Original article
Alimentary tract
Increased Bile Acid Biosynthesis Is Associated With Irritable Bowel Syndrome With Diarrhea

https://doi.org/10.1016/j.cgh.2012.05.006Get rights and content

Background & Aims

Variations in genes that regulate bile acid (BA) synthesis are associated with colonic transit in patients with irritable bowel syndrome (IBS). We investigated features of BA synthesis and excretion and genetic features of patients with different types of IBS.

Methods

In 26 healthy volunteers, 26 patients with IBS and constipation (IBS-C), and 26 with IBS and diarrhea (IBS-D), we measured serum levels of 7α-hydroxy-4-cholesten-3-one (C4; a surrogate for BA synthesis) and fibroblast growth factor (FGF) 19 (an ileal hormone that downregulates BA synthesis). For stool samples, we measured concentration of BA, weight, and amount of fat when participants were given high-fat diets. Spearman correlations were used to explore relationships among factors. We analyzed 1 polymorphism in Klotho-β (KLB) and 3 in fibroblast growth factor receptor-4 (FGFR4) for all members of each group using analysis of covariance.

Results

The concentration of BA in stool was associated with group (for a comparison of 3 groups; P = .057); it was higher in patients with IBS-D than IBS-C (P = .017). The serum level of C4 was higher in patients with IBS-D than IBS-C (P = .02) or healthy volunteers (P = .01); 38% of patients with IBS-D had increased serum levels of C4, compared with healthy volunteers. Serum level of C4 correlated with stool concentration of BA (rs = 0.606; P < .001), serum FGF19 (rs = −0.324; P = .007), and stool weight (rs = 0.366; P = .003). Stool concentration of BA correlated with weight (rs = 0.737; P < .001) and level of fat (rs = 0.528; P < .001). Body mass index correlated with serum level of C4 (rs = 0.423, P < .001) and stool concentration of BA (rs = 0.507, P < .001), and was higher in patients with IBS-D compared with other groups (overall P = .036). FGFR4 rs1966265 was associated with stool level of BA (P = .032).

Conclusions

Patients with IBS-D have greater body mass index and synthesize and excrete higher levels of BA than individuals with IBS-C or healthy volunteers. Serum levels of C4 might be used to identify patients with IBS-D who have BA malabsorption; studies are needed to determine if some patients have a genetic predisposition to this disorder.

Section snippets

Participants

The study was reviewed and approved by Mayo Clinic's Institutional Review Board, and each participant provided signed informed consent. From a cohort of approximately 700 previously genotyped IBS patients (based on Rome II criteria) and healthy volunteers (HV), we invited 78 randomly selected participants: 26 HV, 26 IBS-C, and 26 IBS-D patients. These sample sizes were expected to provide approximately 80% power (based on a 2-sample t test using a 2-sided α level of .05 to detect the effect

Participant Demographics

Table 1 shows the age, body mass index (BMI), and estimated daily fat intake during the study for each of the 3 subgroups. Previous cholecystectomy was recorded in 23% of IBS-D, approximately 4% of IBS-C, and approximately 4% of HV (P = .05). All patients' symptoms anteceded the cholecystectomy and were confirmed by study subjects as not significantly aggravated or changed by subsequent cholecystectomy.

BMI was associated with subgroup (overall P = .036 where the BMI in IBS-D was approximately 4

Discussion

This study demonstrates that IBS-D patients, unselected for clinical response to BA binding, have evidence of higher hepatic BA synthesis and stool BA excretion compared with control subjects and patients with IBS-C. In IBS-D, the upper quartile for 48-hour stool weight and fat were, respectively, 481 g and 8 g, and the 90th percentile for stool fat was 15 g/48 hours. These data suggest that about 25% of IBS-D patients had increased 48-hour stool weight, but that the stool fat was within the

Acknowledgments

The authors thank Mrs Cindy Stanislav for excellent secretarial assistance.

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    Conflicts of interest The authors disclose no conflicts.

    Funding This study was supported in part by NIH grants 1RC1-DK086182 and R01-DK092179 (to Dr Camilleri).

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