn’s disease (CD) may advance our understanding of the role of bacteria in disease aetiology.

Methods

Faecal microbiota composition (16S rRNA gene sequencing), genetic functional capacity (shotgun metagenomics) and faecal short chain fatty acids (SCFA) were compared in unaffected adult relatives of CD children (CDR, n = 17) and adult healthy controls, unrelated to CD patients (HUC, n = 14). The microbiota characteristics of 19 CD children were used as a benchmark of CD ‘dysbiosis’.

Results

The CDR microbiota was less diverse (p = 0.044) than that of the HUC group. Local contribution of β-diversity analysis showed no difference in community structure between the CDR and HUC groups. Twenty one of 1,243 (1.8%) operational taxonomic units discriminated CDR from HUC. The metagenomic functional capacity (p = 0.207) and SCFA concentration or pattern were similar between CDR and HUC (p>0.05 for all SCFA). None of the KEGG metabolic pathways were different between these two groups. Both of these groups (HUC and CDR) had a higher microbiota α-diversity (CDR, p = 0.026 and HUC, p<0.001) with a community structure (β-diversity) distinct from that of children with CD.

Conclusions

While some alterations were observed, a distinct microbial ‘dysbiosis’, characteristic of CD patients, was not observed in their unaffected, genetically linked kindred.

Related collections

Most cited references 3

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Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health?

Marion G. Priebe, K Meijer, Paul Vos (2010)

High-fiber diets have been shown to reduce plasma concentrations of inflammation markers. Increased production of fermentation-derived short-chain fatty acids (SCFAs) is one of the factors that could exert these positive effects. This review examines the effects of SCFAs on immune cells and discusses the relevance of their effects on systemic inflammation, as frequently seen in obesity. SCFAs have been shown to reduce chemotaxis and cell adhesion; this effect is dependent on type and concentration of SCFA. In spite of conflicting results, especially butyrate seems to have an anti-inflammatory effect, mediated by signaling pathways like nuclear factor-κB and inhibition of histone deacetylase. The discrepancies in the results could be explained by differences in cell types used and their proliferative and differentiation status. SCFAs show anti-inflammatory effects and seem to have the potency to prevent infiltration of immune cells from the bloodstream in, for example, the adipose tissue. In addition, their ability to inhibit the proliferation and activation of T cells and to prevent adhesion of antigen-presenting cells could be important as it recently has been shown that obesity-associated inflammation might be antigen-dependent. More studies with concentrations in micromolar range are needed to approach more physiological concentrations.

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Characterization of Phascolarctobacterium succinatutens sp. nov., an asaccharolytic, succinate-utilizing bacterium isolated from human feces.

Yohei Watanabe, Fumiko Nagai, Masami Morotomi (2012)

Isolation, cultivation, and characterization of the intestinal microorganisms are important for understanding the comprehensive physiology of the human gastrointestinal (GI) tract microbiota. Here, we isolated two novel bacterial strains, YIT 12067(T) and YIT 12068, from the feces of healthy human adults. Phylogenetic analysis indicated that they belonged to the same species and were most closely related to Phascolarctobacterium faecium ACM 3679(T), with 91.4% to 91.5% 16S rRNA gene sequence similarities, respectively. Substrate availability tests revealed that the isolates used only succinate; they did not ferment any other short-chain fatty acids or carbohydrates tested. When these strains were cocultured with the xylan-utilizing and succinate-producing bacterium Paraprevotella xylaniphila YIT 11841(T), in medium supplemented with xylan but not succinate, their cell numbers became 2 to 3 orders of magnitude higher than those of the monoculture; succinate became undetectable, and propionate was formed. Database analysis revealed that over 200 uncultured bacterial clones from the feces of humans and other mammals showed high sequence identity (>98.7%) to YIT 12067(T). Real-time PCR analysis also revealed that YIT 12067(T)-like bacteria were present in 21% of human fecal samples, at an average level of 3.34 × 10(8) cells/g feces. These results indicate that YIT 12067(T)-like bacteria are distributed broadly in the GI tract as subdominant members that may adapt to the intestinal environment by specializing to utilize the succinate generated by other bacterial species. The phylogenetic and physiological properties of YIT 12067(T) and YIT 12068 suggest that these strains represent a novel species, which we have designated Phascolarctobacterium succinatutens sp. nov.

