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Gut microbiota dysbiosis worsens the severity of acute pancreatitis in patients and mice

  • Yin Zhu
  • Cong He
  • Xueyang Li
  • Yan Cai
  • Jinxiang Hu
  • Yuanhang Liao
  • Jianhua Zhao
  • Liang Xia
  • Wenhua He
  • Linmeng Liu
  • Chun Luo
  • Xu Shu
  • Qiang Cai
  • Youxiang Chen
  • Nonghua Lu
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

The gut is implicated in the pathogenesis of acute pancreatitis (AP) and the infectious complications of AP are commonly associated with enteric bacteria, yet whether gut microbiota dysbiosis participants in AP severity remains largely unknown.

Methods

We collected clinical information and fecal samples from 165 adult participants, including 41 with mild AP (MAP), 59 with moderately severe AP (MSAP), 30 with severe AP (SAP) and 35 healthy controls (HC). The serum inflammatory cytokines and gut barrier indexes were detected. Male C57BL/6 mice with AP were established and injuries of pancreas were evaluated in antibiotic-treated mice, germ-free mice as well as those transplanted with fecal microbiota. The gut microbiota was analyzed by 16S rRNA gene sequencing.

Results

The structure of gut microbiota was significantly different between AP and HC, and the disturbed microbiota was closely correlated with systematic inflammation and gut barrier dysfunction. Notably, the microbial composition changed further with the worsening of AP and the abundance of beneficial bacteria such as Blautia was decreased in SAP compared with MAP and MSAP. The increased capacity for the inferred pathway, bacterial invasion of epithelial cells in AP, highly correlated with the abundance of EscherichiaShigella. Furthermore, the antibiotic-treated mice and germ-free mice exhibited alleviated pancreatic injury after AP induction and subsequent fecal microbiota transplantation in turn exacerbated the disease.

Conclusions

This study identifies the gut microbiota as an important mediator during AP and its dysbiosis is associated with AP severity, which suggests its role as potential therapeutic target.

Keywords

Acute pancreatitis Gut microbiota Intestinal barrier Antibiotic treatment Fecal microbiota transplantation 

Notes

Acknowledgements

The authors are grateful for all the subjects who participated in this study. The authors acknowledge Dr. Jianping Liu in Karolinska Institute, Sweden for revising the manuscript.

Author contributions

NL and YC designed and supervised the project. YZ obtained funding. YZ, LX, WH and XS performed clinical diagnosis and selected proper cases for this project. YL collected the fecal samples and recorded clinical data. YL, YC and CH measured the clinical parameters. YC and XL performed the animal experiments. CH, JH, JZ, LL and CL performed bioinformatics and statistical analysis and interpreted data. CH drafted the manuscript. YZ and QC revised the manuscript for important content.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81760120, 81460116), the Key Research and Development Program from the Science and Technology Department of Jiangxi Province (no. 20171BBG70084).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

