Staff

AYABE TokiyoshiProfessor

Laboratory
Laboratory of Innate Immunity
Research Theme
Elucidating mechanisms of innate immune responses in mucosal immunity and pathogenesis of inflammatory bowel disease and lifestyle diseases
Research Keywords

mucosal immunology, innate immunity, antimicrobial peptides, alpha-defensin, intestinal microbiota, intestinal environment, Paneth cell, stem cell, inflammatory bowel disease, lifestyle diseases, gastroenterology, food and medicine, priventive medicine, therapeutics

Overview of Research

Paradigm shift for the mucosal immune system:
Through both biological and medical insights, we test mechanisms in the innate enteric immunity both microbial elimination and symbiosis with the intestinal microbiota with molecular and cellular levels, and beyond. We will make paradigm shift in the mucosal immunity from viewpoint of the host-microbe interaction.

Elucidating roles of antimicrobial peptides in the innate immunity:
We will clarify pathogenesis of inflammatory bowel disease (Crohn’s disease and ulcerative colitis) and lifestyle diseases, based on innate immune functions of antimicrobial peptides, especially alpha-defensin secreted by Paneth cells in the small intestine. We have been studying Paneth cell functions in the innate enteric immunity, regeneration, and symbiosis. Elucidating mechanisms for action of alpha-defensin from structure-activity relationship and interaction with the intestinal bacteria will contribute to solving global health problems.

Understanding the intestinal environment created with foods, intestinal epithelial cells and intestinal microbiota:
We conduct researches to understand various intestinal functions such as absorption, metabolism, immunity, and brain-gut axis from the molecular and cellular perspectives. We create unique intestinal environment evaluation methods that is compatible with biological functions in vivo using the latest intestinal epithelial cell isolation, culture and imaging technologies and contribute to the development of functional foods and new therapeutics.

Charge

Message

Mucosal immunology serves an important role in the host defense. One goal of our laboratory is to understand molecular mechanisms that regulate function of innate immunity. Focusing on antimicrobial peptides (AMPs) as well as Paneth cells that produce and secrete those molecules, we aim to test new paradigms in the field of mucosal immunity. At the surface of intestinal epithelia, where a vast number and variety of microbes create resident intestinal microbiota, the host must deal with the microbiota as well as potential pathogens that might cause infection. α-Defensins are abundant components of Paneth cell secretory granules and secreted into the lumen in response to cholinergic or bacterial stimuli. By developing ex vivo functional assay systems using isolated intact crypts and intestinal organoids, we have been analyzing how host cells detect microbes, how AMP activation and secretion are regulated, and how microbes and intestinal epithelia such as Paneth cells crosstalk.

The number of patients with inflammatory bowel disease (IBD) as well as lifestyle diseases have been increasing continuously in world-wide, including in Japan. Finally, to understand pathophysiology and pathogenesis of IBD, Crohn’s disease and ulcerative colitis in particular and lifestyle diseases such as obesity, diabetes, and nonalcoholic steatohepatitis, we analyze roles of AMPs, related signal molecules in Paneth cells and crosstalk between innate and adaptive immunity in the gut. Taken together, we will contribute to improving quality of life of patients with IBD and lifestyle diseases by getting our knowledge of AMPs as effectors of the mucosal immunity and by developing preventive medicine and novel therapeutics.

Representative Publications

Nakamura K, Yokoi Y, Fukaya R, Ohira S, Shinozaki R, Nishida T, Kikuchi M, Ayabe T. Expression and localization of Paneth cells and their alpha-defensins in the small intestine of adult mouse. Front Immunol 2020. 11: 570296. doi: 10.3389/fimmu.2020.570296.

Shimizu Y, Nakamura K, Yoshii A, Yokoi Y, Kikuchi M, Shinozaki R, Nakamura S, Ohira S, Sugimoto R, Ayabe T. Paneth cell alpha-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice. Life Science Alliance 2020. 3(6):e201900592. doi: 10.26508/lsa.201900592.

Yokoi Y, Nakamura K, Yoneda T, Kikuchi M, Sugimoto R, Shimizu Y, Ayabe T. Paneth cell granule dynamics on secretory responses to bacterial stimuli in enteroids. Sci Rep 2019. doi.org/10.1038/s41598-019-39610-7.

Takakuwa A, Nakamura K, Kikuchi M, Sugimoto R, Ohira S, Yokoi Y, Ayabe T. Butyric acid and leucine induce alpha-defensin secretion from small intestinal Paneth cells. Nutrients 2019, 11(11), 2817; doi.org/10.3390/nu11112817.                                                                                                                

Eriguchi Y, Nakamura K, Yokoi Y, Takahashi S, Hashimoto D, Teshima T, Ayabe T, Selsted ME, Ouellette AJ. Essential role of interferon-gamma in T cell-associated intestinal inflammation. JCI Insight 2018. 3(18): e121886. doi.org/10.1172/jci.insight.121886.

Hayase E, Hashimoto D, Nakamura K, Noizat C, Ogasawara R, Takahashi S, Ohigashi H, Yokoi Y, Sugimoto R, Matsuoka S, Ara T, Yokoyama E, Yamakawa T, Ebata K, Kondo T, Hiramine R, Aizawa T, Ogura Y, Hayashi T, Mori H, Kurokawa K, Tomizuka K, Ayabe T, Teshima T., R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease., J Exp Med 2017. 214: 3507-3518.

Refer to HOKKAIDO UNIVERSITY RESEARCHERS DIRECTORY
(https://researchers.general.hokudai.ac.jp/profile/en.bblcHx9s1OIVNuwqyv0YtQ==.html)

Note

<Office Hour>
– Time: Anytime during the lecture period
– Place: Frontier-AMLS, 4F
Please contact in advance by E-mail.
E-mail: ayabe[at]sci.hokudai.ac.jp

<Related SDGs>                                         3. GOOD HEALTH AND WELL-BEING
4. QUALITY EDUCATION
9. INDUSTRY, INNOVATION AND INFRASTRUCTURE
17. PARTNERSHIPS FOR THE GOALS

Affiliation