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Do steroids ameliorate bile acid malabsorption in Crohn’s disease?
  1. R S Kwon,
  2. M C Carey
  1. Department of Medicine, Harvard Medical School, Division of Gastroenterology, Brigham and Women’s Hospital and Harvard Digestive Diseases Center, Boston, MA, USA
  1. Correspondence to:
    Dr M C Carey
    Brigham and Women’s Hospital, Division of Gastroenterology, 75 Francis Street, Boston, MA, 02115, USA; mccareyrics.bwh.harvard.edu

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Steroids may partially restore impaired bile salt absorption in Crohn’s disease patients, highlighting a new modus operandi for steroids as their beneficial effects have traditionally been attributed to immunomodulatory effects alone

Steroids are among the mainstays of medical therapy for Crohn’s disease but may lead to unfavourable long term complications. Recently, budesonide has been shown to be effective in inducing remission in mild to moderate disease while undergoing less systemic absorption compared with other corticosteroids.1 It is hypothesised that steroids exert their salutary effect through an immunomodulatory action on the small bowel mucosa.2 In this issue of Gut, Jung and colleagues3 shed light on the possibility of another potentially beneficial effect of steroid therapy—namely, the partial restoration of impaired bile salt absorption in Crohn’s patients with distal ileal involvement [see page 78].

The integrity of the enterohepatic circulation of bile salts is dependent on active uptake from the ileum, which is mediated by SLC10A2, known previously as the apical sodium dependent bile acid transporter (ASBT).4 Given the malady’s proclivity for the distal ileum, one of the classic hallmarks of intestinal Crohn’s disease is bile salt malabsorption.5–7 Bile salt malabsorption occurs when intestinal transport is appreciably disrupted, and the degree to which this occurs depends on the length of ileal involvement and/or resection.8 Therefore, the activity and functioning of the remaining ASBT, as well as colonic compensation by passive absorption of bacterially modified (secondary) bile acids are essential for keeping the enterohepatic circulation of bile salts partially intact.9,10 Mild bile salt malabsorption may result in cholerrhoeic enteropathy that is easily controlled with low dose bile salt sequestrants. However, more extensive ileal involvement is accompanied by severe bile salt malabsorption, fat malabsorption, and steatorrhoea, as well as frequent diarrhoea made worse by sequestrants.

Previously, ASBT expression was shown to be upregulated by glucocorticoids in a rat model.11 Jung and colleagues3 have built upon this framework by showing that this response also takes place in humans. Employing ileal biopsies obtained at colonoscopy, the authors determined that a 21 day course of budesonide induced a 34% increase in ileal ASBT expression in 10 apparently normal volunteers. Within the promoter region of ASBT, the authors identified two inverted repeat (IR3) motifs that were shown to function as glucocorticoid response elements (GRE). They cotransfected the glucocorticoid receptor (GR) with a luciferase promoter construct of the ASBT gene into an in vitro cell line. When the cells were treated with dexamethasone, a known GR ligand, and budesonide (both at concentrations of 0.1–1 μmol/l), ASBT promoter activity increased 15–20-fold. Utilising electrophoretic mobility assays, the authors demonstrated that the IR3 sequences formed DNA-protein complexes with GR that could be inhibited with anti-GR antibodies.

A most interesting finding was that when compared with normal control tissue, ASBT expression was reduced significantly in ileal biopsies taken from 16 Crohn’s disease patients obtained from a Zurich inflammatory bowel disease (IBD) tissue bank. This seems to us rather surprising given that there were no inflammatory histological changes in the biopsies, except one with “mild” inflammation. Unfortunately, the Jung3 study did not include detailed clinical information on the patients, such as demographics (for example, age), duration, extent or symptomatology of their disease, how the biopsies were obtained, their Crohn’s disease activity index scores, use of any medications, or whether these patients exhibited any evidence of clinically significant or subclinical bile salt malabsorption. This dearth of clinical information makes it difficult to interpret the true significance of the reduction in ASBT expression in ex vivo banked tissue samples. If a similar reduction could be found in the ileum of patients with newly diagnosed disease and therefore with no prior therapy, then this would support the possibility that functional ileocyte abnormalities occur prior to microscopic inflammatory changes classically associated with Crohn’s disease. Clearly the authors’ findings will need to be validated in further in vitro and clinical studies but their observations raise the intriguing question that bile salt malabsorption may be a precursor to histologically evident Crohn’s disease. This would be a novel concept especially if the reduction in ASBT expression serves as a marker for the extent and even activity of the disease, particularly when the inflammation primarily affects other sites in the gastrointestinal tract, such as the colon. Nevertheless, the possibility must be borne in mind that if the index patients in this study3 had resolving ileitis aided by the use of medications, then the biopsies could represent histological ileocyte recovery in the face of delayed return of physiological ASBT expression.