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References

  1. 1.
    Shah AU, Sarwar A, Orabi AI, et al. Protease activation during in vivo pancreatitis is dependent on calcineurin activation. Am J Physiol Gastrointest Liver Physiol. 2009;297:G967–73.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis-2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102–11.CrossRefPubMedGoogle Scholar
  3. 3.
    Pezzilli R, Uomo G, Zerbi A, et al. Diagnosis and treatment of acute pancreatitis: the position statement of the Italian Association for the study of the pancreas. Dig Liver Dis. 2008;40:803–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Fishman JE, Levy G, Alli V, et al. The intestinal mucus layer is a critical component of the gut barrier that is damaged during acute pancreatitis. Shock. 2014;42:264–70.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Capurso G, Zerboni G, Signoretti M, et al. Role of the gut barrier in acute pancreatitis. J Clin Gastroenterol. 2012;46(Suppl):S46–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Desai MS, Seekatz AM, Koropatkin NM, et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell. 2016;167(1339–53):e21.Google Scholar
  7. 7.
    Gil-Cardoso K, Gines I, Pinent M, et al. Effects of flavonoids on intestinal inflammation, barrier integrity and changes in gut microbiota during diet-induced obesity. Nutr Res Rev. 2016;29:234–48.CrossRefPubMedGoogle Scholar
  8. 8.
    Xue L, He J, Gao N, et al. Probiotics may delay the progression of nonalcoholic fatty liver disease by restoring the gut microbiota structure and improving intestinal endotoxemia. Sci Rep. 2017;7:45176.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    De Palma G, Lynch MD, Lu J, et al. Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice. Sci Transl Med. 2017;9(379).  https://doi.org/10.1126/scitranslmed.aaf6397.
  10. 10.
    Guo ZZ, Wang P, Yi ZH, et al. The crosstalk between gut inflammation and gastrointestinal disorders during acute pancreatitis. Curr Pharm Des. 2014;20:1051–62.CrossRefPubMedGoogle Scholar
  11. 11.
    Tan C, Ling Z, Huang Y, et al. Dysbiosis of intestinal microbiota associated with inflammation involved in the progression of acute pancreatitis. Pancreas. 2015;44:868–75.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang XM, Zhang ZY, Zhang CH, et al. Intestinal microbial community differs between acute pancreatitis patients and healthy volunteers. Biomed Environ Sci. 2018;31:81–6.PubMedGoogle Scholar
  13. 13.
    Flemer B, Lynch DB, Brown JM, et al. Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut. 2017;66:633–43.CrossRefPubMedGoogle Scholar
  14. 14.
    Ding SP, Li JC, Jin C. A mouse model of severe acute pancreatitis induced with caerulein and lipopolysaccharide. World J Gastroenterol. 2003;9:584–9.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chen J, Huang C, Wang J, et al. Dysbiosis of intestinal microbiota and decrease in Paneth cell antimicrobial peptide level during acute necrotizing pancreatitis in rats. PLoS One. 2017;12:e0176583.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Memba R, Duggan SN, Ni Chonchubhair HM, et al. The potential role of gut microbiota in pancreatic disease: a systematic review. Pancreatology. 2017;17:867–74.CrossRefPubMedGoogle Scholar
  17. 17.
    Li Q, Wang C, Tang C, et al. Identification and characterization of blood and neutrophil-associated microbiomes in patients with severe acute pancreatitis using next-generation sequencing. Front Cell Infect Microbiol. 2018;8:5.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature. 2011;473:174–80.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334:105–8.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    De Andres J, Manzano S, Garcia C, et al. Modulatory effect of three probiotic strains on infants’ gut microbial composition and immunological parameters on a placebo-controlled, double-blind, randomised study. Benef Microbes. 2018;9:573–84.CrossRefPubMedGoogle Scholar
  21. 21.
    Routy B, Gopalakrishnan V, Daillere R, et al. The gut microbiota influences anticancer immunosurveillance and general health. Nat Rev Clin Oncol. 2018;15:382–96.CrossRefPubMedGoogle Scholar
  22. 22.
    Ryan CM, Schmidt J, Lewandrowski K, et al. Gut macromolecular permeability in pancreatitis correlates with severity of disease in rats. Gastroenterology. 1993;104:890–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Ammori BJ. Role of the gut in the course of severe acute pancreatitis. Pancreas. 2003;26:122–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Liu H, Li W, Wang X, et al. Early gut mucosal dysfunction in patients with acute pancreatitis. Pancreas. 2008;36:192–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Besselink MG, van Santvoort HC, Boermeester MA, et al. Timing and impact of infections in acute pancreatitis. Br J Surg. 2009;96:267–73.CrossRefPubMedGoogle Scholar
  26. 26.
    Chen J, Kang B, Jiang Q, et al. Alpha-Ketoglutarate in low-protein diets for growing pigs: effects on cecal microbial communities and parameters of microbial metabolism. Front Microbiol. 2018;9:1057.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ma N, Wu Y, Xie F, et al. Dimethyl fumarate reduces the risk of mycotoxins via improving intestinal barrier and microbiota. Oncotarget. 2017;8:44625–38.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Liu J, Yue S, Yang Z, et al. Oral hydroxysafflor yellow A reduces obesity in mice by modulating the gut microbiota and serum metabolism. Pharmacol Res. 2018;134:40–50.CrossRefPubMedGoogle Scholar
  29. 29.
    Kellingray L, Gall GL, Defernez M, et al. Microbial taxonomic and metabolic alterations during faecal microbiota transplantation to treat Clostridium difficile infection. J Infect. 2018;77(2):107–118.CrossRefPubMedGoogle Scholar
  30. 30.
    Takahashi K, Nishida A, Fujimoto T, et al. Reduced abundance of butyrate-producing bacteria species in the fecal microbial community in Crohn’s disease. Digestion. 2016;93:59–65.CrossRefPubMedGoogle Scholar
  31. 31.
    Rios-Covian D, Ruas-Madiedo P, Margolles A, et al. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol. 2016;7:185.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    De Filippo C, Cavalieri D, Di Paola M, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA. 2010;107:14691–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Wong JM, de Souza R, Kendall CW, et al. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol. 2006;40:235–43.CrossRefPubMedGoogle Scholar
  34. 34.
    Tedelind S, Westberg F, Kjerrulf M, et al. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J Gastroenterol. 2007;13:2826–32.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kelly CJ, Zheng L, Campbell EL, et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe. 2015;17:662–71.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ribet D, Cossart P. How bacterial pathogens colonize their hosts and invade deeper tissues. Microbes Infect. 2015;17:173–83.CrossRefPubMedGoogle Scholar
  37. 37.
    Li Q, Wang C, Tang C, et al. Bacteremia in patients with acute pancreatitis as revealed by 16S ribosomal RNA gene-based techniques*. Crit Care Med. 2013;41:1938–50.CrossRefPubMedGoogle Scholar
  38. 38.
    Schmidt PN, Roug S, Hansen EF, et al. Spectrum of microorganisms in infected walled-off pancreatic necrosis—impact on organ failure and mortality. Pancreatology. 2014;14:444–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Hanna EM, Hamp TJ, McKillop IH, et al. Comparison of culture and molecular techniques for microbial community characterization in infected necrotizing pancreatitis. J Surg Res. 2014;191:362–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Huang C, Chen J, Wang J, et al. Dysbiosis of intestinal microbiota and decreased antimicrobial peptide level in Paneth cells during hypertriglyceridemia-related acute necrotizing pancreatitis in rats. Front Microbiol. 2017;8:776.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2018

Authors and Affiliations

  • Yin Zhu
    • 1
  • Cong He
    • 1
  • Xueyang Li
    • 1
  • Yan Cai
    • 1
  • Jinxiang Hu
    • 2
  • Yuanhang Liao
    • 1
  • Jianhua Zhao
    • 2
  • Liang Xia
    • 1
  • Wenhua He
    • 1
  • Linmeng Liu
    • 2
  • Chun Luo
    • 2
  • Xu Shu
    • 1
  • Qiang Cai
    • 3
  • Youxiang Chen
    • 1
  • Nonghua Lu
    • 1
  1. 1.Department of GastroenterologyThe First Affiliated Hospital of Nanchang UniversityNanchangChina
  2. 2.Shanghai Major Bio-pharm Technology Co., LtdShanghaiChina
  3. 3.Division of Digestive Diseases, Department of MedicineEmory University School of MedicineAtlantaUSA

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