Acceleration of cecal tumorigenesis in AhR-deficient mice by the alternation of gut microbiota.

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K23883
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Shinshu University
• Principal Investigator: Matoba Hisanori 信州大学, 医学部, 特任助教 (10849277)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Keywords: AhR / 炎症性発癌 / B. fragilis (ETBF)

Outline of Final Research Achievements

Aryl hydrocarbon receptor (AhR) is a transcription factor known as a dioxin receptor. We analyzed cecal tumorigenesis in AhR knockout (KO) mice and revealed that the lesions developed from hyperplasia to neoplasia with inflammation observed specifically in the lesion sites. However, tumor incidence was significantly lower than previously reported in the study . The reason for this decrease could be attributed to differences in the intestinal microbiota between the facilities.
In this study, we analyzed whether the administration of Enterotoxigenic Bacteroides fragilis (ETBF) accelerated tumorigenesis in AhR KO mice. ETBF treatment increased mortality in AhR KO mice. In contrast to previous reports, no lesions were observed in AhR KO mice without ETBF treatment. However, microscopic and gross lesions were observed in 20-30% of AhR KO mice treated with ETBF. ETBF treatment increased mortality in mice by inducing an inflammatory response in the intestine, but also promoted tumorigenesis.

Free Research Field

病理学

Academic Significance and Societal Importance of the Research Achievements

本研究では、腸内細菌叢の変化などの原因によりAhR KOマウスの炎症に対する感受性や腫瘍の発生率がこれまでの結果と比較して低下していたが、ETBFの投与がこの低下した炎症感受性や腫瘍発生を回復・促進させることが示唆された。AhRがヒトの炎症性腸疾患の感受性遺伝子の1つであることを考慮すると、本研究がヒトの炎症性腸疾患からの発癌における特定の遺伝子変異と腸内細菌叢との関連性の解明や、腸内細菌叢の制御による発癌予防の糸口となることが期待される。