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Oligosaccharides from Human Milk Block Binding and Activity of the Escherichia coli Heat-Stable Enterotoxin (STa) in T84 Intestinal Cells^1,2,3,

University of Texas-Houston Health Sciences Center, Houston, TX 77030 ^* Shriver Center for Mental Retardation, Waltham, MA 02254

Enterotoxin-producing Escherichia coli are major causes of pediatric diarrhea in developing countries. The heat-stable enterotoxin of Escherichia coli (STa) causes diarrhea by virtue of its ability to bind to and stimulate intestinal membrane-bound guanylate cyclase, generating cyclic GMP (cGMP). Previous work showed that a fucosylated oligosaccharide fraction of human milk was able to protect suckling mice from the secretory effects of STa, but the mechanism of the protection could not be determined. Oligosaccharide fractions from human milk were tested for their ability to block the biochemical effects of STa in T84 cells, a human colon carcinoma line responsive to the toxin. Total and fucosylated oligosaccharide fractions were found to inhibit STa-stimulated guanylate cyclase activity in T84 cell membranes and cGMP production in intact T84 cells by 60–80%. In addition, the total oligosaccharide fraction and the fucosylated oligosaccharide fraction inhibited ¹²⁵I-STa binding significantly (17% and 27% inhibition, respectively). These findings demonstrate the protective activity of human milk oligosaccharides against STa in a human-derived cell line and show that the biochemical step blocked by oligosaccharides is STa-mediated stimulation of guanylate cyclase. This represents a novel mechanism by which human milk oligosaccharides project against diarrhea.

KEY WORDS: • bacterial enterotoxin • guanylate cyclase • human milk carbohydrates • cyclic GMP • T84 cells

¹ Presented in part at the 93rd General Meeting of the American Society for Microbiology, May 1993, Atlanta, GA [Crane, J. K., Azar, S. S., Stam, A. & Newburg, D. S. (1993) Oligosaccharides from human milk block binding and activity of the Escherichia coli heat-stable enterotoxin (STa) in the T84 intestinal cell line. (abs. B101)].

² Supported by NIH Program Project Grant HD 13021 (D.S.N.) and by funds from the Department of Internal Medicine, University of Texas Medical School at Houston (J.K.C.).

³ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

⁴ To whom correspondence should be addressed at the current address: Division of Infectious Diseases, State University of New York of Buffalo, 462 Grider Street, Buffalo, NY 14215.

Manuscript received 8 March 1994. Revision accepted 27 June 1994.

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