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

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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.

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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.

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Authors and Affiliations

  1. Department of Emergency Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan

    Shuhei Takauji

  2. Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan

    Shuhei Takauji, Mikihiro Fujiya, Nobuhiro Ueno, Hiroki Sato, Shotaro Isozaki, Shin Kashima & Kentaro Moriichi

  3. Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan

    Hiroaki Konishi & Mikihiro Fujiya

  4. Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan

    Hiroki Tanaka

  5. Cancer Genetics, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan

    Yusuke Mizukami

  6. Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan

    Toshikatsu Okumura

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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.

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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).

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Takauji, S., Konishi, H., Fujiya, M. et al. Polyphosphate, Derived from Lactobacillus brevis, Modulates the Intestinal Microbiome and Attenuates Acute Pancreatitis. Dig Dis Sci 66, 3872–3884 (2021). https://doi.org/10.1007/s10620-020-06747-9

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