Polyphosphate, Derived from Lactobacillus brevis, Modulates the Intestinal Microbiome and Attenuates Acute Pancreatitis

Abstract

Background

We previously showed that Lactobacillus brevis-derived polyphosphate (poly P) exerts a curative effect on intestinal inflammation. However, whether or not poly P improves the inflammation and injury of distant organs remains unclear.

Aims

We aimed to investigate the change in the intestinal microbiome and to evaluate the protective effect of poly P on injuries in a cerulein-induced acute pancreatitis (AP) mouse.

Methods

Poly P was orally administered to BALB/C mice every day for 24 days, and then mice were intraperitoneally injected with cerulein. Before cerulein injection, stool samples were collected and analyzed by 16S rRNA gene sequencing. Mice were sacrificed at 24 h after the last cerulein injection; subsequently, the serum, pancreas, and colon were collected.

Results

The microbial profile differed markedly between poly P and control group. Notably, the levels of beneficial bacteria, including Alistipes and Candidatus_Saccharimonas, were significantly increased, while those of the virulent bacteria Desulfovibrio were decreased in the poly P group. The elevations of the serum amylase and lipase levels by cerulein treatment were suppressed by the pre-administration of poly P for 24 days, but not for 7 days. The numbers of cells MPO-positive by immunohistology were decreased and the levels of MCP-1 significantly reduced in the AP + Poly P group. An immunofluorescence analysis showed that the ZO-1 and occludin in the colon was strongly augmented in the epithelial cell membrane layer in the AP + Poly P group.

Conclusions

Poly P attenuates AP through both modification of the intestinal microbiome and enhancement of the intestinal barrier integrity.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R. Current understanding of the human microbiome. Nat Med.. 2018;24:392–400.

    CAS  Article  Google Scholar 

  2. 2.

    Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation. Gastroenterology.. 2013;145:946–953.

    Article  Google Scholar 

  3. 3.

    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  Google Scholar 

  4. 4.

    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  Google Scholar 

  5. 5.

    FAO/WHO. Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria. 2001.

  6. 6.

    Segawa S, Fujiya M, Konishi H, et al. Probiotic-derived polyphosphate enhances the epithelial barrier function and maintains intestinal homeostasis through integrin-p38 MAPK pathway. PLoS ONE. 2011;6:e23278.

    CAS  Article  Google Scholar 

  7. 7.

    Kornberg A, Rao NN, Ault-Riche D. Inorganic polyphosphate: a molecule of many functions. Annu Rev Biochem.. 1999;68:89–125.

    CAS  Article  Google Scholar 

  8. 8.

    Tanaka K, Fujiya M, Konishi H, et al. Probiotic-derived polyphosphate improves the intestinal barrier function through the caveolin-dependent endocytic pathway. Biochem Biophys Res Commun.. 2015;467:541–548.

    CAS  Article  Google Scholar 

  9. 9.

    Kashima S, Fujiya M, Konishi H, et al. Polyphosphate, an active molecule derived from probiotic Lactobacillus brevis, improves the fibrosis in murine colitis. Transl Res.. 2015;166:163–175.

    CAS  Article  Google Scholar 

  10. 10.

    Fujiya M, Ueno N, Kashima S, et al. Long-Chain polyphosphate is a potential agent for inducing mucosal healing of the colon in ulcerative Colitis. Clin Pharmacol Ther.. 2020;107:452–461.

    CAS  Article  Google Scholar 

  11. 11.

    Algul H, Tando Y, Schneider G, Weidenbach H, Adler G, Schmid RM. Acute experimental pancreatitis and NF-kappaB/Rel activation. Pancreatology.. 2002;2:503–509.

    Article  Google Scholar 

  12. 12.

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

    CAS  Article  Google Scholar 

  13. 13.

    Watanabe T, Kudo M, Strober W. Immunopathogenesis of pancreatitis. Mucosal Immunol.. 2017;10:283–298.

    CAS  Article  Google Scholar 

  14. 14.

    Maier SK, Scherer S, Loessner MJ. Long-chain polyphosphate causes cell lysis and inhibits Bacillus cereus septum formation, which is dependent on divalent cations Appl Environ Microbiol. 1999;65:3942-3949; Lee RM, Hartman PA, Stahr HM, Olson DG, Williams FD. Antibacterial Mechanism of Long-Chain Polyphosphates in Staphylococcus aureus J Food Prot. 1994;57:289-294.

  15. 15.

    Hasebe T, Ueno N, Musch MW, et al. Daikenchuto (TU-100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K. Pharmacol Res Perspect.. 2016;4:e00215.

    Article  Google Scholar 

  16. 16.

    Caporaso JG, Kuczynski J, Stombaugh J, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods.. 2010;7:335–336.

    CAS  Article  Google Scholar 

  17. 17.

    Segata N, Izard J, Waldron L, et al. Metagenomic biomarker discovery and explanation. Genome Biol.. 2011;12:R60.

    Article  Google Scholar 

  18. 18.

    Yang ZW, Meng XX, Xu P. Central role of neutrophil in the pathogenesis of severe acute pancreatitis. J Cell Mol Med.. 2015;19:2513–2520.

    CAS  Article  Google Scholar 

  19. 19.

    Rychter JW, van Minnen LP, Verheem A, et al. Pretreatment but not treatment with probiotics abolishes mouse intestinal barrier dysfunction in acute pancreatitis. Surgery.. 2009;145:157–167.

    Article  Google Scholar 

  20. 20.

    van Minnen LP, Timmerman HM, Lutgendorff F, et al. Modification of intestinal flora with multispecies probiotics reduces bacterial translocation and improves clinical course in a rat model of acute pancreatitis. Surgery.. 2007;141:470–480.

    Article  Google Scholar 

  21. 21.

    Muftuoglu MAT, Isikgor S, Tosun S, Saglam A. Effects of probiotics on the severity of experimental acute pancreatitis. Eur J Clin Nutrit.. 2005;60:464–468.

    Article  Google Scholar 

  22. 22.

    Jin D-Y, Lutgendorff F, Nijmeijer RMet al.. Probiotics Prevent Intestinal Barrier Dysfunction in Acute Pancreatitis in Rats via Induction of Ileal Mucosal Glutathione Biosynthesis PLoS ONE. 2009;4.

  23. 23.

    Jo IJ, Bae GS, Choi SBet al.. Fisetin attenuates cerulein-induced acute pancreatitis through down regulation of JNK and NF-kappaB signaling pathways Eur J Pharmacol. 2014;737:149-158; Ren Z, Li H, Zhang Met al.. A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis Front Immunol. 2018;9:2513.

  24. 24.

    Zhang H, Yang W, Li Y, et al. Astaxanthin ameliorates cerulein-induced acute pancreatitis in mice. Int Immunopharmacol.. 2018;56:18–28.

    CAS  Article  Google Scholar 

  25. 25.

    Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc National Acad Sci United States America.. 2007;104:13780–13785.

    CAS  Article  Google Scholar 

  26. 26.

    Wu M, Li P, An Y, et al. Phloretin ameliorates dextran sulfate sodium-induced ulcerative colitis in mice by regulating the gut microbiota. Pharmacol Res.. 2019;150:104489.

    CAS  Article  Google Scholar 

  27. 27.

    Huang Y, Li M, Zhou L, et al. Effects of Qingluo Tongbi decoction on gut flora of rats with adjuvant-induced arthritis and the underlying mechanism evid based complement. Alternat Med.. 2019;2019:6308021.

    Google Scholar 

  28. 28.

    Rowan F, Docherty NG, Murphy M, Murphy B, Calvin Coffey J, O’Connell PR. Desulfovibrio bacterial species are increased in ulcerative colitis. Diseases Colon Rectum.. 2010;53:1530–1536.

    Article  Google Scholar 

  29. 29.

