Skip to main content

Oral administration of d-serine prevents the onset and progression of colitis in mice

Journal of Gastroenterology volume 56, pages 732–745 (2021)Cite this article

Abstract

Background

l-amino acids are the predominant forms of organic molecules on the planet, but recent studies have revealed that various foods contain d-amino acids, the enantiomers of l-amino acids. Though diet plays important roles in both the development and progression of inflammatory bowel disease (IBD), to our best knowledge, there has been no report on any potential interactions between d-amino acids and IBD. In this report, we aim to assess the effects of d-serine in a murine model of IBD.

Materials and methods

To induce chronic colitis, naïve CD4 T cells (CD4+ CD62+ CD44low) from wild-type mice were adoptively transferred into Rag2−/− mice, after or before the mice were orally administered with d-serine. In vitro proliferation assays were performed to assess naïve CD4 T cell activation under the Th-skewing conditions in the presence of d-serine.

Results

Mice treated with d-serine prior to the induction of colitis exhibited a reduction in T-cell infiltration into the lamina propria and colonic inflammation that were not seen in mice fed with water alone or l-serine. Moreover, d-serine suppressed the progression of chronic colitis when administered after the disease induction. Under in vitro conditions, d-serine suppressed the proliferation of activated CD4 T cells and limited their ability to differentiate to Th1 and Th17 cells.

Conclusion

Our results suggest that d-serine not only can prevent, but also has efficacious effects as a treatment for IBD.

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

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

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

References

  1. Hashimoto A, Nishikawa T, Hayashi T, et al. The presence of free d-serine in rat brain. FEBS Lett. 1992;296:33–6.

    Article  CAS  Google Scholar 

  2. Wolosker H, Sheth KN, Takahashi M, et al. Purification of serine racemase: biosynthesis of the neuromodulator d-serine. Proc Natl Acad Sci USA. 1999;96:721–5.

    Article  CAS  Google Scholar 

  3. Genchi G. An overview on d-amino acids. Amino Acids. 2017;49:1521–33.

    Article  CAS  Google Scholar 

  4. Basu AC, Tsai GE, Ma CL, et al. Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry. 2009;14:719–27.

    Article  CAS  Google Scholar 

  5. Sasaki T, Kinoshita Y, Matsui S, et al. N-methyl-d-aspartate receptor coagonist d-serine suppresses intake of high-preference food. Am J Physiol Regul Integr Comp Physiol. 2015;309:R561–75.

    Article  CAS  Google Scholar 

  6. Matsumoto M, Kunisawa A, Hattori T, et al. Free d-amino acids produced by commensal bacteria in the colonic lumen. Sci Rep. 2018;8:17915.

    Article  CAS  Google Scholar 

  7. Sasabe J, Miyoshi Y, Rakoff-Nahoum S, et al. Interplay between microbial d-amino acids and host d-amino acid oxidase modifies murine mucosal defence and gut microbiota. Nat Microbiol. 2016;1:16125.

    Article  CAS  Google Scholar 

  8. Nakade Y, Iwata Y, Furuichi K, et al. Gut microbiota-derived d-serine protects against acute kidney injury. JCI Insight. 2018;3:e97957.

    Article  Google Scholar 

  9. Marcone GL, Rosini E, Crespi E, et al. D-amino acids in foods. Appl Microbiol Biotechnol. 2020;104:555–74.

    Article  CAS  Google Scholar 

  10. Brückner H, Westhauser T. Chromatographic determination of D-amino acids as native constituents of vegetables and fruits. Chromatographia. 1994;39:419–26.

    Article  Google Scholar 

  11. Gogami Y, Ito K, Kamitani Y, et al. Occurrence of D-serine in rice and characterization of rice serine racemase. Phytochemistry. 2009;70:380–7.

    Article  CAS  Google Scholar 

  12. Preston RL. Occurrence of D-amino acids in higher organisms: a survey of the distribution of D-amino acids in marine inverte- brates. Comp Biochem Physiol. 1987;87B:55–62.

    CAS  Google Scholar 

  13. Okuma E, Fujita E, Amano H, et al. Distribution of free d-amino acids in the tissues of crustaceans. Fish Sci. 1995;61:157–60.

    Article  CAS  Google Scholar 

  14. Brückner H, Hausch M. Gas Chromatographic detection of d-amino acids as common constituents of fermented foods. Chromatographia. 1989;28:487–92.

    Article  Google Scholar 

  15. Khalili H, Chan SSM, Lochhead P, et al. The role of diet in the aetiopathogenesis of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2018;15:525–35.

    Article  CAS  Google Scholar 

  16. Reddavide R, Rotolo O, Caruso MG, et al. The role of diet in the prevention and treatment of inflammatory bowel diseases. Acta Biomed. 2018;89:60–75.

    CAS  PubMed  Google Scholar 

  17. Andou A, Hisamatsu T, Okamoto S, et al. Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages. Gastroenterology. 2009;136:564–74.

    Article  CAS  Google Scholar 

  18. MacKay MB, Kravtsenyuk M, Thomas R, et al. d-Serine: potential therapeutic agent and/or biomarker in schizophrenia and depression? Front Psychiatry. 2019;10:25.

    Article  Google Scholar 

  19. Yamaji O, Nagaishi T, Totsuka T, et al. The development of colitogenic CD4(+) T cells is regulated by IL-7 in collaboration with NK cell function in a murine model of colitis. J Immunol. 2012;188:2524–36.

