The disease is caused by Vibrio cholerae, a bacterium that infects cells of the small intestine. Epidemiologists first noticed four decades ago that people with blood type O were more likely to be hospitalized for cholera than people of other blood types, but the reasons for the difference had never been determined.

Although the blood group antigens—A, B, AB, and O—are best known for their presence on red blood cells, they also are found on the surface of many other cell types, including the cells that line the intestine.

Because O blood group has been associated with more severe cholera infections, it has been hypothesized that cholera toxin (CT) may bind non-O blood group antigens of the intestinal mucosae, thereby preventing efficient interaction with target GM1 gangliosides required for uptake of the toxin and activation of cyclic adenosine monophosphate (cAMP) signaling in target epithelia. Herein, we show that after exposure to CT, human enteroids expressing O blood group exhibited marked increase in cAMP relative to cells derived from blood group A individuals. Likewise, using CRISPR/Cas9 engineering, a functional group O line (HT-29-A−/−) was generated from a parent group A HT-29 line. CT stimulated robust cAMP responses in HT-29-A−/− cells relative to HT-29 cells. These findings provide a direct molecular link between blood group O expression and differential cellular responses to CT, recapitulating clinical and epidemiologic observations.

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Blood Group O–Dependent Cellular Responses to Cholera Toxin: Parallel Clinical and Epidemiological Links to Severe Cholera