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^Okra) exerts at least 80-fold higher oral toxicity in mice compared with that from serotype A1 (L-PTC/A^62A). Here, we show that L-PTC/B^Okra is predominantly absorbed through enterocytes, whereas LPTC/A^62A 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^Okra 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.