Objective The incidence of IBS increases following enteric infections, suggesting a causative role for microbial imbalance. However, analyses of faecal microbiota have not demonstrated consistent alterations. Here, we used metaproteomics to investigate potential associations between mucus-resident microbiota and IBS symptoms.
Design Mucus samples were prospectively collected from sigmoid colon biopsies from patients with IBS and healthy volunteers, and their microbial protein composition analysed by mass spectrometry. Observations were verified by immunofluorescence, electron microscopy and real-time PCR, further confirmed in a second cohort, and correlated with comprehensive profiling of clinical characteristics and mucosal immune responses.
Results Metaproteomic analysis of colon mucus samples identified peptides from potentially pathogenic Brachyspira species in a subset of patients with IBS. Using multiple diagnostic methods, mucosal Brachyspira colonisation was detected in a total of 19/62 (31%) patients with IBS from two prospective cohorts, versus 0/31 healthy volunteers (p<0.001). The prevalence of Brachyspira colonisation in IBS with diarrhoea (IBS-D) was 40% in both cohorts (p=0.02 and p=0.006 vs controls). Brachyspira attachment to the colonocyte apical membrane was observed in 20% of patients with IBS and associated with accelerated oro-anal transit, mild mucosal inflammation, mast cell activation and alterations of molecular pathways linked to bacterial uptake and ion–fluid homeostasis. Metronidazole treatment paradoxically promoted Brachyspira relocation into goblet cell secretory granules—possibly representing a novel bacterial strategy to evade antibiotics.
Conclusion Mucosal Brachyspira colonisation was significantly more common in IBS and associated with distinctive clinical, histological and molecular characteristics. Our observations suggest a role for Brachyspira in the pathogenesis of IBS, particularly IBS-D.
- irritable bowel syndrome
- bacterial adherence
- bacterial pathogenesis
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MS and GCH are joint senior authors.
Contributors KSJ, MS and GCH conceived the original idea; KSJ, BD, LE, CW, AE and ÅJ performed experimental procedures and data analysis; HT and MS supervised subject enrolment; KSJ, LE, HT and MS analysed clinical data, KSJ drafted the manuscript with input from all authors.
Funding This work was supported by the National Institute of Allergy and Infectious Diseases (U01AI095473), Knut and Alice Wallenberg Foundation, European Research Council (ERC), Swedish Research Council, AFA insurance, IngaBritt and Arne Lundberg Foundation, Sahlgrenska University Hospital (ALF), Wilhelm and Martina Lundgren Foundation, Adlerbert Research Foundation. The funders were not involved in the decision to publish; and had no role in the design and execution of the study, or in the preparation of the manuscript.
Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Competing interests MS has received unrestricted research grants from Danone Nutricia Research and Ferring Pharmaceuticals, has served as a Consultant/Advisory Board member for AstraZeneca, Danone, Nestlé, Almirall, Allergan, Albireo, Glycom, and Shire, and as a speaker for Tillotts, Menarini, Takeda, Shire, Allergan, and Almirall.
Patient consent for publication Not required.
Ethics approval The study was approved by the Gothenburg Ethical Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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