This provocative study also sheds further light on the clinical relevance of bile salt malabsorption during the course of Crohn’s disease and its complications. The first dysfunctional ASBT mutation was actually identified in the ileum of a Crohn’s disease patient.12 Diminution in ASBT expression found by Jung and colleagues3 suggests the importance of including early therapy against bile salt malabsorption (for example, bile acid sequestrants) in conjunction with traditional immunomodulatory therapy for Crohn’s disease. The findings from the current study would suggest that budesonide itself would be particularly beneficial in early Crohn’s disease as it may be capable of targeting both therapeutic goals. Therapy against bile salt malabsorption may not only be beneficial in terms of controlling diarrhoea but also in preventing pigment gall stone formation, for which Crohn’s disease patients are at appreciably higher risk.13 In a systematic study, Brink and colleagues14 demonstrated elevations in total bilirubin levels in gall bladder bile (hyperbilirubinbilia) obtained from Crohn’s disease patients with extensive ileitis (>50 cm) or ileal resections, work that was confirmed by another group.15 The likely mechanism for this pigment lithogenicity is passive enterohepatic cycling of bilirubin from the large intestine caused by solubilisation of unconjugated bilirubin (UCB) by increased colonic bile salt concentrations, as well as prevention of urobilinoid formation.13 UCB resorbed from the colon is taken up and reconjugated in the liver and secreted in excess into bile where the elevated levels provide supraphysiological substrate concentrations for deconjugation by biliary β-glucuronidase. The resulting higher biliary concentrations of UCB may precipitate as calcium salts in gall bladder bile and therefore increase the risk of “black” pigment gall stone formation.

The work by Jung and colleagues3 also contributes to the recent explosion of studies investigating the regulation of the enterohepatic circulation and of bile salt metabolism. In particular, information on the extraordinary complexity of control of ASBT expression continues to grow at an amazing pace. Two recent studies, including one from the same Zurich group, have demonstrated the central role of hepatocyte nuclear factors HNF-4α and HNF-1α in the transcriptional regulation of ASBT.16,17 Now, with the addition of the GREs in the ASBT gene identified in the current study,3 our understanding of the complexity of ASBT regulation increases further. The authors’ findings, in conjunction with the observation that expression of fatty acid binding protein (FABP6), formerly known as ileal bile acid binding protein (IBABP), is also regulated by glucocorticoids,18 highlight a new modus operandi for steroids as their salutary results have traditionally been attributed to their immunomodulatory effects alone. Perhaps this knowledge will yield a role for earlier and more frequent use of corticosteroids in this disease and, in particular, budesonide which reduces the risk of untoward systemic complications associated with chronic steroid therapy. Certainly, the authors’ findings of lower ASBT levels in Crohn’s disease brings to mind the benefits of early and routine use of newer bile acid sequestrants that are now in existence (for example, colesevelam), which are more potent and better tolerated than traditional ones. However, before such changes in the management of Crohn’s disease occurs, the functional and clinical relevance of decreased ASBT expression in histologically normal ileal biopsies from IBD patients will need to be clarified. In addition, to answer our rhetorical title, it remains to be shown whether the regulatory effect of budesonide or other corticosteroids on ASBT expression can be observed in acutely inflamed ileal tissue and whether this will translate into any clinical benefit for Crohn’s patients.

Steroids may partially restore impaired bile salt absorption in Crohn’s disease patients, highlighting a new modus operandi for steroids as their beneficial effects have traditionally been attributed to immunomodulatory effects alone

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