Prevention of indigenous infection of mice with Escherichia coli by nonspecific immunostimulation

We have previously reported that the lethal toxicity of 5-fluorouracil (5- FU) in specific-pathogen-free mice is due to an intestinal infection with indigenous Escherichia coli induced by the drug (K. Nomoto, T. Yokokura, Y. Yoshikai, M. Mitsuyama, and K. Nomoto, Can J. Microbiol. 37:244-247, 1991). In the present study we demonstrate that nonspecific immunostimulation is effective in the protection of mice from the lethal indigenous infection induced by 5-FU. Intravenous or subcutaneous injection of a preparation of heat-killed Lactobacillus casei YIT 9018, a potent nonspecific immunostimulant, into BALB/c mice reduced the lethal toxicity of 5-FU at doses ranging from 338 to 800 mg/kg of body weight if YIT 9018 was injected 7 to 40 days before administration of 5-FU. Systemic infection with E. coli developed in all of the 5-FU-treated control mice 7 days or more after administration of 5-FU in large doses and was accompanied by overgrowth of the bacteria in the intestinal tract. Pretreatment of mice with YIT 9018 resulted in a decreased occurrence of systemic infection with E. coli to levels of 0 to 20% and no significant changes in the population levels of E. coli in the intestinal tract during the 14 days after administration of 5-FU. The levels of leukopenia in the spleen and peripheral blood were lower, and recovery of granulocyte-macrophage precursor cells in the spleen and femur began earlier in the treated animals than in the 5-FU-treated controls. Intravenous transfusion of syngeneic normal bone marrow cells or spleen cells into the mice at an early period after administration of 5-FU diminished markedly the occurrence of the lethal indigenous infection, suggesting that an earlier recovery from chemotherapy-induced myelosuppression is important in the mechanisms of protection of the host from the infection.