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A pilot study of fecal bile acid and microbiota profiles in inflammatory bowel disease and primary sclerosing cholangitis.

ABSTRACT: Introduction:Inflammatory bowel disease (IBD) is thought to arise from an abnormal immune response to the gut microbiota. IBD is associated with altered intestinal microbial community structure and functionality, which may contribute to inflammation and complications such as colon cancer and liver disease. Primary sclerosing cholangitis (PSC) is associated with IBD and markedly increases the risk of colon cancer. We hypothesized that secondary bile acids, which are products of microbial metabolism, are increased in PSC patients. Aim:Here, we profiled the fecal bile acid composition and gut microbiota of participants with IBD and PSC, as well as healthy participants. Additionally, we tested the effects of vancomycin, a proposed treatment for PSC, on gut microbiota and fecal bile acid composition in participants with IBD and PSC. Methods:Fecal samples were collected from patients with IBD, IBD/PSC and healthy controls and fecal bile acids and DNA for microbiota analysis were extracted. Fecal bile acids were averaged over a seven-day period. For subjects with IBD/PSC, oral vancomycin 500mg twice a day was administered and fecal samples were collected for up to eleven weeks. Results:Participants with IBD and PSC had less fecal microbial diversity at baseline relative to controls. While there was some evidence of altered conversion of cholic acid to deoxycholic acid, no substantial differences were found in the fecal bile acid profiles of patients with IBD and PSC (n=7) compared to IBD alone (n=8) or healthy controls (n=8). Oral vancomycin was a potent inhibitor of secondary bile acid production in participants with IBD and PSC, particularly deoxycholic acid, although no changes in liver biochemistry patterns were noted over a two week period. Conclusion:In this pilot study, bile acid profiles were overall similar among patients with IBD and PSC, IBD alone, and healthy controls. Microbiota diversity was reduced in those with PSC and IBD compared to IBD alone or healthy controls.

SUBMITTER: Vaughn BP

PROVIDER: S-EPMC6330977 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A pilot study of fecal bile acid and microbiota profiles in inflammatory bowel disease and primary sclerosing cholangitis.

Vaughn Byron P BP Kaiser Thomas T Staley Christopher C Hamilton Matthew J MJ Reich Jon J Graiziger Carolyn C Singroy Stephanie S Kabage Amanda J AJ Sadowsky Michael J MJ Khoruts Alexander A

Clinical and experimental gastroenterology 20190110

<h4>Introduction</h4>Inflammatory bowel disease (IBD) is thought to arise from an abnormal immune response to the gut microbiota. IBD is associated with altered intestinal microbial community structure and functionality, which may contribute to inflammation and complications such as colon cancer and liver disease. Primary sclerosing cholangitis (PSC) is associated with IBD and markedly increases the risk of colon cancer. We hypothesized that secondary bile acids, which are products of microbial ...[more]

PMID: 30666146

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Project description:Background and aimsAltered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility.Approach and resultsPlasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86).ConclusionsPatients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.

Project description:OBJECTIVE:Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic liver disease that is characterized by severe peri-biliary tract inflammation and fibrosis, elevated oxidative stress and hepatocellular injury. A hallmark of PSC patients is the concurrent diagnosis of Inflammatory Bowel Disease occurring in approximately 70%-80% of PSC patients (PSC/IBD). The objective of this study was to determine the impact of end stage PSC/IBD on cellular antioxidant responses and the formation of protein carbonylation. METHODS:Using hepatic tissue and whole cell extracts isolated from age-matched healthy humans and patients diagnosed with end stage PSC/IBD, overall inflammation, oxidative stress, and protein carbonylation were assessed by Western blotting, and immunohistochemistry. RESULTS:Increased immunohistochemical staining for CD3+ (lymphocyte), CD68 (Kupffer cell) and myeloperoxidase (neutrophil) colocalized with the extensive Picrosirius red stained fibrosis confirming the inflammatory aspect of PSC. Importantly, the increased inflammation also colocalized with elevated periportal post-translational modification by the reactive aldehydes 4-HNE, MDA and acrolein. 4-HNE, MDA and acrolein IHC all displayed a significant component in hepatocytes adjacent to fibrotic regions. Furthermore, acrolein was also elevated within the nuclei of periportal inflammatory cells whereas MDA staining was increased in hepatocytes across the lobule. Prussian Blue staining, when compared to the positive controls (ALD, NASH), did not display any evidence of iron accumulation in PSC/IBD livers. Western analysis of PSC/IBD anti-oxidant responses revealed elevated expression of SOD2, GST? as well as upregulation of Akt Ser473 phosphorylation. In contrast, expression of GST?, GSTA4, catalase, Gpx1 and Hsp70 were suppressed. These data were further supported by a significant decrease in measured GST activity. Dysregulation of anti-oxidant responses in the periportal region of the liver was supported by elevated SOD2 and GST? IHC signals in periportal hepatocytes and cholangiocytes. Expression of the Nrf2-regulated proteins HO-1, NAD(P)H quinone reductase (NQO1) and Gpx1 was primarily localized to macrophages. In contrast, catalase staining decreased within periportal hepatocytes and was not evident within cholangiocytes. CONCLUSIONS:Results herein provide additional evidence that cholestasis induces significant increases in periportal oxidative stress and suggest that there are significant differences in the cellular and subcellular generation of reactive aldehydes formed during cholestatic liver injury. Furthermore, these data suggest that anti-oxidant responses are dysregulated during end-stage PSC/IBD supporting pathological data. This work was funded by NIH5R37AA009300-22 D.R.P.

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A pilot study of fecal bile acid and microbiota profiles in inflammatory bowel disease and primary sclerosing cholangitis.

Publications

A pilot study of fecal bile acid and microbiota profiles in inflammatory bowel disease and primary sclerosing cholangitis.

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