Gut mucin fucosylation dictates the entry of botulinum toxin complexes

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 α1,2-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.