Irritable bowel syndrome (IBS) is a disorder of lower gastrointestinal function associated with mucosal immune activation, colonic motor and sensory dysfunctions. The etiological factors that impact on all these functions include endogenous substances, like bile acids (BA). Hydrophobic di ? hydroxyl BA, such as chenodeoxycholic acid (CDC), are endogenous, surface-active agents that may alter mucosal function, stimulate release of serotonin, alter mucosal permeability, induce low grade inflammation and protein loss through their detergency, and increase colonic secretion and motility. BA malabsorption is reported in 20-75% of patients with chronic diarrhea;BA deficiency is reported in rare cases of childhood constipation. We have previously used microarray and confirmatory qRT-PCR to quantify the expression in colorectal mucosa of SLC6A4 (the solute carrier protein that controls serotonin [5-HT] re-uptake, or SERT), p11 (another solute carrier, which modifies function of 5-HT receptor subtypes) and 12 genes involved in protection (e.g. mucin production) and defense against bacteria (e.g. generation of reactive oxygen species) in colonic mucosa from IBS patients. Among 15 SNPs and tag SNPs in the 7 genes involved in BA metabolism (ASBT, FGFR4, OST-alpha, OST-beta, Klotho B [KLB] SHP, and CYP7A1), we identified significant association of SNP rs17618244 (which is functional, influencing protein synthesis) in the KLB gene with colonic transit in patients with IBS-D. We have identified a possible association of TGR5 SNP rs 11554825 with small bowel transit, particularly in IBS-D, and with colonic transit. This gene encodes a member of the G protein-coupled receptor (GPCR) superfamily, and functions as a cell surface receptor for BA. The overarching hypothesis is that BA kinetics, and genetic variation of the BA modulating proteins and TGR5 are associated with the phenotypes of IBS-D and IBS-C, and mediated through changes in colonic mucosal expression of factors controlling 5-HT and BA actions.
Our aims are: first, to examine the prevalence and pathophysiology (colonic transit, mucosal permeability, serum FGF19 and 7alphaC4, fecal bile acids) of BA malabsorption (BAM) in patients with IBS-D, and of BA deficiency in IBS-C compared to healthy controls;second, to evaluate prevalence and impact on colon transit of genetic variation in molecular mechanisms controlling bile acid synthesis and absorption, as well as the separate bile acid G- protein coupled receptor, TGR5, in IBS and health;third, to compare In patients with IBS-D with and without BAM and healthy controls, fecal bile acid excretion colonic mucosal permeability, tone, contractions, and mucosal expression of serotonergic, bile acid transporters (FXR and ASBT), TGR5, MUC20 and PARM1. Significance: These integrative, translational studies will enhance understanding of BA kinetics, mucosal permeability, and colon motility, and should usher in new treatment in a sizeable subset of patients with lower functional GI diseases presenting with diarrhea or constipation.

Public Health Relevance

Irritable bowel syndrome (IBS) affects about 10% of the U.S. population, about 5% having predominant diarrhea and 5% predominant constipation;current treatment is suboptimal as it may not be tolerated, leads to side effects or insufficient benefit. This proposal addresses the prevalence, mechanism, and disturbance of functions due to bile acid malabsorption (BAM), and genetic variations in patients with IBS and diarrhea or the deficiency of bile acids in those with IBS and constipation. Understanding these disturbed functions and their cause (including genetic control) will provide the basis for more effective and safe medications for patients with BAM and diarrhea associated with IBS and, therefore, will likely have impact on the public health.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DKUS-C (06))
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Hamilton, Frank A
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Mayo Clinic, Rochester
United States
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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
Waldman, Scott A; Camilleri, Michael (2018) Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders. Gut 67:1543-1552
Halawi, H; Vijayvargiya, P; Busciglio, I et al. (2018) Effects of naloxegol on whole gut transit in opioid-naïve healthy subjects receiving codeine: A randomized, controlled trial. Neurogastroenterol Motil 30:e13298
Camilleri, Michael; Sellin, Joseph H; Barrett, Kim E (2017) Pathophysiology, Evaluation, and Management of Chronic Watery Diarrhea. Gastroenterology 152:515-532.e2
Halawi, Houssam; Camilleri, Michael (2017) Pharmacogenetics and the treatment of functional gastrointestinal disorders. Pharmacogenomics 18:1085-1094
Khemani, D; Camilleri, M; Roldan, A et al. (2017) Opioid analgesic use among patients presenting with acute abdominal pain and factors associated with surgical diagnoses. Neurogastroenterol Motil 29:
Peleman, Cédric; Camilleri, Michael; Busciglio, Irene et al. (2017) Colonic Transit and Bile Acid Synthesis or Excretion in Patients With Irritable Bowel Syndrome-Diarrhea Without Bile Acid Malabsorption. Clin Gastroenterol Hepatol 15:720-727.e1
Camilleri, Michael; Lembo, Anthony; Katzka, David A (2017) Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits. Clin Gastroenterol Hepatol 15:1338-1349

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