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Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn's disease and their unaffected siblings.

Natalie Prescott, Petra Louis, J. Lindsay … (2014)

Crohn's disease (CD) is associated with intestinal dysbiosis, altered blood T cell populations, elevated faecal calprotectin (FC) and increased intestinal permeability (IP). CD-associated features present in siblings (increased risk of CD) but not in healthy controls, provide insight into early CD pathogenesis. We aimed to (1) Delineate the genetic, immune and microbiological profile of patients with CD, their siblings and controls and (2) Determine which factors discriminate between groups. Faecal microbiology was analysed by quantitative PCR targeting 16S ribosomal RNA, FC by ELISA, blood T cell phenotype by flow cytometry and IP by differential lactulose-rhamnose absorption in 22 patients with inactive CD, 21 of their healthy siblings and 25 controls. Subject's genotype relative risk was determined by Illumina Immuno BeadChip. Strikingly, siblings shared aspects of intestinal dysbiosis with patients with CD (lower concentrations of Faecalibacterium prausnitzii (p=0.048), Clostridia cluster IV (p=0.003) and Roseburia spp. (p=0.09) compared with controls). As in CD, siblings demonstrated a predominance of memory T cells (p=0.002) and elevated naïve CD4 T cell β7 integrin expression (p=0.01) compared with controls. FC was elevated (>50 μg/g) in 8/21 (38%) siblings compared with 2/25 (8%) controls (p=0.028); whereas IP did not differ between siblings and controls. Discriminant function analysis determined that combinations of these factors significantly discriminated between groups (χ(2)=80.4, df=20, p<0.001). Siblings were separated from controls by immunological and microbiological variables. Healthy siblings of patients with CD manifest immune and microbiological abnormalities associated with CD distinct from their genotype-related risk and provide an excellent model in which to investigate early CD pathogenesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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Author and article information

Contributors

Mathias Chamaillard: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 21 February 2017

Publication date Collection: 2017

Volume: 12

Issue: 2

Electronic Location Identifier: e0172605

Affiliations

[1 ]School of Engineering, University of Glasgow, Glasgow, United Kingdom

[2 ]Warwick Medical School, University of Warwick, Warwick, United Kingdom

[3 ]Human Nutrition, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom

[4 ]Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom

[5 ]Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom

[6 ]Department of Paediatric Gastroenterology, Hepatology and Nutrition, Royal Hospital for Children, Glasgow, United Kingdom

"INSERM", FRANCE

Author notes

Competing Interests: R K Russell has received speaker’s fees, travel support, and/or participated in medical board meetings with Nestle, MSD Immunology, AbbVie, Dr Falk, Takeda, Napp, Mead Johnson, Nutricia, 4D Pharma. P McGrogan received speaker fees, travel support and participated in medical board meetings with Nestle. K Gerasimidis received speaker’s fees and travel support from Nutricia and Nestle. Dr Gaya received honoraria for educational meetings from MSD, AbbVie, Takeda & Ferring. The other authors have no conflicts of interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Conceptualization: LH CAE PM RKR KG.
Data curation: UZI KG.
Formal analysis: UZI CQ KG.
Funding acquisition: KG CAE RKR CQ PM.
Investigation: LH STC MB DRG RH RKR PM KG.
Methodology: UZI CQ LH NL STC MB KG.
Project administration: KG.
Resources: UZI CQ LH NL STC MB CAE DRG RH PM RKR KG.
Software: UZI CQ NL.
Supervision: KG CAE PM RKR.
Visualization: UZI KG.
Writing – original draft: KG UZI.
Writing – review & editing: UZI CQ LH CAE DRG RH PM RKR KG.

* E-mail: konstantinos.gerasimidis@ 123456glasgow.ac.uk

Article

Publisher ID: PONE-D-16-24076

DOI: 10.1371/journal.pone.0172605

PMC ID: 5319678

PubMed ID: 28222161

SO-VID: 67403ae5-f7ad-42cd-970b-9e40bbe4986b

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 15 June 2016

Date accepted : 7 February 2017