Dataset Information

Alterations in microbiota and their metabolites are associated with beneficial effects of bile acid sequestrant on icteric primary biliary Cholangitis.

ABSTRACT: Background: Increasing data suggests an interaction between bile acids and intestinal microbiota in the pathogenesis of primary biliary cholangitis (PBC). Bile acid sequestrants are widely used to bind bile acids in the intestinal lumen and are therefore posited to impact gut bacteria. Herein we aimed to investigate the effects of cholestyramine on the bile acid profile and gut microbiome in a cohort of icteric PBC patients.Results: Thirty-three PBC patients were treated with cholestyramine, serum and stool samples were collected at baseline, 4 and 16 weeks. Shotgun metagenomic sequencing and targeted metabolomic profiling were performed. Following cholestyramine administration, patients exhibited a high interpersonal variability in remission of cholestasis, and were therefore dichotomized according to the decrease of total bilirubin. Gut microbial co-abundance networks showed distinct taxa interactions between subjects with superior remission (SR) and those with inferior remission (IR) at baseline. After treatment, compositional shifts of the microbiome in the SR group were characterized with enrichment of two Lachnospiraceae species, typically producing short-chain fatty acids (SCFAs). In contrast, Klebsiella pneumonia, a commensal pathobiont, was only increased in the IR group. Correspondingly, metabolome analysis demonstrated that patients with SR, but not IR, were marked by elevations of SCFAs including valeric acid and caproic acid. Finally, integrative analysis identified robust associations between the variations of microbiota, metabolites, and inflammatory cytokines in SR group, indicating potential mechanistic links.Conclusions: Beneficial responses caused by cholestyramine were closely related with compositional and functional alterations in gut commensal, highlighting the possibility of exploring bile acid-microbiota interactions for treating PBC.

SUBMITTER: Li B

PROVIDER: S-EPMC8405155 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:The role of host-microbiota interactions in primary biliary cholangitis (PBC) has received increased attention. However, the impact of PBC on the oral microbiota and contribution of the oral microbiota to PBC are unclear. In this study, thirty-nine PBC patients without other diseases and 37 healthy controls (HCs) were enrolled and tested for liver functions and haematological variables. Saliva specimens were collected before and after brushing, microbiota was determined using 16S rDNA sequencing, metabolomics was profiled using Gas Chromatography-Mass Spectrometer (GC-MS), 80 cytokines were assayed using biochips, and inflammation inducibility was evaluated using OKF6 keratinocytes and THP-1 macrophages. Finally, the effect of ultrasonic scaling on PBC was estimated. Compared with HCs, PBC saliva had enriched taxa such as Bacteroidetes, Campylobacter, Prevotella and Veillonella and depleted taxa such as Enterococcaceae, Granulicatella, Rothia and Streptococcus. PBC saliva also had enriched sCD163, enriched metabolites such as 2-aminomalonic acid and 1-dodecanol, and depleted metabolites such as dodecanoic acid and propylene glycol. sCD163, 4-hydroxybenzeneacetic acid and 2-aminomalonic acid were significantly correlated with salivary cytokines, bacteria and metabolites. Salivary Veillonellaceae members, 2-aminomalonic acid, and sCD163 were positively correlated with liver function indicators such as serum alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PBC salivary microbes induced more soluble interleukin (IL)-6 receptor α (sIL-6Rα), sIL-6Rβ and tumour necrosis factor ligand superfamily (TNFSF)13B from OKF6 keratinocytes, and PBC salivary supernatant induced more IL-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine (C-C motif) ligand (CCL)13, C-X-C motif chemokine (CXC)L1 and CXCL16 from THP-1 macrophages. Toothbrushing significantly reduced the expression of inflammatory cytokines such as IL-1β, IL-8 and TNF-α and harmful metabolites such as cadaverine and putrescine in PBC but not HC saliva after P-value correction. The levels of ALP and bilirubin in PBC serum were decreased after ultrasonic scaling. Together, PBC patients show significant alterations in their salivary microbiota, likely representing one cause and treatment target of oral inflammation and worsening liver functions.

Project description:ERα, one of the classical receptors of estrogen, has been found to be abnormally up-regulated in patients with primary biliary cholangitis (PBC), which is an important factor leading to ductopenia. ERα-mediated signaling pathways are involved in proliferation of human intrahepatic biliary epithelial cells (HiBECs) and portal inflammation. Our previous studies have shown that the expression levels of ERα in the liver tissues of PBC patients are positively correlated with the levels of serum pro-inflammatory cytokines. The present study was designed to assess the relationship between abnormal ERα expression in small bile ducts and the progression of PBC. We examined the levels of multiple cytokines and analyzed their relationship with clinical parameters of livers functions in a cohort of 43 PBC patients and 45 healthy controls (HC). The levels of ERα expression and the relation with the levels of cytokines were further assessed. The localization of cytokines and ERα-mediated signaling pathways in liver were examined using immunohistochemistry. The possible underlying mechanisms of these alterations in PBC were explored in vitro. Our results demonstrated that the levels of IL-6, IL-8, and TNF-α were increased in PBC patients, and positively correlated with the serum AKP levels and ERα expression levels. Moreover, the expression of these cytokines were up-regulated in HiBECs that were stimulated with 17β-estradiol and PPT (an ERα agonist) and they also were positive in intrahepatic bile duct of PBC patients. The ERα-mediated expression of pro-inflammatory cytokines was induced by JNK, P38, and STAT3 phosphorylation in HiBECs. In addition, the CD54 expression was increased in HiBECs after ERα activation, which induced peripheral blood monouclear cells (PBMCs) recruitment. In conclusion, the present study highlighted a key role of abnormal ERα expression in inducing an inflammatory phenotype of HiBECs, which was critical in the development of inflammation and damage in small bile duct.

Dataset Information

Alterations in microbiota and their metabolites are associated with beneficial effects of bile acid sequestrant on icteric primary biliary Cholangitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets