300 results found
Walters JRF, 2021, The role of bile acids and their TGR5 receptor in irritable bowel syndrome and diarrhoea, DIGESTIVE AND LIVER DISEASE, Vol: 53, Pages: 1118-1119, ISSN: 1590-8658
Hiner GE, Walters JRF, 2021, A practical approach to the patient with chronic diarrhoea, CLINICAL MEDICINE, Vol: 21, Pages: 124-126, ISSN: 1470-2118
Storr M, Gross M, Madisch A, et al., 2021, [Bile acid diarrhea, stepchild of chronic diarrhea - prevalence, diagnosis and treatment. Update 2021]., Z Gastroenterol
Bile acid diarrhea is one of the most frequently undiagnosed causes of chronic diarrhea. A variety of different pathophysiologic causes can underlie chronic diarrhea. Even after exclusion of the more frequent causes, up to 5 % of the population remains affected by unexplained chronic diarrhea. In up to 50 % within this cohort, bile acid diarrhea is the underlying cause.The various pathophysiologies leading to bile acid diarrhea are well characterized. In this way, bile acid diarrhea can be divided into primary, secondary and tertiary subtypes. Common to all causes is the increased amount of bile acids in the colon and in the faeces and the resulting secretory-osmotic diarrhea, in more severe forms in combination with steatorrhea. The diagnosis of bile acid diarrhea follows a clear algorithm which, in addition to the search for the cause and possibly a therapeutic trial, recognizes the 75SeHCAT test as the reference method for the detection of an increased loss of bile acids. In view of the chronic nature of the symptoms and the need for permanent, lifelong therapy, the use of a one-time, reliable diagnostic test is justified, though the test is currently only available at a few centers. In addition to the treatment of identifiable underlying diseases, the current treatment includes the use of drugs that bind bile acids, with additional nutritional recommendations and vitamin substitutions.The present review article summarizes the pathophysiology and importance of bile acid diarrhea and discusses the current approach towards diagnosis and treatment.
Mitchell AL, Ovadia C, Syngelaki A, et al., 2021, Re-evaluating diagnostic thresholds for intrahepatic cholestasis of pregnancy: case-control and cohort study., BJOG
OBJECTIVE: To determine the optimal total serum bile acid (TSBA) threshold and sampling time for accurate intrahepatic cholestasis of pregnancy (ICP) diagnosis. DESIGN: Case-control, retrospective cohort studies. SETTING: Antenatal clinics, clinical research facilities. POPULATION: Women with ICP or uncomplicated pregnancies. METHODS: Serial TSBA measurements were performed pre-/post-prandially in 42 women with ICP or uncomplicated pregnancy. Third trimester non-fasting TSBA reference ranges were calculated from 561 women of black, south Asian and white ethnicity. Rates of adverse perinatal outcomes for women with ICP but peak non-fasting TSBA below the upper reference range limit were compared with healthy populations. MAIN OUTCOME MEASURES: Sensitivity and specificity of common TSBA thresholds for ICP diagnosis, using fasting and postprandial TSBA. Calculation of normal reference ranges of non-fasting TSBA. RESULTS: TSBA concentrations increased markedly postprandially in all groups, with overlap between healthy pregnancy and mild ICP (TSBA<40μmol/L). The specificity of ICP diagnosis was higher when fasting, however, corresponded to <30% sensitivity for diagnosis of mild disease. Using TSBA ≥40μmol/L to define severe ICP, fasting measurements identified 9% (1/11), while non-fasting measurements detected over 91% with severe ICP. The highest upper limit of the non-fasting TSBA reference range was 18.3µmol/L (95% confidence interval 15.0 to 35.6μmol/L). A re-evaluation of published ICP meta-analysis data demonstrated no increase in spontaneous preterm birth or stillbirth in women with TSBA <19µmol/L. CONCLUSIONS: Postprandial TSBA levels are required to identify high-risk ICP pregnancies (TSBA≥40μmol/L). The postprandial TSBA rise in normal pregnancy indicates that a non-fasting threshold of ≥19µmol/L would improve diagnostic accuracy.
