The Impact of NOD2 Variants on Fecal Microbiota in Crohn’s Disease and Controls Without Gastrointestinal Disease

Nicholas A Kennedy (Corresponding Author), Christopher A Lamb, Susan H Berry, Alan W Walker, John Mansfield, Miles Parkes, Rachel Simpkins, Mark Tremelling, Sarah Nutland, UK IBD Genetics Consortium, Julian Parkhill, Chris Probert, Georgina L Hold, Charlie W. Lees

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Abstract

Background/AimsCurrent models of Crohn’s disease (CD) describe an inappropriate immune response to gut microbiota in genetically susceptible individuals. NOD2 variants are strongly associated with development of CD, and NOD2 is part of the innate immune response to bacteria. This study aimed to identify differences in fecal microbiota in CD patients and non-IBD controls stratified by NOD2 genotype.
MethodsPatients with CD and non-IBD controls of known NOD2 genotype were identified from patients in previous UK IBD genetics studies and the Cambridge bioresource (genotyped/phenotyped volunteers). Individuals with known CD-associated NOD2 mutations were matched to those with wild-type genotype. We obtained fecal samples from patients in clinical remission with low fecal calprotectin (<250 µg/g) and controls without gastrointestinal disease. After extracting DNA, the V1-2 region of 16S rRNA genes were polymerase chain reaction (PCR)-amplified and sequenced. Analysis was undertaken using the mothur package. Volatile organic compounds (VOC) were also measured.
ResultsNinety-one individuals were in the primary analysis (37 CD, 30 bioresource controls, and 24 household controls). Comparing CD with nonIBD controls, there were reductions in bacterial diversity, Ruminococcaceae, Rikenellaceae, and Christensenellaceae and an increase in Enterobacteriaceae. No significant differences could be identified in microbiota by NOD2 genotype, but fecal butanoic acid was higher in Crohn’s patients carrying NOD2 mutations.
ConclusionsIn this well-controlled study of NOD2 genotype and fecal microbiota, we identified no significant genotype-microbiota associations. This suggests that the changes associated with NOD2 genotype might only be seen at the mucosal level, or that environmental factors and prior inflammation are the predominant determinant of the observed dysbiosis in gut microbiota.
Original languageEnglish
Pages (from-to)583-592
Number of pages10
JournalInflammatory Bowel Diseases
Volume24
Issue number3
Early online date15 Feb 2018
DOIs
Publication statusPublished - Mar 2018

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Gastrointestinal Diseases
Microbiota
Crohn Disease
Genotype
Dysbiosis
Leukocyte L1 Antigen Complex
Volatile Organic Compounds
Mutation
Butyric Acid
Enterobacteriaceae
rRNA Genes
Innate Immunity
Volunteers
Inflammation
Bacteria
Polymerase Chain Reaction
DNA

Keywords

  • Crohn’s disease
  • NOD2
  • microbiota
  • genotype

Cite this

The Impact of NOD2 Variants on Fecal Microbiota in Crohn’s Disease and Controls Without Gastrointestinal Disease. / Kennedy, Nicholas A (Corresponding Author); Lamb, Christopher A ; Berry, Susan H; Walker, Alan W; Mansfield, John; Parkes, Miles; Simpkins, Rachel ; Tremelling, Mark; Nutland, Sarah; UK IBD Genetics Consortium; Parkhill, Julian; Probert, Chris ; Hold, Georgina L; Lees, Charlie W.

In: Inflammatory Bowel Diseases, Vol. 24, No. 3, 03.2018, p. 583-592.

