Copyright © 2008 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited. Altered Bile Acid Metabolism in Childhood Functional Constipation: Inactivation of Secretory Bile Acids by Sulfation in a Subset of Patients  Alan F. Hofmann, y Vera Loening-Baucke, z Joel E. Lavine,  Lee R. Hagey,  Joseph H. Steinbach, § Christine A. Packard, § Terrance L. Griffin, and § Dale A. Chatfield  Division of Gastroenterology, Department of Medicine, { Department of Pediatrics, University of Iowa, Iowa City, { Department of Pediatrics, University of California, San Diego, La Jolla, and § Department of Chemistry, San Diego State University, San Diego, CA ABSTRACT Objective: An elevated concentration in the colon of the primary bile acid chenodeoxycholic acid (CDCA) or the secondary bile acid deoxycholic acid (DCA) is known to induce water secretion, causing diarrhea. We hypothesized that of the many fecal bile acids, only CDCA and DCA function as endogenous laxatives; therefore, a decrease in their proportion may be a cause of childhood functional constipation. To test this possibility, fecal bile acid compo- sition was determined in children with functional constipation and in nonconstipated control children. Patients and Methods: Fecal samples were obtained from 207 children, 103 with functional constipation and 104 with normal bowel habits. Bile acid classes were determined by use of electrospray ionization—single ion monitoring—mass spectrometry (ESI-SIM-MS), and individual bile acids were measured by gas chromatography (GC)-MS (GC-MS). The structure of individual sulfated bile acids was obtained by use of liquid chromatography (LC)-MS (LC-MS). Results: By ESI-SIM-MS, the proportions of DCA did not differ in constipated children (n ¼ 73) from that in control children (n ¼ 92), but monosulfated dihydroxy bile acids were greater (P < 0.05). The difference was attributable to 6 patients in the constipated group whose major fecal bile acid by LC-MS was the 3-sulfate of CDCA. Sulfation of CDCA is known to abolish its secretory activity. By GC-MS, the bile acid profile was identical in the 2 groups. Conclusions: In most children with functional constipation, the fecal bile acid profile seems to be normal. There is a small subset of children, however, whose dominant fecal bile acid is the 3-sulfate of CDCA, indicating a novel disturbance in bile acid metabolism. Such sulfation abolishes the secretory activity of CDCA and may contribute to constipation. JPGN 47:598– 606, 2008. Key Words: Bile acid conjugation—Bile acid sulfation. # 2008 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Constipation is a common problem of children world- wide. Estimates of the prevalence of functional consti- pation in the pediatric population have varied from 1% to 30%, with a median of 9% (1). Constipation is a frequent cause of medical visits (2) and has been reported to be a predictor of irritable bowel syndrome in later life (3). Symptoms of constipation vary from mild and short lived to severe and chronic and are sometimes accompanied by fecal impaction, fecal and urinary incontinence, urinary tract infections, and abdominal pain (4–6). The cause of childhood functional constipation is not known. We hypothesized that some cases of childhood constipation are caused by a deficiency of secretory bile acids in the colon. Several lines of evidence have pro- vided support for the assumption that dihydroxy bile acids act as endogenous laxatives. First, 2 dihydroxy bile acids—chenodeoxycholic acid (3a,7a-dihydroxy, CDCA), a primary bile acid, and deoxycholic acid (3a,12a-dihydroxy, DCA), a secondary bile acid— induce concentration-dependent secretion when perfused into the human (7) or canine (8) colon. Second, in in vitro studies, using polarized monolayers of T84 cells, secretion is induced by these 2 bile acids and by Received October 31, 2007; accepted November 29, 2007. Address correspondence and reprint requests regarding bile acids to Dr Alan F. Hofmann, Division of Gastroenterology, Department of Medicine, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0063 (e-mail: HofmannAF@cs.com). Address correspondence regarding functional constipation to Dr Vera Loening-Baucke, Department of Pediatrics, University of Iowa Hospi- tals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242 (e-mail: Vera- Loening-Baucke@uiowa.edu). Supported in part by NIH grant NIDDK 64891 to A.F.H. None of the authors has any conflicts of interest regarding the work reported herein. Journal of Pediatric Gastroenterology and Nutrition 47:598–606 # 2008 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition 598