McGlone ER, Malallah K, Cuenco J, et al., 2021, DIFFERENTIAL EFFECTS OF BILE ACIDS ON THE POST-PRANDIAL SECRETION OF GUT HORMONES: a randomised crossover study., Am J Physiol Endocrinol Metab
AIMS Bile acids (BA) regulate post-prandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The post-prandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effect of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on post-prandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon and ghrelin. METHODS Twelve healthy volunteers underwent a mixed meal test 60 minutes after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg) or no BA in a randomised cross-over study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin and fibroblast growth factor 19 were measured prior to BA administration at -60, 0 (just prior to mixed meal) and 15, 30, 60, 120, 180 and 240 minutes after the meal. RESULTS UDCA and CDCA provoked differential gut hormone responses: UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced post-prandial secretion of GIP, with an associated reduction in post-prandial insulin secretion. CONCLUSIONS Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmedin obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.
Sagar NM, Duboc H, Kay GL, et al., 2020, The pathophysiology of bile acid diarrhoea: differences in the colonic microbiome, metabolome and bile acids, Scientific Reports, Vol: 10, Pages: 1-12, ISSN: 2045-2322
Bile acid diarrhoea (BAD) is a common disorder resulting from increased loss of bile acids (BAs), overlapping irritable bowel syndrome with diarrhoea (IBS-D). The gut microbiota metabolises primary BAs to secondary BAs, with differing impacts on metabolism and homeostasis. The aim of this study was to profile the microbiome, metabolic products and bile acids in BAD. Patients with BAD diagnosed by SeHCAT testing, were compared with other IBS-D patients, and healthy controls. Faecal 16S ribosomal RNA gene analysis was undertaken. Faecal short chain fatty acid (SCFA) and urinary volatile organic compounds (VOCs) were measured. BAs were quantified in serum and faeces. Faecal bacterial diversity was significantly reduced in patients with BAD. Several taxa were enriched compared to IBS-D. SCFA amounts differed in BAD, controls and IBS-D, with significantly more propionate in BAD. Separation of VOC profiles was evident, but the greatest discrimination was between IBS-D and controls. Unconjugated and primary BA in serum and faeces were significantly higher in BAD. The faecal percentage primary BA was inversely related to SeHCAT. BAD produces dysbiosis, with metabolite differences, including VOC, SCFA and primary BAs when compared to IBS-D. These findings provide new mechanistic insights into the pathophysiology of BAD.
Walters JRF, 2020, Making the diagnosis of bile acid diarrhea., American Journal of Gastroenterology, Vol: 115, Pages: 1974-1975, ISSN: 0002-9270
Bile acid diarrhea is a frequent, treatable cause of functional diarrhea but is difficult to diagnose when the nuclear medicine seleno-taurohomocholic acid test is unavailable. An alternative approach is testing blood for the bile acid precursor, 7α-OH-4-cholesten-3-one, which is raised with increased bile acid synthesis. A recent article has defined measurements that have high negative and positive predictive values, further exploring how they can be improved by incorporating measures such as age, stool number, fibroblast growth factor 19, or plasma sulfated bile acids. Other articles have looked at the percentage of fecal primary bile acids. Together, they promise better use of diagnostic biomarkers for this condition.