Research output: Contribution to journalArticle

Kennedy, NA, Lamb, CA, Berry, SH, Walker, AW, Mansfield, J, Parkes, M, Simpkins, R, Tremelling, M, Nutland, S, UK IBD Genetics Consortium, Parkhill, J, Probert, C, Hold, GL & Lees, CW 2018, 'The Impact of NOD2 Variants on Fecal Microbiota in Crohn’s Disease and Controls Without Gastrointestinal Disease' Inflammatory Bowel Diseases, vol. 24, no. 3, pp. 583-592. https://doi.org/10.1093/ibd/izx061
Kennedy, Nicholas A ; Lamb, Christopher A ; Berry, Susan H ; Walker, Alan W ; Mansfield, John ; Parkes, Miles ; Simpkins, Rachel ; Tremelling, Mark ; Nutland, Sarah ; UK IBD Genetics Consortium ; Parkhill, Julian ; Probert, Chris ; Hold, Georgina L ; Lees, Charlie W. / The Impact of NOD2 Variants on Fecal Microbiota in Crohn’s Disease and Controls Without Gastrointestinal Disease. In: Inflammatory Bowel Diseases. 2018 ; Vol. 24, No. 3. pp. 583-592.
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abstract = "Background/AimsCurrent models of Crohn’s disease (CD) describe an inappropriate immune response to gut microbiota in genetically susceptible individuals. NOD2 variants are strongly associated with development of CD, and NOD2 is part of the innate immune response to bacteria. This study aimed to identify differences in fecal microbiota in CD patients and non-IBD controls stratified by NOD2 genotype.MethodsPatients with CD and non-IBD controls of known NOD2 genotype were identified from patients in previous UK IBD genetics studies and the Cambridge bioresource (genotyped/phenotyped volunteers). Individuals with known CD-associated NOD2 mutations were matched to those with wild-type genotype. We obtained fecal samples from patients in clinical remission with low fecal calprotectin (<250 µg/g) and controls without gastrointestinal disease. After extracting DNA, the V1-2 region of 16S rRNA genes were polymerase chain reaction (PCR)-amplified and sequenced. Analysis was undertaken using the mothur package. Volatile organic compounds (VOC) were also measured.ResultsNinety-one individuals were in the primary analysis (37 CD, 30 bioresource controls, and 24 household controls). Comparing CD with nonIBD controls, there were reductions in bacterial diversity, Ruminococcaceae, Rikenellaceae, and Christensenellaceae and an increase in Enterobacteriaceae. No significant differences could be identified in microbiota by NOD2 genotype, but fecal butanoic acid was higher in Crohn’s patients carrying NOD2 mutations.ConclusionsIn this well-controlled study of NOD2 genotype and fecal microbiota, we identified no significant genotype-microbiota associations. This suggests that the changes associated with NOD2 genotype might only be seen at the mucosal level, or that environmental factors and prior inflammation are the predominant determinant of the observed dysbiosis in gut microbiota.",
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T1 - The Impact of NOD2 Variants on Fecal Microbiota in Crohn’s Disease and Controls Without Gastrointestinal Disease

AU - Kennedy, Nicholas A

AU - Lamb, Christopher A

AU - Berry, Susan H

AU - Walker, Alan W

AU - Mansfield, John

AU - Parkes, Miles

AU - Simpkins, Rachel

AU - Tremelling, Mark

AU - Nutland, Sarah

AU - UK IBD Genetics Consortium

AU - Parkhill, Julian

AU - Probert, Chris

AU - Hold, Georgina L

AU - Lees, Charlie W.

N1 - Funding was supported by CORE, the Digestive Diseases Foundation and the Wellcome Trust [grant number 097943 to NAK, 093885 to CAL and 098051 to Alan W Walker and Julian Parkhill . Dr. Walker receives core funding support from the Scottish Government Rural and Environmental Science and Analysis Service (RESAS). We also acknowledge the NIHR Biomedical Research Centre awards to Addenbrooke’s Hospital/University of Cambridge School of Clinical Medicine and acknowledge the NIHR Newcastle Biomedical Research Centre.

PY - 2018/3

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N2 - Background/AimsCurrent models of Crohn’s disease (CD) describe an inappropriate immune response to gut microbiota in genetically susceptible individuals. NOD2 variants are strongly associated with development of CD, and NOD2 is part of the innate immune response to bacteria. This study aimed to identify differences in fecal microbiota in CD patients and non-IBD controls stratified by NOD2 genotype.MethodsPatients with CD and non-IBD controls of known NOD2 genotype were identified from patients in previous UK IBD genetics studies and the Cambridge bioresource (genotyped/phenotyped volunteers). Individuals with known CD-associated NOD2 mutations were matched to those with wild-type genotype. We obtained fecal samples from patients in clinical remission with low fecal calprotectin (<250 µg/g) and controls without gastrointestinal disease. After extracting DNA, the V1-2 region of 16S rRNA genes were polymerase chain reaction (PCR)-amplified and sequenced. Analysis was undertaken using the mothur package. Volatile organic compounds (VOC) were also measured.ResultsNinety-one individuals were in the primary analysis (37 CD, 30 bioresource controls, and 24 household controls). Comparing CD with nonIBD controls, there were reductions in bacterial diversity, Ruminococcaceae, Rikenellaceae, and Christensenellaceae and an increase in Enterobacteriaceae. No significant differences could be identified in microbiota by NOD2 genotype, but fecal butanoic acid was higher in Crohn’s patients carrying NOD2 mutations.ConclusionsIn this well-controlled study of NOD2 genotype and fecal microbiota, we identified no significant genotype-microbiota associations. This suggests that the changes associated with NOD2 genotype might only be seen at the mucosal level, or that environmental factors and prior inflammation are the predominant determinant of the observed dysbiosis in gut microbiota.

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KW - NOD2

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SN - 1078-0998

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