Identification of an Intestinal Microbiota Signature Associated With Severity of Irritable Bowel Syndrome

doi:10.1053/j.gastro.2016.09.049

Gastroenterology

Volume 152, Issue 1, January 2017, Pages 111-123.e8

https://doi.org/10.1053/j.gastro.2016.09.049 Get rights and content

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Background & Aims

We have limited knowledge about the association between the composition of the intestinal microbiota and clinical features of irritable bowel syndrome (IBS). We collected information on the fecal and mucosa-associated microbiota of patients with IBS and evaluated whether these were associated with symptoms.

Methods

We collected fecal and mucosal samples from adult patients who met the Rome III criteria for IBS at a secondary/tertiary care outpatient clinics in Sweden, as well as from healthy subjects. The exploratory set comprised 149 subjects (110 with IBS and 39 healthy subjects); 232 fecal samples and 59 mucosal biopsy samples were collected and analyzed by 16S ribosomal RNA targeted pyrosequencing. The validation set comprised 46 subjects (29 with IBS and 17 healthy subjects); 46 fecal samples, but no mucosal samples, were collected and analyzed. For each subject, we measured exhaled H₂ and CH₄, oro-anal transit time, and the severity of psychological and gastrointestinal symptoms. Fecal methanogens were measured by quantitative polymerase chain reaction. Numerical ecology analyses and a machine learning procedure were used to analyze the data.

Results

Fecal microbiota showed covariation with mucosal adherent microbiota. By using classic approaches, we found no differences in fecal microbiota abundance or composition between patients with IBS vs healthy patients. A machine learning procedure, a computational statistical technique, allowed us to reduce the 16S ribosomal RNA data complexity into a microbial signature for severe IBS, consisting of 90 bacterial operational taxonomic units. We confirmed the robustness of the intestinal microbial signature for severe IBS in the validation set. The signature was able to discriminate between patients with severe symptoms, patients with mild/moderate symptoms, and healthy subjects. By using this intestinal microbiota signature, we found IBS symptom severity to be associated negatively with microbial richness, exhaled CH₄, presence of methanogens, and enterotypes enriched with Clostridiales or Prevotella species. This microbiota signature could not be explained by differences in diet or use of medications.

Conclusions

In analyzing fecal and mucosal microbiota from patients with IBS and healthy individuals, we identified an intestinal microbiota profile that is associated with the severity of IBS symptoms. Trial registration number: NCT01252550.

Keywords

Functional Bowel Disorder

Bacteria

Microbiome

Abbreviations used in this paper

AUC

area under the curve

AUROC

area under the receiver operating characteristic curve

BMI

body mass index

FODMAP

Fermentable, Oligo-, Di-, Mono-saccharides And Polyols

gastrointestinal

HAD

Hospital Anxiety and Depression

IBS

irritable bowel syndrome

IBS-C

irritable bowel syndrome with constipation

IBS-D

irritable bowel syndrome with diarrhea

IBS-M

mixed irritable bowel syndrome

IBS-SSS

Irritable Bowel Syndrome Severity Scoring System

JSD

Jensen Shannon divergence

LASSO

least absolute shrinkage and selection operator

OATT

oro-anal transit time

OTU

operational taxonomic unit

principal component

PCR

polymerase chain reaction

rRNA

ribosomal RNA

regression vector

Cited by (0)

: Conflicts of interest These authors disclose the following: Boris Le Nevé, Muriel Derrien, Rémi Brazeilles, Stéphanie Cools-Portier, and Julien Tap are employees of Danone Research; Muriel Simrén has received unrestricted research grants from Danone and AstraZeneca, and has served as a consultant/advisory board member for AstraZeneca, Danone, Novartis, Almirall, Albiroe, Shire, Nestlé, Glycom, and Chr Hansen, and has served on the speaker’s bureau for Takeda, Tillotts, Shire, Almirall, Menarini, and Danone; Lena Öhman has received financial support for research from Danone Research, has served as a consultant for Genetic Analyses, and has received lecture fees from AbbVie and Takeda; Joël Doré has received financial support for research from Danone Research, Pfizer, and PiLeJe, and has served as a consultant/advisory board member for Danone Research, AlphaWasserman, Enterome Bioscience, and MaaT Pharma; and Hans Törnblom has served as a consultant/advisory board member for Almirall, Allergan, Danone, and Shire, and has been on the speakers’ bureau for Tillotts, Takeda, Shire, and Almirall. The remaining author discloses no conflicts.

: Funding This research was supported by the Swedish Medical Research Council (grants 13409, 21691, and 21692), AFA (Arbetsmarknadens Försäkringsaktiebolag) Insurance, The Marianne and Marcus Wallenberg Foundation, Centre for Person-Centered Care, Sahlgrenska Academy, University of Gothenburg, the Faculty of Medicine at the University of Gothenburg, VINNOVA, as well as by Danone Nutricia Research.

^∗: Authors share co-first authorship

^§: Authors share co-senior authorship.