Walters J, Arasaradnam R, Andreyev J, 2020, Diagnosis and management of bile acid diarrhoea: a survey of UK expert opinion and practice, Frontline Gastroenterology, Vol: 11, Pages: 358-363, ISSN: 2041-4137
Objective Bile acid diarrhoea (BAD), which includes bile acid malabsorption, causes a variety of digestive symptoms. Diagnostic rates and management vary considerably. We conducted a survey of current practice to review expert opinion and provide guidance on diagnosis and management.Design/method An online survey was conducted of clinical members of the UK Bile Acid Related Diarrhoea Network, who had all published research on BAD (n=21). Most were National Health Service consultants who had diagnosed over 50 patients with the condition.Results The preferred terminology was to use BAD, with primary and secondary to classify causes. A wide range of presenting symptoms and associated conditions were recognised. SeHCAT (tauroselcholic acid) was the preferred diagnostic test, and 50% of respondents thought general practitioners should have access to this. Patients who met the Rome IV diagnostic criteria for functional diarrhoea, irritable bowel syndrome (IBS) with predominant diarrhoea or postcholecystectomy diarrhoea were usually investigated by SeHCAT, which was used sometimes in other types of IBS. Treatment with a bile acid sequestrant was offered to patients with low SeHCAT values, with expected response rates >70% in the most severe. Colestyramine was the usual sequestrant, starting between 2 g and 8 g daily; colesevelam was an alternative. In patients who had an incomplete response, increasing the dose, changing to an alternative sequestrant, use of loperamide and a low fat diet were suggested. Recommendations for follow-up and to improve the overall patient experience were made.Conclusion This expert survey indicates current best practice in the diagnosis and management of BAD.
Camilleri M, Nord SL, Burton D, et al., 2020, Randomised clinical trial: Significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Vol: 52, Pages: 808-820, ISSN: 0269-2813
Quraishi MN, Acharjee A, Beggs AD, et al., 2020, A pilot integrative analysis of colonic gene expression, gut microbiota and immune infiltration in primary sclerosing cholangitis-inflammatory bowel disease: association of disease with bile acid pathways, Journal of Crohns & Colitis, Vol: 14, Pages: 935-947, ISSN: 1873-9946
BACKGROUND: Although majority of patients with PSC have colitis (PSC-IBD) this is phenotypically different from UC. We sought to define further the pathophysiologic differences in PSC-IBD and UC, by applying a comparative and integrative approach in this pilot study. METHODS: Colonic biopsies were collected from patients with PSC-IBD (n=10), UC (n=10) and healthy controls (HC; n=10). Shotgun RNA-sequencing for differentially expressed colonic mucosal genes (DEGs), 16S rRNA analysis for microbial profiling and immunophenotyping were performed followed by multi-omic integration. RESULTS: The colonic transcriptome differed significantly between groups (P=0.01). Colonic transcriptomes from HC were different from both UC (1343 DEGs) and PSC-IBD (4312 DEGs). Of these genes, only 939 had shared differential gene expression in both UC and PSC-IBD compared to HC. Imputed pathways were predominantly associated with upregulation of immune response and microbial defence in both disease cohorts compared to HC. There were 1692 DEGs between PSC-IBD and UC. Bile acid signalling pathways were upregulated in PSC-IBD compared to UC (P=0.02). Microbiota profiles were different between the three groups (P=0.01); with inferred function in PSC-IBD also being consistent with dysregulation of bile acid metabolism. Th17 cells and IL17 producing CD4 cells were increased in both PSC-IBD and UC when compared to HC (P<0.05). Multi-omic integration revealed networks involved in bile acid homeostasis and cancer regulation in PSC-IBD. CONCLUSIONS: Colonic transcriptomic and microbiota analysis in PSC-IBD points toward dysregulation of colonic bile acid homeostasis compared to UC. This highlights important mechanisms and suggests the possibility of novel approaches in treating PSC-IBD.
Labarile N, Ghosh S, Ng SC, et al., 2020, Tests that now deserve to be more widely adopted in IBD clinical practice, Therapeutic Advances in Gastroenterology, Vol: 13, Pages: 1-14, ISSN: 1756-2848
Inflammatory bowel diseases are chronic relapsing immune-mediated diseases of the intestinal tract with multifaceted manifestations and treatment related morbidity. Faecal and blood tests, radiological, endoscopic and histologic investigations are now widely used for managing both ulcerative colitis and Crohn’s disease. Over the years, a number of new investigations have been proposed but not widely adopted yet. Patients with Crohn’s disease may have multiple causes of diarrhoea, not always attributable to disease exacerbation, but sometimes linked to bile acid malabsorption; we have a reliable serum test, C4, that allows us to recognize and treat this cause of diarrhoea efficaciously and not empirically, but it is not available or used widely. There is genetic inter-individual variability in drug responses, in terms of both efficacy and toxicity, leading to high rates of therapeutic failure. Patients treated with thiopurine or, more rarely, 5-aminosalicylic acid may suffer from unpredictable and serious adverse events, some of these with pathogenesis related to genetic variants: myelosuppression, acute pancreatitis and nephrotoxicity. The identification of pre-treatment genetic tests can optimize therapeutic choice and avoid adverse events. With regard to biological drugs, patients can experience primary non-response or loss of response due to induction of immune responses to the drugs affecting drug efficacy and determining hypersensitivity reactions. We have specifically reviewed a number of investigations, whose use is currently limited, and highlighted four tests that deserve to be more widely incorporated in clinical practice as these could improve medical decision-making and patient outcomes.