    Article  CAS  Google Scholar 

  20. Webb RC, Bakker H, Koboziev I, et al. Differential susceptibility to T cell-induced colitis in mice: role of the intestinal microbiota. Inflamm Bowel Dis. 2018;24:361–79.

    Article  Google Scholar 

  21. Savage DC, Dubos R. Alterations in the mouse cecum and its flora produced by antibacterial drugs. J Exp Med. 1968;128:97–110.

    Article  CAS  Google Scholar 

  22. Kahlfuß S, Simma N, Mankiewicz J, et al. Immunosuppression by N-methyl-d-aspartate receptor antagonists is mediated through inhibition of Kv13 and KCa31 channels in T cells. Mol Cell Biol. 2014;34:820–31.

    Article  Google Scholar 

  23. Li YX, Yang JY, Alcantara M, et al. Inhibitors of the Neutral Amino Acid Transporters ASCT1 and ASCT2 Are Effective in In Vivo Models of Schizophrenia and Visual Dysfunction. J Pharmacol Exp Ther. 2018;367:292–301.

    Article  CAS  Google Scholar 

  24. Chairoungdua A, Y Kanai Y, Matsuo H, et al. Identification and characterization of a novel member of the heterodimeric amino acid transporter family presumed to be associated with an unknown heavy chain. J Biol Chem. 2001;276:49390–9.

  25. Holm TL, Poulsen SS, Markholst H, et al. Pharmacological Evaluation of the SCID T Cell Transfer Model of Colitis: As a Model of Crohn’s Disease. Int J Inflam. 2012;2012:412178.

    Google Scholar 

  26. Brasseit J, Althaus-Steiner E, Faderl M, et al. CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis. Mucosal Immunol. 2016;9:689–701.

    Article  CAS  Google Scholar 

  27. Richman E, Rhodes JM. Review article: evidence-based dietary advice for patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2013;38:1156–71.

    Article  CAS  Google Scholar 

  28. Lee D, Albenberg L, Compher C, et al. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology. 2015;148:1087–106.

    Article  CAS  Google Scholar 

  29. Kantrowitz JT, Malhotra AK, Cornblatt B, et al. High dose D-serine in the treatment of schizophrenia. Schizophr Res. 2010;121:125–30.

    Article  Google Scholar 

  30. Sasabe J, Miyoshi Y, Suzuki M, et al. d-amino acid oxidase controls motoneuron degeneration through d-serine. Proc Natl Acad Sci USA. 2012;109:627–32.

    Article  CAS  Google Scholar 

  31. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27–31.

    Article  Google Scholar 

  32. Brückner H, Westhauser T. Chromatographic determination of l- and d-amino acids in plants. Amino Acids. 2003;24:43–55.

    Article  Google Scholar 

  33. Kanai T, Matsuoka K, Naganuma M, et al. Diet, microbiota, and inflammatory bowel disease: lessons from Japanese foods. Korean J Intern Med. 2014;29:409–15.

    Article  Google Scholar 

  34. Mutaguchi Y, Ohmori T, Akano H, et al. Distribution of D-amino acids in vinegars and involvement of lactic acid bacteria in the production of D-amino acids. Springerplus. 2013;2:691.

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge the IMSUT FACS Core laboratory for assistance with cell sorting and Techno-Suruga Laboratory Co., Ltd. (Sizuoka, Japan) for microbiome analysis. We thank Bao Duong for editing a draft of this manuscript. This work was supported by JSPS KAKENHI (JP17H04024, JP17K19675, JP19H01050).

Author information

Author notes

  1. Takehito Asakawa and Michio Onizawa contributed equally.

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan

    Takehito Asakawa, Michio Onizawa, Daiki Yamada, Ai Minamidate, Shigeru Oshima, Takashi Nagaishi, Kiichiro Tsuchiya, Ryuichi Okamoto & Mamoru Watanabe

  2. Department of Gastroenterology and Hepatology, Fukushima Medical University, Fukushima, 960-129, Japan

    Michio Onizawa, Chikako Saito, Rie Hikichi, Tomoaki Mochimaru & Hiromasa Ohira

  3. Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan

    Shun-ichiro Asahara & Yoshiaki Kido

  4. Division of Metabolism and Disease, Department of Biophysics, Kobe University Graduate School of Health Science, Kobe, 654-0142, Japan

    Yoshiaki Kido

Authors
  1. Takehito Asakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michio Onizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chikako Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rie Hikichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daiki Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ai Minamidate
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomoaki Mochimaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shun-ichiro Asahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshiaki Kido
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shigeru Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takashi Nagaishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kiichiro Tsuchiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hiromasa Ohira
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ryuichi Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Mamoru Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TA planned, performed majority of the experiments and wrote the manuscript. MO performed the initial experiments, wrote the manuscript and directed the research. CS, RH, DY, AM, TM and SA performed the experiments. YK, SO, TN, KT, HO and RO planned the experiments and provided technical assistance. MW directed the research.

Corresponding authors

Correspondence to Michio Onizawa or Mamoru Watanabe.

Ethics declarations

Conflict of interest

The authors have declared that no competing interests exist.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PPTX 1418 KB)

Supplementary file2 (DOCX 29 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Asakawa, T., Onizawa, M., Saito, C. et al. Oral administration of d-serine prevents the onset and progression of colitis in mice. J Gastroenterol 56, 732–745 (2021). https://doi.org/10.1007/s00535-021-01792-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-021-01792-1

Keywords

  • Mouse IBD model
  • Colitis
  • d-amino acids
  • d-serine