Xanthine oxidase (XO) has been recognized as an important host defense enzyme for decades. In our recent study in Infection and Immunity, we found that enteropathogenic and ShigatoxigenicE. coli (EPEC and STEC) were far more resistant to killing by the XO pathway than laboratoryE. colistrains used in the past. Although XO plus hypoxanthine substrate rarely generated enough H2O2to kill EPEC and STEC, the pathogens were able to sense the H2O2and react to it with an increase in expression of virulence factors, most notably Shiga toxin (Stx). H2O2produced by XO also triggered a chloride secretory response in T84 cell monolayers studied in the Ussing chamber. Adding exogenous XO plus its substrate in vivo did not decrease the number of STEC bacteria recovered from ligated intestinal loops, but instead appeared to worsen the infection and increased the amount of Stx2 toxin produced. XO plus hypoxanthine also increases the ability of Stx2 to translocate across intestinal monolayers. With regard to EPEC and STEC, the role of XO appears more complex and subtle than what has been reported in the past, since XO also plays a role in host-pathogen signaling, in regulating virulence in pathogens, in Stx production and in toxin translocation. Uric acid produced by XO may also be in itself an immune modulator in the intestinal tract.