Dataset Information

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.

ABSTRACT:

Background

Although a majority of patients with PSC have colitis [PSC-IBD; primary sclerosing cholangitis-inflammatory bowel disease], this is phenotypically different from ulcerative colitis [UC]. We sought to define further the pathophysiological differences between PSC-IBD and UC, by applying a comparative and integrative approach to colonic gene expression, gut microbiota and immune infiltration data.

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 with HC. Imputed pathways were predominantly associated with upregulation of immune response and microbial defense in both disease cohorts compared with HC. There were 1692 DEGs between PSC-IBD and UC. Bile acid signalling pathways were upregulated in PSC-IBD compared with 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 with 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 point toward dysregulation of colonic bile acid homeostasis compared with UC. This highlights important mechanisms and suggests the possibility of novel approaches in treating PSC-IBD.

SUBMITTER: Quraishi MN

PROVIDER: S-EPMC7392170 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

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.

Quraishi Mohammed Nabil MN Acharjee Animesh A Beggs Andrew D AD Horniblow Richard R Tselepis Chris C Gkoutos Georgios G Ghosh Subrata S Rossiter A E AE Loman Nicholas N van Schaik Willem W Withers David D Walters Julian R F JRF Hirschfield Gideon M GM Iqbal Tariq H TH

Journal of Crohn's & colitis 20200701 7

<h4>Background</h4>Although a majority of patients with PSC have colitis [PSC-IBD; primary sclerosing cholangitis-inflammatory bowel disease], this is phenotypically different from ulcerative colitis [UC]. We sought to define further the pathophysiological differences between PSC-IBD and UC, by applying a comparative and integrative approach to colonic gene expression, gut microbiota and immune infiltration data.<h4>Methods</h4>Colonic biopsies were collected from patients with PSC-IBD [n = 10], ...[more]

PMID: 32016358

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Project description:IntroductionInflammatory 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.AimHere, 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.MethodsFecal 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.ResultsParticipants 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.ConclusionIn 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.

Project description:Background & aimsPrimary sclerosing cholangitis (PSC) carries significant morbidity and mortality compared with inflammatory bowel disease (IBD). We characterized epidemiology trends and outcomes in those with PSC-IBD and IBD, paying particular attention to the impact of PSC-IBD diagnostic sequence on outcomes.MethodsIncidence and prevalence of PSC-IBD and IBD (2002-2018) were evaluated using validated health administrative data-derived cohorts from Ontario, Canada (population ∼15 million). Transplant and death outcomes were assessed, with PSC-IBD diagnostic sequence as the exposure of interest.ResultsIncidence of PSC-IBD and IBD was 0.46 and 24.6/100,000 person-years (PYs) respectively, whereas prevalence was 5.53 and 588/100,000 PY respectively. Incidence/prevalence of PSC-IBD increased over time, unlike for IBD. Age at IBD diagnosis was earlier among those with PSC-IBD compared with those with IBD alone. Higher socioeconomic status associated with high PSC-IBD incidence rates and fastest incidence rise. Those diagnosed with IBD before PSC had higher risk of transplant/death compared with PSC before IBD (hazard ratio [HR] 1.34, 95% CI 1.02-1.75), driven by an increased risk of death (HR 2.73, 95% CI 1.68-4.45). PSC-IBD had a 4.5-fold greater risk of transplant/death compared with IBD alone. Liver-related and luminal gastrointestinal disease, particularly hepatopancreatobiliary malignancy, were predominant causes of death among those with PSC-IBD, while cardiovascular and respiratory diseases were predominant among those with IBD.ConclusionsPopulation-level data support distinct epidemiological patterns among people living with PSC-IBD compared with IBD, including a higher socioeconomic status and worse outcomes in those found to have IBD before PSC.Impact and implicationsIndividuals with primary sclerosing cholangitis (PSC) face increased morbidity and mortality compared with the general population and those with inflammatory bowel disease (IBD); yet, most individuals with PSC are found to have concomitant IBD during their lifetime. This study describes the distinctive epidemiological differences and mortality trends at the population level between PSC-IBD and IBD. While PSC-IBD remains a rare condition, diagnoses are on the rise (particularly among higher socioeconomic status populations), with most patients being diagnosed with IBD before PSC; this group also experienced higher mortality post-PSC diagnosis compared with those diagnosed with PSC first, with a large proportion of deaths caused by liver- and gut-related causes. Practical applications of these findings include further studies to evaluate whether earlier identification of PSC-IBD affects disease outcomes, as well as educating patients, clinicians, and policymakers on the importance of recognizing PSC-IBD as a distinct entity from IBD alone.

Dataset Information

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.

Background

Methods

Results

Conclusions

Publications

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.

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