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.
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.
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.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Hashimoto A, Nishikawa T, Hayashi T, et al. The presence of free d-serine in rat brain. FEBS Lett. 1992;296:33–6.
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.
Genchi G. An overview on d-amino acids. Amino Acids. 2017;49:1521–33.
Basu AC, Tsai GE, Ma CL, et al. Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry. 2009;14:719–27.
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.
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.
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.
Nakade Y, Iwata Y, Furuichi K, et al. Gut microbiota-derived d-serine protects against acute kidney injury. JCI Insight. 2018;3:e97957.
Marcone GL, Rosini E, Crespi E, et al. D-amino acids in foods. Appl Microbiol Biotechnol. 2020;104:555–74.
Brückner H, Westhauser T. Chromatographic determination of D-amino acids as native constituents of vegetables and fruits. Chromatographia. 1994;39:419–26.
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.
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.
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.
Brückner H, Hausch M. Gas Chromatographic detection of d-amino acids as common constituents of fermented foods. Chromatographia. 1989;28:487–92.
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.
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.
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.
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.
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.
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.
Savage DC, Dubos R. Alterations in the mouse cecum and its flora produced by antibacterial drugs. J Exp Med. 1968;128:97–110.
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.
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.
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.
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.
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.
Richman E, Rhodes JM. Review article: evidence-based dietary advice for patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2013;38:1156–71.
Lee D, Albenberg L, Compher C, et al. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology. 2015;148:1087–106.
Kantrowitz JT, Malhotra AK, Cornblatt B, et al. High dose D-serine in the treatment of schizophrenia. Schizophr Res. 2010;121:125–30.
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.
Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27–31.
Brückner H, Westhauser T. Chromatographic determination of l- and d-amino acids in plants. Amino Acids. 2003;24:43–55.
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.
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.
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).
Conflict of interest
The authors have declared that no competing interests exist.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
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
- Mouse IBD model
- d-amino acids