    Sawin EA, De Wolfe TJ, Aktas B, et al. Glycomacropeptide is a prebiotic that reduces Desulfovibrio bacteria, increases cecal short-chain fatty acids, and is anti-inflammatory in mice. Am J Physiol Gastrointest Liver Physiol.. 2015;309:G590–G601.

    CAS  Article  Google Scholar 

  30. 30.

    Roediger WE, Moore J, Babidge W. Colonic sulfide in pathogenesis and treatment of ulcerative colitis. Dig Dis Sci.. 1997;42:1571–1579. https://doi.org/10.1023/A:1018851723920.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Hagiya H, Kimura K, Nishi I, et al. Desulfovibrio desulfuricans bacteremia: A case report and literature review. Anaerobe.. 2018;49:112–115.

    Article  Google Scholar 

  32. 32.

    Zhang J, Yu WQ, Wei T, et al. Effects of short-peptide-based enteral nutrition on the intestinal microcirculation and mucosal barrier in mice with severe acute pancreatitis. Mol Nutr Food Res.. 2020;64:e1901191.

    Article  Google Scholar 

  33. 33.

    Jia L, Chen H, Yang J, et al. Combinatory antibiotic treatment protects against experimental acute pancreatitis by suppressing gut bacterial translocation to pancreas and inhibiting NLRP3 inflammasome pathway. Innate Immun.. 2020;26:48–61.

    CAS  Article  Google Scholar 

  34. 34.

    Ryan CM, Schmidt J, Lewandrowski K, et al. Gut macromolecular permeability in pancreatitis correlates with severity of disease in rats. Gastroenterology.. 1993;104:890–895.

    CAS  Article  Google Scholar 

  35. 35.

    Tsuji Y, Watanabe T, Kudo M, Arai H, Strober W, Chiba T. Sensing of commensal organisms by the intracellular sensor NOD1 mediates experimental pancreatitis. Immunity.. 2012;37:326–338.

    CAS  Article  Google Scholar 

  36. 36.

    Rau B, Baumgart K, Kruger CM, Schilling M, Beger HG. CC-chemokine activation in acute pancreatitis: enhanced release of monocyte chemoattractant protein-1 in patients with local and systemic complications. Intensive Care Med.. 2003;29:622–629.

    Article  Google Scholar 

  37. 37.

    Ishibashi T, Zhao H, Kawabe K, et al. Blocking of monocyte chemoattractant protein-1 (MCP-1) activity attenuates the severity of acute pancreatitis in rats. J Gastroenterol.. 2008;43:79–85.

    CAS  Article  Google Scholar 

  38. 38.

    Bhatia M, Ramnath RD, Chevali L, Guglielmotti A. Treatment with bindarit, a blocker of MCP-1 synthesis, protects mice against acute pancreatitis. Am J Physiol Gastrointest Liver Physiol.. 2005;288:G1259–G1265.

    CAS  Article  Google Scholar 

  39. 39.

    Frossard JL, Lenglet S, Montecucco F, et al. Role of CCL-2, CCR-2 and CCR-4 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury. J Clin Pathol.. 2011;64:387–393.

    Article  Google Scholar 

  40. 40.

    Bedrosian AS, Nguyen AH, Hackman M, et al. Dendritic cells promote pancreatic viability in mice with acute pancreatitis. Gastroenterology.. 2011;141:e1911–e1914.

    Article  Google Scholar 

  41. 41.

    Shrivastava P, Bhatia M. Essential role of monocytes and macrophages in the progression of acute pancreatitis. World J Gastroenterol.. 2010;16:3995–4002.

    CAS  Article  Google Scholar 

  42. 42.

    Tsai MJ, Chen C, Chen SH, Huang YT, Chiu TH. Pomalidomide suppresses cerulein-induced acute pancreatitis in mice. J Gastroenterol.. 2011;46:822–833.

    CAS  Article  Google Scholar 

  43. 43.

    Ding SP, Li JC, Jin C. A mouse model of severe acute pancreatitis induced with caerulein and lipopolysaccharide. World J Gastroenterol.. 2003;9:584–589.

