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Background: Non-alcoholic fatty liver disease (NAFLD) may be associated with changes in bile acid (BA) metabolism. Hepatic BA production, measured by serum levels of the precursor 7α-hydroxy-4-cholesten-3-one (C4), is regulated by the farnesoid-X-receptor (FXR)-dependent ileal hormone fibroblast growth factor 19 (FGF19). Low FGF19 and high C4 are features of chronic BA diarrhea. Obeticholic acid, an FXR agonist, stimulates FGF19 and has shown therapeutic potential in both BA diarrhea and in NAFLD. We hypothesized there are associations of FGF19, C4 and BA diarrhea with NAFLD., Methods and Findings: 127 patients with known NAFLD were recruited prospectively. Clinical features, including metformin use, markers of NAFLD severity and BA synthesis were analyzed. The overall incidence of chronic diarrhea was 25%, with features of BA diarrhea in 12%. FGF19 negatively correlated with C4 (rs = -0.43, p = 0.001) and with alanine aminotransferase (rs = -0.22, p = 0.03), but not with either NAFLD fibrosis or Fibroscan scores. High C4 was associated with a higher NAFLD fibrosis score (p < 0.05), and with diarrhea (p = 0.001). The median NAFLD fibrosis score was higher in those with diarrhea (p = 0.002). Metformin use, in 44% overall, was particularly associated with diarrhea (in 36% vs 17%, p = 0.02), and a lower median FGF19 (74 vs 105 pg/mL, p < 0.05)., Conclusions: Increased hepatic BA production and diarrhea, but not low FGF19, were associated with increased NAFLD fibrosis score, indicating dysregulation of the FXR-FGF19 axis and suggesting hepatic FGF19 resistance. Metformin use was an important factor in a subgroup, lowering FGF19, and resulting in bile acid diarrhea., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: JW has been a consultant, speaker or advisory board member for Intercept Pharmaceuticals, GE Healthcare, Novartis, Albireo, Falk, Enyo and Metacrine. Funding for this study was received in the form of an institutional award to support RA from a Intercept Pharmaceuticals. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD., Methods: A cohort of patients with chronic diarrhoea who underwent 75 selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively. Additional clinical details available from the electronic patient record, including imaging, colonoscopy, chemistry and histopathology reports were used to calculate the prevalence of fatty liver disease, gallstones, colonic neoplasia and microscopic colitis, which was compared for BAD, the primary BAD subset and control patients with diarrhoea., Findings: Of 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (r s =-0.19, p<0.0001). Patients with BAD had an OR of 3.1 for an ALT >31 ng/mL with imaging showing fatty liver (p<0.001); similar figures occurred in the primary BAD group. FGF19 was not significantly related to fatty liver but low levels were predictive of ALT >40 IU/L. In 176 subjects with gallbladder imaging, 27% had gallstones, 7% had a prior cholecystectomy and 34% either of these. The median SeHCAT values were lower in those with gallstones (3.8%, p<0.0001), or gallstones/cholecystectomy (7.2%, p<0.001), compared with normal gallbladder imaging (14%). Overall, BAD had an OR of 2.0 for gallstones/cholecystectomy (p<0.05). BAD was not significantly associated with colonic adenoma/carcinoma or with microscopic colitis., Interpretation: The diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these associations require further investigation into potential metabolic causes., Competing Interests: Competing interests: None declared.

Chronic diarrhoea is a common condition, resulting from a number of different disorders. Bile acid diarrhoea, occurring in about a third of these patients, is often undiagnosed. We hypothesised that a positive diagnosis of bile acid diarrhoea would reduce the need for subsequent investigations for alternative diagnoses., Methods: Patients previously recruited to a study of chronic diarrhoea who had selenium homocholic acid taurine (SeHCAT) testing and subsequent follow-up at our institution were identified. In a retrospective analysis, the numbers of defined investigations undertaken from the first 3 months after SeHCAT in the following 5 years were compared., Results: 90 patients were identified with primary bile acid diarrhoea (SeHCAT retention <15%, n=36) or idiopathic diarrhoea (SeHCAT retention >15%, n=54). Follow-up had been performed on 29 and 39 subjects, respectively, with no differences in previous investigations or the last contact date. In the follow-up period, the proportions of these patients who had undergone endoscopic procedures (gastroscopy, colonoscopy and sigmoidoscopy) were the same. However, there was a higher proportion of patients in the SeHCAT-negative group who had other investigations, including imaging, physiological tests and blood tests (p=0.037). The use of cross-sectional imaging was significantly higher in this group (p=0.015) with greater proportions having CT (0.44 vs 0.10) and MRI (0.26 vs 0.07). Ultrasound use and the number of blood tests were higher in the SeHCAT-negative group whereas the SeHCAT-positive group attended more clinic appointments (p=0.013)., Conclusion: A positive diagnosis of bile acid diarrhoea, made by a SeHCAT test, resulted in reduced use of diagnostic investigations over the subsequent 5 years., Competing Interests: Competing interests: JRFW has received research grant support and has been a consultant for Albireo, GE Healthcare, Intercept, Novartis, Prometheus, Pendopharm.

Objectives: Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD., Methods: Patients with PBAD, defined by reduced (75)Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR., Results: FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention <10% (P=0.01)., Conclusions: These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.

Background: Bile acids are increasingly implicated in the pathogenesis of functional GI disorders. New mechanisms have recently been described in the irritable bowel syndrome, chronic diarrhea and chronic idiopathic constipation. Identification of bile acid signaling through farnesoid X receptor (FXR), transmembrane G-coupled receptor 5 (TGR5) and fibroblast growth factor 19 (FGF19) has led to the development of new, directly acting therapeutic agents. Despite these advances primary bile acid diarrhea remains under-recognized partly because of the lack of a widely available diagnostic test., Purpose: In this review we will summarize the effects of bile acids on bowel function throughout the gastrointestinal tract and their roles in the pathogenesis of functional diseases. We will review established diagnostic tests and therapies for functional heartburn, dyspepsia and bile acid diarrhea. There will be a particular emphasis on recent trial data for emerging therapies such as Elobixibat and Obeticholic acid and novel diagnostic tests for bile acid diarrhea such as 7α-Hydroxy-4-cholesten-3-one (C4) and FGF19. Finally we will discuss future directions for research in this rapidly evolving field, such as bacterial bile acid modification and identification of genetic anomalies associated with functional disorders., (© 2014 John Wiley & Sons Ltd.)

Mechanical loading and interleukin-1 beta (IL-1 beta) influence the release of nitric oxide (*NO) and prostaglandin E2 (PGE2) from articular chondrocytes via distinct signalling mechanisms. The exact nature of the interplay between the respective signalling pathways remains unclear. Recent studies have shown that integrins act as mechanoreceptors and may transduce extracellular stimuli into intracellular signals, thereby influencing cellular response. The current study demonstrates that the application of dynamic compression induced an inhibition of *NO and an upregulation of cell proliferation and proteoglycan synthesis in the presence and absence of IL-1 beta. PGE2 release was not affected by dynamic compression in the absence of IL-1 beta but was inhibited in the presence of the cytokine. The integrin binding peptide, GRGDSP, abolished or reversed the compression-induced alterations in all four parameters assessed in the presence and absence of IL-1 beta. The non-binding control peptide, GRADSP, had no effect. These data clearly demonstrate that the metabolic response of the chondrocytes to dynamic compression in the presence and absence of IL-1 beta, are integrin mediated.