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; Yukako Fujinaga

doi:10.1038/s41467-025-65384-w

MicrobiologyNature CommunicationsNov 25, 2025

Peer-reviewed journal article

Gut mucin fucosylation dictates the entry of botulinum toxin complexes

Sho Amatsu iD, Takuhiro Matsumura iD, Chiyono Morimoto, Sunanda Keisham, Yoshiyuki Goto iD, Tomoko Kohda iD, Jun Hirabayashi iD, Kengo Kitadokoro iD, Takane Katayama iD, Hiroshi Kiyono iD, Hiroaki Tateno iD, Masahiko Zuka iD, Yukako Fujinaga iD

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Abstract

Botulinum toxins (BoNTs) are the most potent known bacterial toxins. The BoNT complex from Clostridium botulinum B-Okra (large progenitor toxin complex (L-PTC)/BOkra, hyper-oral-toxic) exerts at least 80-fold higher oral toxicity1 in mice compared with that from serotype A1 (L-PTC/A62A, non-hyper-oral-toxic). Here, we showed that L-PTC/BOkra was predominantly absorbed through enterocytes, whereas L-PTC/A62A targeted intestinal microfold cells. Furthermore, we demonstrated that 1,2-fucosylation of intestinal mucin determined the oral toxicity of L-PTCs as well as their entry routes; more specifically, these routes were governed by the carbohydrate-binding spectrum of hemagglutinin (HA) complex, which is one of the L-PTC components. Disruption of fucosylation in fucosyltrasferase-2 (Fut2)-null mice hindered the intestinal mucin penetration of L-PTC/BOkra via HA and reduced the susceptibility to its oral intoxication. Our data establish the molecular mechanism by which the oral toxicity of BoNTs is increased after they cross intestinal mucus layers.