A receptor decoy inhibits the enterotoxic effects of Clostridium difficile toxin A in rat ileum.
OBJECTIVE
Clostridium difficile toxin A causes secretion and intestinal inflammation in rodents by binding to a specific trisaccharide Gal alpha 1-3Gal beta 1-4 GlcNAc on enterocyte receptors. The purpose of this study was to explore the ability of Synsorb 90 (Synsorb Biotech Inc., Calgary, Alberta, Canada), and inert support carrying this trisaccharide, to bind toxin A in vitro and to inhibit its enterotoxic effects in vivo.


METHODS
Binding of [3H]toxin A to Synsorb 90, Synsorb 83 (beta-mannose attached), and Chromosorb P (inert support with no sugar attached) (Synsorb Biotech Inc.) was measured. The inhibitory effects of these compounds on toxin A-mediated fluid secretion, mannitol permeability, and histological damage were measured in ileal loops in vivo.


RESULTS
Toxin A showed specific binding to Synsorb 90, bearing the specific trisaccharide that binds toxin A, but not to Synsorb 83 or to Chromosorb P. Pretreatment of rats with Synsorb 90 by gavage (200 mg/kg body wt), but no Synsorb 83 or Chromosorb P at the same doses, dramatically reduced toxin A-associated fluid secretion and permeability.


CONCLUSIONS
An immobilized toxin A receptor sequesters toxin A in the intestinal lumen and inhibits its effects of ileal mucosa. These results suggest a potential use for this agent in treating patients with C. difficile colitis.
Castagliuolo
I
I
Division of Gastroenterology, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts, USA.
LaMont
J T
JT
Qiu
B
B
Nikulasson
S T
ST
Pothoulakis
C
C
D000818:Animals; D001427:Bacterial Toxins; D001826:Body Fluids / Q000378:metabolism; D002240:Carbohydrate Sequence; D016360:Clostridioides difficile / Q000378:metabolism*; D004751:Enteritis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004768:Enterotoxins / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008353:Mannitol / Q000493:pharmacokinetics; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000378:metabolism / Q000494:pharmacology*; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000378:metabolism*
D001427:Bacterial Toxins; D004768:Enterotoxins; D009844:Oligosaccharides; D018000:Receptors, Peptide; C041348:tcdA protein, Clostridium difficile; D008353:Mannitol; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled