Irritable bowel syndrome (IBS) is associated with colonic motor, sensory, mucosal and psychological dys- functions. The etiology of IBS with diarrhea (IBS-D) includes exogenous factors (e.g. stress or infections) and endogenous molecules [e.g. bile acids (BA) and short chain fatty acids (SCFA)] that increase 5-HT release, mucosal permeability, low grade inflammation, and colonic secretion and motility. There are univariate genetic associations of single nucleotide polymorphisms (SNPs in 5-HTTLPR, 5-HT3R, FAAH, CNR1, KLB, FGFR4, TGR5, TLR9, CDH1, TNFSF15, IL6, NXPH1, KDELR2 , GRID2IP, NPSR1, HLA DQ2/8) with IBS phenotype (including GWAS) or quantitative traits. We previously examined the association of BA in IBS-D traits with: colonic transit, sensation, permeability, BA synthesis and excretion. On meta-analysis,~28% of patients IBS-D have BA diarrhea, reduced secretion of the ileal hormone FGF-19, and univariate association with 3 BA- related genes: KLB, FGFR4, and TGR5. Overall aim of this proposal is to understand mechanisms in IBS-D, especially in IBS-D patients with increased BA excretion. Preliminary data explored exome DNA sequencing, and colonic mucosal mRNA expression in IBS-D: (i). Our exome DNA sequencing study (16 IBS-D, 50 controls) confirmed SNPs in FGFR4 and KLB are associated with colonic transit and BA homeostasis, and identified new single nucleotide variants (SNVs) in FGFR4 and KLB in IBS-D. However, the relationship of the SNVs to IBS-D quantitative traits is unknown. (ii).Our first-ever RNA-Seq study of rectosigmoid mucosa (9 IBS-D and 9 controls) showed 4 pathways with increased expression of neurotransmitters or their receptors (P2RY4, VIP), ion transport (GUC2AB, PDZD3), cytokines (C4BPA), BA modulation (FGFR4), and decreased expression of barrier mechanisms (FN1). (iii). In 47 IBS-D patients, we confirmed mRNA changes in ion transport, immune and barrier functions. (iv). Open-label treatment with BA sequestrant, normalized stool consistency in IBS-D with increased fecal BA. Our data demonstrate feasibility to use deep phenotyping, next generation sequencing of 5 BA-related genes, and colonic mucosal mRNA expression to identify mechanism in IBS-D. With unique capability to perform deep phenotyping of IBS-D (transit, sensation, permeability, mucosal barrier, BA kinetics, fecal SCFA profile, mucosal transcriptome and proteomics), we aim to test 3 hypotheses: 1. Genes controlling BA absorption, synthesis or receptors are associated with quantitative traits in IBS-D 2. Altered mRNA and protein expression of neurotransmitters, cytokines and ion channels in ileal and colonic mucosa, and BA homeostasis in ileal and colonic mucosa are associated with quantitative in traits in IBS-D; 3. BA sequestration normalizes colonic transit, intestinal permeability, barrier junction proteins and bowel function in IBS-D with increased fecal BA excretion. Significance: These innovative studies will enhance understanding the mechanisms, diagnosis and treatment of BA-associated IBS-D.

Public Health Relevance

/ RELEVANCE Irritable bowel syndrome (IBS) affects about 11% of the U.S. population with about 5% having predominant diarrhea (IBS-D); current treatment is suboptimal as the mechanisms and dysfunctions leading to the symptoms are incompletely understood. This proposal addresses the need to understand the bile acid-related mechanisms causing IBS-D by studies of the genes (DNA) and ileal and colonic mucosal expression of proteins associated with subgroups of IBS-D with high or normal BA excretion characterized by quantifiable gastrointestinal dysfunctions (that contribute to the symptoms). These innovative studies provide the basis for improved diagnosis and more effective, individualized treatment for patients with IBS, and will, therefore, impact the public health.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Chedid, Victor; Vijayvargiya, Priya; Halawi, Houssam et al. (2018) Audit of the diagnosis of rectal evacuation disorders in chronic constipation. Neurogastroenterol Motil :e13510
Camilleri, Michael (2018) Management Options for Irritable Bowel Syndrome. Mayo Clin Proc 93:1858-1872
Vijayvargiya, Priya; Camilleri, Michael; Chedid, Victor et al. (2018) Analysis of Fecal Primary Bile Acids Detects Increased Stool Weight and Colonic Transit in Patients With Chronic Functional Diarrhea. Clin Gastroenterol Hepatol :
Vijayvargiya, Priya; Busciglio, Irene; Burton, Duane et al. (2018) Bile Acid Deficiency in a Subgroup of Patients With Irritable Bowel Syndrome With Constipation Based on Biomarkers in Serum and Fecal Samples. Clin Gastroenterol Hepatol 16:522-527
Chedid, Victor; Vijayvargiya, Priya; Camilleri, Michael (2018) Elobixibat for the Treatment of Constipation. Expert Rev Gastroenterol Hepatol :
Camilleri, M (2018) Cannabinoids and gastrointestinal motility: Pharmacology, clinical effects, and potential therapeutics in humans. Neurogastroenterol Motil 30:e13370
Vijayvargiya, P; Camilleri, M; Carlson, P et al. (2017) Performance characteristics of serum C4 and FGF19 measurements to exclude the diagnosis of bile acid diarrhoea in IBS-diarrhoea and functional diarrhoea. Aliment Pharmacol Ther 46:581-588
Malhi, Harmeet; Camilleri, Michael (2017) Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases. Curr Opin Pharmacol 37:80-86