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Abstract
Objective There are altered mucosal functions in irritable bowel syndrome with diarrhoea (IBS-D); ~30% of patients with IBS-D have abnormal bile acid (BA) metabolism (ABAM) and diarrhoea (summarised as BAD).
Aim To compare biochemical parameters, gastrointestinal and colonic transit, rectal sensation and pathobiological mechanisms in IBS-D without ABAM and in BAD (serum 7C4>52 ng/mL).
Design In patients with Rome III criteria of IBS-D, we compared biochemical features, colonic transit, rectal sensation, deep genotype of five BA-related genes, ileal and colonic mucosal mRNA (differential expression (DE) analysis) and stool dysbiosis (including functional analysis of microbiome). Results in BAD were compared with IBS-D without ABAM.
Results Compared with 161 patients with IBS-D without ABAM, 44 patients with BAD had significantly faster colonic transit, lower microbial alpha diversity, different compositional profile (beta diversity) and higher Firmicutes to Bacteroidetes ratio with evidence of decreased expression of bile acid thiol ligase (involved in transformation of primary to secondary BAs) and decreased sulfatases. In BAD (compared with IBS-D without ABAM), terminal ileal biopsies showed downregulation of SLC44A5 (a BA transporter), and ascending colon biopsies showed upregulation in barrier-weakening genes (CLDN2), serine protease inhibitors, immune activation, cellular differentiation and a cellular transporter (FABP6; BA binding). No DE of genes was documented in descending colon biopsies. The two groups had similar rectal sensation.
Conclusion Though sharing clinical symptoms with IBS-D, BAD is associated with biological differences and mechanisms that have potential to enhance diagnosis and treatment targeting barrier dysfunction, inflammatory and microbial changes.
- BILE ACID
- BILE ACID METABOLISM
- INFLAMMATION
- BARRIER FUNCTION
- DIARRHOEA
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. Data transparency statement: data will be available, consistent with data sharing National Institutes of Health (NIH) policy for studies supported by NIH (in this case, R01-DK115950); in addition, all relevant data are included in the paper and/or in the online supplemental materials.
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Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. Data transparency statement: data will be available, consistent with data sharing National Institutes of Health (NIH) policy for studies supported by NIH (in this case, R01-DK115950); in addition, all relevant data are included in the paper and/or in the online supplemental materials.
Footnotes
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Contributors MC: As guarantor of the article, he accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish.
MC: conceptualisation of study, analysis of data and senior authorship. PC: biospecimen preparation, genomics and RNA-sequencing data, and co-authorship. SM and AT: recruitment, management of studies in clinical research trials unit (CRTU) and co-authorship. PV, JA and TZ: care of patients in CRTU and co-authorship. YM: analysis of RNA-sequencing data and co-authorship. JB, SJ and JC: analysis of microbiome data and co-authorship. WS: analysis of clinical and biochemical data and co-authorship. XJW, VC and DM: acquisition of ileo-colonic mucosal biopsies, care of patients in CRTU and co-authorship. AAN and NKN: bioinformatics RNA sequencing and co-authorship. DB and IB: laboratory management, data collation, measurement of rectal sensation; endoscopy support; and co-authorship.
Funding MC is supported from National Institutes of Health (NIH) (grant number: R01-DK115950). The study was facilitated by the CCaTS Clinical Research Trials Unit at Mayo Clinic (grant number: UL1-TR002377) from NIH.
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
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