Gut mucin fucosylation dictates the entry of botulinum toxin complexes
Botulinum toxins (BoNTs) produced by Clostridium botulinum are the most potent known bacterial toxins. The BoNT complex from serotype B-Okra (LPTC/B<sup>Okra</sup>) exerts at least 80-fold higher oral toxicity in mice compared with that from serotype A1 (L-PTC/A<sup>62A</sup>). Here, we show that L-PTC/B<sup>Okra</sup> is predominantly absorbed through enterocytes, whereas LPTC/A<sup>62A</sup> 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/B<sup>Okra</sup> 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.
Authors
- Jun Hirabayashi (ORCID: https://orcid.org/0000-0002-8571-359X)
- Sho Amatsu (ORCID: https://orcid.org/0000-0003-0692-264X)
- Yukako Fujinaga (ORCID: https://orcid.org/0000-0001-8623-1376)
- Takuhiro Matsumura (ORCID: https://orcid.org/0000-0002-3747-829X)
- Tomoko Kohda (ORCID: https://orcid.org/0000-0002-5605-5321)
- Kengo Kitadokoro (ORCID: https://orcid.org/0000-0001-5969-7939)
- Chiyono Morimoto
- Takane Katayama (ORCID: https://orcid.org/0000-0003-4009-7874)
- Hiroaki Tateno (ORCID: https://orcid.org/0000-0003-3006-1659)
- Hiroshi Kiyono (ORCID: https://orcid.org/0000-0001-7307-4658)
- Masahiko Zuka
- Sunanda Keisham
- Yoshiyuki Goto
Institutions
- Kanazawa University (JP)
- University of Tsukuba (JP)
- Chiba University (JP)
- Kanazawa Medical University (JP)
- Kyoto University (JP)
- Kyoto Institute of Technology (JP)
- University of California San Diego (US)
- Chiba University Hospital (JP)
- Osaka Metropolitan University (JP)
- Nagoya University (JP)
- Tokyo Metropolitan University (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-25
- DOI
- https://doi.org/10.1038/s41467-025-65384-w
- Citations
- 2
- Primary Topic
- Toxin Mechanisms and Immunotoxins
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- Japan Agency for Medical Research and Development
- Chiba University
- University of California, San Diego
- Japan Society for the Promotion of Science
- National Institute of Diabetes and Digestive and Kidney Diseases