    Article  Google Scholar 

Download references

Acknowledgments

We thank Akemi Kita and Chikage Yamamura for their technical assistance.

Funding

This paper was supported by Grants-in-Aid for Scientific Research (C), No. 18K08906 (S. Takauji), the Akiyama Life Science Foundation (2019). This study was partially supported by Grants-in-Aid for Scientific Research, No. 26460956 (M. Fujiya), Translational Research Network Program of Japan Agency for Medical Research and Development, No. C40 (M. Fujiya) and Development and Intractable Disease Health, and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare.

Author information

Affiliations

Authors

Contributions

S.T., H.K. and M.F. conceived and planned the experiments, wrote the manuscript and supervised all investigations. S.T. and H.K. carried out the experiments. N.U., H.T., H.S., and S.I. helped design the studies and interpret the data. S.K., Y.M., K.M., and K.O. supervised the findings of this work. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Mikihiro Fujiya.

Ethics declarations

Conflict of interest

Dr. Fujiya reports grants from Japanese Grants-in-Aid for Scientific Research, grants from Translational Research Network Program of Japan Agency for Medical Research and Development, non-financial support from Development and Intractable Disease Health, and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare. During the conduct of the study, he reports grants and personal fees from Yakult Honsha Co., Ltd., grants and personal fees from Nippon Kayaku Co., Ltd., grants, personal fees and non-financial support from EA Pharma Co., Ltd., personal fees from Novartis Pharmaceuticals, grants from Boehringer Ingelheim GmbH, personal fees from Technical Information Institute Co., Ltd., personal fees from Pfizer Inc., grants and personal fees from Takeda Pharmaceutical Company Limited, grants and personal fees from Daiichi Sankyo Company, Limited, grants from Shionogi & Co., Ltd., personal fees from Olympus Co., Ltd., personal fees from Janssen Pharmaceutical K.K., personal fees from Kyorin Pharmaceutical Co., Ltd., personal fees from Taisho Toyama Pharmaceutical Co., Ltd., grants from AstraZeneca, personal fees from Tomakomai Minpo Co., Ltd., personal fees from Meiji Seika Pharma Co., Ltd., grants and personal fees from Mochida Pharmaceutical Co., Ltd., grants from Astellas Pharma Inc., personal fees from Mitsubishi Tanabe Pharma Corporation, grants from Baxter International Inc, personal fees from Bristol-Myers Company, grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants from MSD K.K., grants and personal fees from Otsuka Pharmaceutical Co., Ltd., grants and personal fees from Kyowa Hakko Kirin Co., Ltd., grants from Taiho Pharmaceutical Co., Ltd., personal fees from Zeria Pharmaceutical Co., Ltd., grants from Alexion Pharmaceutical Co., Ltd., grants, personal fees and non-financial support from Ajinomoto Pharmaceutical Co., Ltd., personal fees from Asahi Kasei Corporation, grants and non-financial support from Sapporo Breweries Ltd., grants and personal fees from Eisai Co., Ltd., grants from GlaxoSmithKline K.K., grants from AbbVie Inc, grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Asuka Pharmaceutical Co., Ltd., grants from Boston Scientific Corporation or its affiliates, and grants and non-financial support from Kamui Pharma. Inc. outside the submitted work. In addition, Dr. Fujiya has been issued patents for intestinal protectants (JP 5660508 and EP 2559437).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

An editorial commenting on this article is available at https://doi.org/10.1007/s10620-020-06809-y.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 26 kb)

Supplemetary Figure 1 (EPS 2916 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Takauji, S., Konishi, H., Fujiya, M. et al. Polyphosphate, Derived from Lactobacillus brevis, Modulates the Intestinal Microbiome and Attenuates Acute Pancreatitis. Dig Dis Sci (2021). https://doi.org/10.1007/s10620-020-06747-9

Download citation

Keywords

  • Polyphosphate
  • Probiotics
  • Intestinal microbiome
  • Acute pancreatitis
  • 16S rRNA gene sequencing