Ovadia C, Perdones Montero A, Fan HM, et al., 2020, Ursodeoxycholic acid enriches intestinal bile salt hydrolase-expressing Bacteroidetes in cholestatic pregnancy, Scientific Reports, Vol: 10, ISSN: 2045-2322
Ursodeoxycholic acid (UDCA) treatment can reduce itch and lower endogenous serum bile acids in intrahepatic cholestasis of pregnancy (ICP). We sought to determine how it could influence the gut environment in ICP to alter enterohepatic signalling.The gut microbiota and bile acid content were determined in faeces from 35 pregnant women (14 with uncomplicated pregnancies and 21 with ICP, 17 receiving UDCA). Faecal bile salt hydrolase activity was measured using a precipitation assay. Serum fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) concentrations were measured following a standardised diet for 21 hours. Women with a high ratio of Bacteroidetes to Firmicutes were more likely to be treated with UDCA (Fisher’s exact test p=0.0178) than those with a lower ratio. Bile salt hydrolase activity was reduced in women with low Bacteroidetes:Firmicutes. Women taking UDCA had higher faecal lithocholic acid (p<0.0001), with more unconjugated bile acids than women with untreated ICP or uncomplicated pregnancy. UDCA-treatment increased serum FGF19, and reduced C4 (reflecting lower bile acid synthesis). During ICP, UDCA treatment can be associated with enrichment of the gut microbiota with Bacteroidetes. These demonstrate high bile salt hydrolase activity, which deconjugates bile acids enabling secondary modification to FXR agonists, enhancing enterohepatic feedback via FGF19.
Sadowski DC, Camilleri M, Chey WD, et al., 2020, Canadian association of gastroenterology clinical practice guideline on the management of bile acid diarrhea., Journal of the Canadian Association of Gastroenterology, Vol: 3, Pages: e10-e27, ISSN: 2515-2084
Background and Aims: Chronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. Methods: We performed a systematic search of publication databases for studies of assessment and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach. Patient population, intervention, comparator and outcome questions were developed through an iterative process and were voted on by a group of specialists. Results: The certainty of evidence was generally rated as very low. Therefore, 16 of 17 recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors (terminal ileal resection, cholecystectomy or abdominal radiotherapy), but not additional symptoms, was recommended for identification of patients with possible BAD. The group suggested testing using 75selenium homocholic acid taurine (where available) or 7α-hydroxy-4-cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional diarrhea and Crohn's disease without inflammation. Testing was suggested over empiric bile acid sequestrant therapy (BAST). Once remediable causes are managed, the group suggested cholestyramine as initial therapy, with alternate BAST when tolerability is an issue. The group suggested against BAST for patients with extensive ileal Crohn's disease or resection and suggested alternative antidiarrheal agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose, with a trial of intermittent, on-demand administration, concurrent medication review and reinvestigation for patients whose symptoms persist despite BAST. Conclusions: Based on a systematic review, BAD should be considered for patients with chronic diarrhea. For patients with positive results from tests for BAD, a trial of BAS
Sadowski DC, Camilleri M, Chey WD, et al., 2020, Canadian Association of Gastroenterology Clinical Practice Guideline on the Management of Bile Acid Diarrhea, CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, Vol: 18, Pages: 24-+, ISSN: 1542-3565
Walters JR, Marchesi JR, 2019, Chronic diarrhea, bile acids, and Clostridia., Journal of Clinical Investigation, Vol: 130, Pages: 77-79, ISSN: 0021-9738
Excessive fecal bile acid (BA) loss causes symptoms in a large proportion of people diagnosed with irritable bowel syndrome with diarrhea, a common functional bowel disorder. This BA diarrhea (BAD) results from increased hepatic synthesis of BAs, with impaired negative feedback regulation by the ileal hormone fibroblast growth factor 19 (FGF19). In this issue of the JCI, Zhao et al. investigated BA metabolism, including fecal BAs, serum BAs, and FGF19, in patients and controls. They identified associations between fecal bacterial BA metabolism and specific microbiota, especially Clostridium scindens. These findings have been tested in a mouse model using microbiota transplants and antibiotic treatment. This group of organisms has potential as a biomarker for BAD and to be a target for therapy.
