Gut mucin fucosylation dictates the entry of botulinum toxin complexes

Sho Amatsu, Takuhiro Matsumura, Chiyono Morimoto, Sunanda Keisham, Yoshiyuki Goto, Tomoko Kohda, Jun Hirabayashi, Kengo Kitadokoro, Takane Katayama, Hiroshi Kiyono, Hiroaki Tateno, Masahiko Zuka and Yukako Fujinaga ()
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Sho Amatsu: Kanazawa University, Department of Bacteriology, Graduate School of Medical Sciences
Takuhiro Matsumura: Kanazawa University, Department of Bacteriology, Graduate School of Medical Sciences
Chiyono Morimoto: Kanazawa University, Department of Bacteriology, Graduate School of Medical Sciences
Sunanda Keisham: National Institute of Advanced Industrial Science and Technology (AIST), Cellular and Molecular Biotechnology Research Institute
Yoshiyuki Goto: Chiba University, Division of Molecular Immunology, Medical Mycology Research Center
Tomoko Kohda: Osaka Metropolitan University, Graduate School of Veterinary Sciences
Jun Hirabayashi: Nagoya University, Institute for Glyco-core Research (iGCORE)
Kengo Kitadokoro: Kyoto Institute of Technology, Faculty of Molecular Chemistry and Engineering, Graduate School of Science and Technology
Takane Katayama: Kyoto University, Graduate School of Biostudies
Hiroshi Kiyono: Chiba University, Chiba University Synergy Institute for Futuristic Mucosal Vaccine Research and Development (cSIMVa)
Hiroaki Tateno: National Institute of Advanced Industrial Science and Technology (AIST), Cellular and Molecular Biotechnology Research Institute
Masahiko Zuka: Kanazawa University, Department of Forensic Medicine and Pathology, Graduate School of Medical Sciences
Yukako Fujinaga: Kanazawa University, Department of Bacteriology, Graduate School of Medical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract Botulinum toxins (BoNTs) produced by Clostridium botulinum are the most potent known bacterial toxins. The BoNT complex from serotype B-Okra (LPTC/BOkra) exerts at least 80-fold higher oral toxicity in mice compared with that from serotype A1 (L-PTC/A62A). Here, we show that L-PTC/BOkra is predominantly absorbed through enterocytes, whereas LPTC/A62A targets intestinal microfold cells. Furthermore, α1,2-fucosylation of intestinal mucin determines the oral toxicity of L-PTCs as well as their entry routes, due to differential carbohydrate-binding spectrum of one of the L-PTC components, the hemagglutinin (HA) complex. Fucosylation-deficient mice display reduced intestinal mucin penetration of L-PTC/BOkra via HA, and lower susceptibility to oral intoxication with this toxin. Thus, our results shed light on the molecular mechanisms by which the oral toxicity of BoNTs is increased after crossing intestinal mucus layers

Date: 2025
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DOI: 10.1038/s41467-025-65384-w

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