D-Tryptophan suppresses enteric pathogen and pathobionts and prevents colitis by modulating microbial tryptophan metabolism

Natsumi Seki; Tatsuki Kimizuka; Monica Gondo; Genki Yamaguchi; Yuki Sugiura; Masahiro Akiyama; Kyosuke Yakabe; Jun Uchiyama; Seiichiro Higashi; Takeshi Haneda; Makoto Suematsu; Koji Hase; Yun-Gi Kim

doi:10.1016/j.isci.2022.104838

_D-Tryptophan suppresses enteric pathogen and pathobionts and prevents colitis by modulating microbial tryptophan metabolism

iScience. 2022 Aug 3;25(8):104838. doi: 10.1016/j.isci.2022.104838. eCollection 2022 Aug 19.

Authors

Natsumi Seki^{1

2}, Tatsuki Kimizuka^{1

2}, Monica Gondo^{1

2}, Genki Yamaguchi^{1

2}, Yuki Sugiura³, Masahiro Akiyama¹, Kyosuke Yakabe^{1

2}, Jun Uchiyama^{1

2}, Seiichiro Higashi⁴, Takeshi Haneda⁵, Makoto Suematsu³, Koji Hase², Yun-Gi Kim¹

Affiliations

¹ Research Center for Drug Discovery, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan.
² Department of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan.
³ Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
⁴ Co-Creation Center, Meiji Holdings Co., Ltd., 1-29-1 Nanakuni, Hachiouji, Tokyo 192-0919, Japan.
⁵ Laboratory of Microbiology, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan.

Abstract

_D-Amino acids (_D-AAs) have various functions in mammals and microbes. _D-AAs are produced by gut microbiota and can act as potent bactericidal molecules. Thus, _D-AAs regulate the ecological niche of the intestine; however, the actual impacts of _D-AAs in the gut remain unknown. In this study, we show that _D-Tryptophan (_D-Trp) inhibits the growth of enteric pathogen and colitogenic pathobionts. The growth of Citrobacter rodentium in vitro is strongly inhibited by _D-Trp treatment. Moreover, _D-Trp protects mice from lethal C. rodentium infection via reduction of the pathogen. Additionally, _D-Trp prevents the development of experimental colitis by the depletion of specific microbes in the intestine. _D-Trp increases the intracellular level of indole acrylic acid (IA), a key molecule that determines the susceptibility of enteric microbes to _D-Trp. Treatment with IA improves the survival of mice infected with C. rodentium. Hence, _D-Trp could act as a gut environmental modulator that regulates intestinal homeostasis.

Keywords: cell biology; cellular physiology; microbiology; microbiome.