The immunomodulatory properties of bacterial superantigens (SAgs) have been defined, yet comparatively little is known of how SAgs may affect enteric physiology. Staphylococcus aureus enterotoxin B (SEB) was used to examine the ability of SAgs to alter epithelial ion transport. BALB/c mice, severe combined immunodeficient (SCID, lack T cells) mice, or SCID mice reconstituted with lymphocytes or CD4(+) T cells received SEB intraperitoneally, and jejunal segments were examined in Ussing chambers; controls received saline only. Baseline short-circuit current (I-sc, indicates net ion transport) and I-sc responses evoked by electrical nerve stimulation, histamine, carbachol, or forskolin were recorded. Serum levels of interleukin-fl (IL-2) and interferon-gamma (IFN-gamma) were measured. SEB-treated BALB/c mice showed elevated serum IL-2 and IFN-gamma levels, and jejunal segments displayed a time-and dose-dependent increase in baseline I-sc compared with controls. Conversely, evoked ion secretion was selectively reduced in jejunum from SEB-treated mice. Elevated cytokine levels and changes in jejunal I-sc were not observed in SEB-treated SCID mice. In contrast, SCID mice reconstituted with T cells were responsive to SEB challenge as shown by increased cytokine production and altered jejunal I-sc responses that were similar to those observed in jejunum from SEB-treated BALB/c mice. We conclude that exposure to a model bacterial SAg causes distinct changes in epithelial physiology and that these events can be mediated by CD4(+) T cells.