Arasaradnam RP, Walters JRF, 2019, Role of endoscopy in chronic diarrhoea when functional bowel disease is suspected, Gut, Vol: 69, Pages: 190-191, ISSN: 0017-5749
McGlone ER, Tan T, Bloom SR, et al., 2019, What Can We Learn From Mouse Models About Bile Acid–Mediated Changes After Bariatric Surgery?, Gastroenterology, Vol: 157, Pages: 4-8, ISSN: 0016-5085
Ovadia C, Perdones-Montero A, Spagou K, et al., 2019, Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis, Hepatology, Vol: 70, Pages: 276-293, ISSN: 0270-9139
Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF)19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor(FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole genome sequencing and UPLC-MS were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary cholic acid supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy due to elevated bile salt hydrolase-producing Bacteroidetes. Cholic acid supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. CONCLUSION: the altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis
Walters J, Arasaradnam R, Andreyev J, 2019, PWE-037 Diagnosis and management of bile acid diarrhoea: UK consensus survey of expert opinion and practice FREE, Annual Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ Publishing Group, Pages: A169-A169, ISSN: 0017-5749
Introduction Bile acid diarrhoea (BAD), including bile acid malabsorption (BAM), causes a variety of digestive symptoms and is increasingly recognised, although diagnostic rates and management vary considerably. The UK Bile Acid Related Diarrhoea Network (UK-BARDN), established in 2017, conducted a survey of current practice to provide a review of expert opinion and guidance on diagnosis and management.Methods An on-line survey was sent at the end of 2018 to 21 clinical members of UK-BARDN, who had all published research on BAD.Results A response rate of 100% was obtained. 95% were NHS Consultants; 85% estimated they had diagnosed over 50 patients with the condition. BAD was the terminology preferred by 57%, with another 29% using BAD or BAM depending on the clinical circumstances. Primary and secondary were the preferred terms to classify the different causes.A wide range of presenting symptoms and associated conditions were recognised. SeHCAT was the preferred diagnostic test, with a therapeutic trial the second choice. Access to SeHCAT by GPs was thought appropriate by 50%, with greater availability of specific blood tests in hospitals. SeHCAT would usually be requested (>70%) in patients who met the diagnostic criteria for functional diarrhoea, IBS-D, or post-cholecystectomy diarrhoea, and sometimes be requested (>30%) in other types of IBS, and in Crohn’s disease with ileal resection and negative inflammatory markers, where a therapeutic trial was also commonly used.Treatment with a bile acid sequestrant (BAS) would always be given if SeHCAT was <5%, usually if 5–15%, and sometimes if 15–20%. Expected response rates were >70%, falling to 30% in these groups. Colestyramine was the usual first line BAS, with starting doses varying between 2 g od and 4 g bd. Colesevelam was also used. There was a slight preference to give the drug at bedtime. Warnings about drug interactions were usual. In patients who had an incomplete response, incr
Walters JR, Sagar N, Duboc H, et al., 2019, PRIMARY BILE ACIDS IN A SINGLE FECAL SAMPLE FOR THE DIAGNOSIS OF BILE ACID DIARRHEA: RELATIONSHIP TO SEHCAT TESTING, Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S774-S774, ISSN: 0016-5085
Camilleri M, Nord SL, Burton D, et al., 2019, A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, CROSSOVER, MULTIPLE-DOSE STUDY OF TROPIFEXOR, A NON BILE ACID FXR AGONIST, IN PATIENTS WITH PRIMARY BILE ACID DIARRHEA, Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S204-S205, ISSN: 0016-5085
Ovadia C, Perdones-Montero A, Mullish B, et al., 2019, Ursodeoxycholic acid treatment of cholestatic pregnancy can alter the gut microbiota to enhance bile acid modification and production of metabolically-active secondary bile acids - an explanation for 'responders' and 'non-responders'?, Publisher: WILEY, Pages: 17-17, ISSN: 1470-0328
Appleby R, Moghul I, Khan S, et al., 2019, Non-alcoholic fatty liver disease is associated with dysregulated bile acid synthesis and diarrhea: a prospective observational study, PLoS ONE, Vol: 14, ISSN: 1932-6203
BackgroundNon-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 findings127 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).ConclusionsIncreased 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.
