BAM ≢ BAD

Abstract

This issue of Digestive Diseases and Sciences includes an article by Khanna et al. reporting aspects of bile acid metabolism in patients seen at Mayo Clinic with chronic diarrhea and neuroendocrine tumors [1]. Data were gathered retrospectively from a heterogeneous group of patients with a variety of tumors, variable tumor loads, and various treatments, including bowel resection. The bottom line from this study is that most subjects had evidence of bile acid malabsorption (BAM). The contribution of that BAM to their ongoing diarrhea, based on the data presented, is less certain. Bile acids have been studied scientifically over the last 150 years, the retelling of which is a fascinating story that demonstrates the strong dependence of scientific knowledge on evolving technology [2, 3]. As new techniques such as chromatography, mass spectroscopy, and x-ray diffraction developed, novel features of these organic molecules were revealed. Bile acids comprise a diverse group of acid sterols synthesized in the liver, conjugated to amino acids glycine or taurine, and secreted into the bile, that work intraluminally in the intestine to help solubilize fat prior to absorption. Most of the bile acid load to the intestine is reabsorbed by specialized transporters in the ileum and returned to the liver via the mesenteric veins, creating an enterohepatic circulation. The fraction of bile acid that is not reabsorbed by the ileum passes down to the colon where it encounters the microbiome which deconjugates and modifies the primary bile acids, chenodeoxycholic acid and cholic acid, forming the secondary bile acids, deoxycholic acid and lithocholic acid, which can be absorbed from the colon and returned to the liver. Studies reaching back 50 years showed that the functions of bile acids included disposal of cholesterol from the body, solubilization of cholesterol in bile, and solubilization of dietary long chain lipids in the aqueous environment of the intestine which delivered fat to the brush border in the form of mixed micelles [2, 3]. Research in the last 25 years has illuminated an unexpected function of bile acids as signaling molecules [4]. In the ileum, bile acids interact with farnesoid X receptor (FXR) in the nuclei of ileal enterocytes in order to modulate the production of fibroblast growth factor 19 (FGF19) which inhibits hepatic synthesis of endogenous bile acids, thereby autoregulating bile acid synthesis. Impaired feedback inhibition of bile acid synthesis is thought to be the mechanism of BAM in some patients with chronic diarrhea [5]. Bile acid also interacts with a membrane-bound receptor, variously known as G-protein-coupled bile acid receptor 1 (GPBAR1), Takeda G-protein receptor 5 (TGR5) or membrane-type receptor for bile acids (M-BAR). This receptor located in the colonic epithelium, bile duct, gallbladder, and enteric nerves (and also outside the gastrointestinal tract in macrophages and brown fat cells) is linked to adenylate cyclase, modulating fluid and electrolyte secretion by the colon, among other functions. Activation of colonic GPBAR1 by luminal bile acid is thought to be the mechanism by which excess bile acid in the colon causes bile acid diarrhea (BAD). Studies of bile acid malabsorption in animals and humans after ileal resection demonstrate the complexity of the pathophysiology of BAD. The concentration of dihydroxy bile acid in the colon (mainly deoxycholic acid and chenodeoxycholic acid) must exceed 3–5 mmol/L in order to produce diarrhea [6]. This can be achieved with short ileal resections (< 25–50 cm) in which the malabsorbed bile acid is dissolved in a relatively normal volume of ileal effluent, since overall small intestinal fluid absorption is not compromised much by such a small resection. In contrast, since a large ileal resection (> 100 cm) substantially decreases intestinal fluid absorption, malabsorbed bile acid is dissolved in a large volume of ileal effluent and may not reach the cathartic threshold concentration. In both cases, although BAM will * Lawrence R. Schiller [email protected]