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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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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.


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.


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.


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.

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  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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).

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  13. Flemer B, Lynch DB, Brown JM, et al. Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut. 2017;66:633–43.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature. 2011;473:174–80.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334:105–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  23. Ammori BJ. Role of the gut in the course of severe acute pancreatitis. Pancreas. 2003;26:122–9.

    Article  PubMed  Google Scholar 

  24. Liu H, Li W, Wang X, et al. Early gut mucosal dysfunction in patients with acute pancreatitis. Pancreas. 2008;36:192–6.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Ribet D, Cossart P. How bacterial pathogens colonize their hosts and invade deeper tissues. Microbes Infect. 2015;17:173–83.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

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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.


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).

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Authors and Affiliations



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.

Corresponding author

Correspondence to Nonghua Lu.

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The authors declare that they have no competing interests.

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Zhu, Y., He, C., Li, X. et al. Gut microbiota dysbiosis worsens the severity of acute pancreatitis in patients and mice. J Gastroenterol 54, 347–358 (2019).

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