Walters JRF, 2018, Letter: long-term treatment of severe bile acid diarrhoea-obeticholic acid can normalise SeHCAT retention, Alimentary Pharmacology and Therapeutics, Vol: 48, Pages: 1032-1034, ISSN: 0269-2813
Hegyi P, Maléth J, Walters JR, et al., 2018, Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease, Physiological Reviews, Vol: 98, Pages: 1983-2023, ISSN: 1522-1210
Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention.
Arasaradnam RP, Brown S, Forbes A, et al., 2018, Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition, Gut, Vol: 67, Pages: 1380-1399, ISSN: 0017-5749
Chronic diarrhoea is a common problem, hence clear guidance on investigations is required. This is an updated guideline from 2003 for the investigations of chronic diarrhoea commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). This document has undergone significant revision in content through input by 13 members of the Guideline Development Group (GDG) representing various institutions. The GRADE system was used to appraise the quality of evidence and grading of recommendations.
Best D, Kelman L, Walters JR, 2018, PROBLEMS EXPERIENCED BY PATIENTS WITH BILE ACID DIARRHEA: A CONTENT ANALYSIS OF POSTINGS ON A FACEBOOK SUPPORT GROUP, Annual Meeting of the American-Society-for-Gastrointestinal-Endoscopy / Digestive Disease Week, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S912-S912, ISSN: 0016-5085
Lee JM, Ong JR, Vergnes L, et al., 2018, Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants, Journal of Lipid Research, Vol: 59, Pages: 429-438, ISSN: 0022-2275
Diet1 modulates intestinal production of the hormone fibroblast growth factor 15 (FGF15), which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1 null mutation are resistant to hypercholesterolemia compared to wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated Diet1-/- mice on the C57BL6/J genetic background. C57BL/6J Diet1-/- mice had elevated bile acid levels, reduced Fgf15 expression, and increased gastrointestinal motility and intestinal luminal water content, which are symptoms of bile acid diarrhea (BAD) in humans. Natural genetic variation in Diet1 mRNA expression levels across 76 inbred mouse strains correlated positively with Ffg15 mRNA and negatively with serum bile acid levels. This led us to investigate the role of DIET1 genetic variation in primary BAD patients. We identified a DIET1 coding variant (rs12256835) that had skewed prevalence between BAD cases and controls. This variant causes an H1721Q amino acid substitution that increases the levels of FGF19 protein secreted from cultured cells. We propose that genetic variation in DIET1 may be a determinant of FGF19 secretion levels, and may affect bile acid metabolism in both physiological and pathological conditions.
Appleby RN, Nolan JD, Johnston ID, et al., 2017, Novel associations of bile acid diarrhoea with fatty liver disease and gallstones: a cohort retrospective analysis., BMJ Open Gastroenterology, Vol: 4, ISSN: 2054-4774
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 75selenohomocholic 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 (rs=−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 galls
Walters JRF, 2017, Editorial: diagnosing bile acid diarrhoea with blood tests, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Vol: 46, Pages: 699-700, ISSN: 0269-2813
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