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Alterations of gut microbiome and metabolite profiles in choledocholithiasis concurrent with cholangitis

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Abstract

Background and aims

Gut microbiota and their metabolic products might play important roles in regulating the pathogenesis of choledocholithiasis concurrent with cholangitis (CC). The aim of this study was to explore the characteristic gut dysbiosis, metabolite profiles and the possible roles in patients with CC.

Methods

A case–control study was carried out to analyze the alterations in the intestinal microbiota and their metabolites in patients with CC (n = 25) compared with healthy controls (HCs) (n = 25) by metagenomic sequencing to define the gut microbiota community and liquid chromatography/mass spectrometry (LC/MS) analysis to characterize the metabolite profiles.

Results

Significantly reduced Shannon diversity index (p = 0.043) and differential overall fecal microbiota community in CCs were observed. Twelve dominant altered species were identified and analyzed (LDA score > 3.0, p < 0.05) (Q value < 0.05), including unclassified_f_Enterobacteriaceae, Escherichia_coli, Roseburia_faecis and Eubacterium rectale. Moreover, the levels of KEGG pathways related to biofilm formation of Escherichia coli, lipopolysaccharide (LPS) biosynthesis, and the metabolism of propanoate and glutathione in CCs were significantly altered. Finally, 47 markedly changed metabolites (VIP > 1.0 and p < 0.05), including low level of kynurenic acid (KYNA) and high concentration of N-palmitoylsphingosine involving tryptophan metabolism and sphingolipid signaling pathways, were identified to validate aberrant metabolic patterns in CCs, and multiple correlated metabolic modules involving bile inflammation were altered in CCs.

Conclusion

Our study provides novel insights into compositional and functional alterations in the gut microbiome and metabolite profiles in CC and the underlying mechanisms between gut microbiota and bile inflammation.

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Data availability

The metagenome sequencing data are available (at https://cloud.majorbio.com). The data from Changzheng Hospital are available upon reasonable request from the corresponding author (Y.L.). The data from Changzheng Hospital are not publicly available, because they contain protected patient privacy information. The other data relevant to the study are included in the article or uploaded as supplementary information.

Abbreviations

CC:

Choledocholithiasis concurrent with cholangitis

HC:

Healthy control

ERCP:

Endoscopic retrograde cholangiopancreatography

SCFA:

Short-chain fatty acid

NAFLD:

Nonalcoholic fatty liver disease

LC/MS:

Chromatography/mass spectrometry

KEGG:

Kyoto encyclopedia of genes and genomes

QIIME:

Quantitative insights into microbial ecology

PCoA:

Principal coordinate analysis

LDA:

Linear discriminant analysis

LEfSe:

Linear discriminant analysis effect size

VIP:

Variable importance in the projection

WBC:

White blood cell

CRP:

C-reaction protein

KYNA:

Kynurenic acid

TLRs:

Toll-like receptors

NO:

Nitric oxide

LPS:

Lipopolysaccharide

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81670544, 81870416), the Top-Level Clinical Discipline Project of Shanghai Pudong (PWYgf2018-04), the Science and Technology Guidance Plan of Shanghai Science and Technology Commission (19411970500) and the Pilot Talent Plan of Shanghai East Hospital (2019lhrcjh).

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  1. Zhiyuan Hao, Kegong Tao and Kaiming Wu contributed equally to this work

Authors and Affiliations

  1. Department of Gastroenterology, Shanghai Changzheng Hospital, Navy Military Medical University, Shanghai, 200003, China

    Zhiyuan Hao, Kegong Tao, Kaiming Wu, Peimei Shi, Peiqin Wang & Yong Lin

  2. Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China

    Yuanyuan Luo, Yiting Lu & Xin Zeng

  3. Department of Pathology, Shanghai Changzheng Hospital, Navy Military Medical University, Shanghai, 200003, China

    Binbin Li

  4. Department of Gastroenterology, Shanghai Changzheng Hospital, Navy Military Medical University, 415 Fengyang Road, Shanghai, 200003, China

    Xin Zeng & Yong Lin

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  1. Zhiyuan Hao
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Contributions

Designed the experiments: XZ, and YL. Collected the clinical samples: KGT, KMW, and PMS. Performed the microbiome analysis: ZYH, YYL, and YTL. Performed the metabolomic analysis: BBL, and PQW. Draft the manuscript: ZYH, and YL. Revised the manuscript for intellectual content: ZYH, KGT, PQW, XZ and YL.

Corresponding authors

Correspondence to Xin Zeng or Yong Lin.

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Conflict of interest

No potential conflicts of interest were disclosed by Zhiyuan Hao, Kegong Tao, Kaiming Wu, Yuanyuan Luo, Yiting Lu, Binbin Li, Peimei Shi, Peiqin Wang, Xin Zeng, Yong Lin.

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The study was approved by the Institutional Ethics Committee of Shanghai Changzheng Hospital. Informed consent was obtained prior to data collection.

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Hao, Z., Tao, K., Wu, K. et al. Alterations of gut microbiome and metabolite profiles in choledocholithiasis concurrent with cholangitis. Hepatol Int 16, 447–462 (2022). https://doi.org/10.1007/s12072-021-10231-5

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