Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea

Abstract

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.

Figure 1

(A) Association of fasting serum C4 and subgroup. There was a significant overall univariate association with group and a significant difference between IBS-D and both HV and IBS-C groups. (B) Association of fasting serum C4 and serum FGF19; note the significant negative association, based on Spearman correlation. Inset, the same data are plotted based on rank transformation, and the line demonstrates the inverse correlation between serum FGF19 and C4.

Figure 2

Association of total 48-hour stool BA and subgroup. There was a borderline overall univariate association with group and a significant difference between IBS-D and IBS-C groups.

Figure 3

Relationship between fasting serum C4 and total 48-hour stool BA excretion (A) and total 48-hour stool weight (B).

Figure 4

Relationship between total 48-hour stool weight (A) and stool fat (B) and total 48-hour stool BA excretion.

Figure 5

Relationship between BMI and total stool BA excretion.