Effect of intestinal flora modulation by oral polymyxin treatment on hemopoietic stem cell kinetics in mice

After oral treatment with polymyxin for only 1 day, fecal aerobic gram-negative bacteria were found completely suppressed in C3H/Law mice. Complete suppression of aerobic gram-negative bacteria was accompanied by a reduction of the fecal endotoxin concentration from 100 to 10 micrograms endotoxin per gram of feces as measured with the Limulus amebocyte lysate assay. Oral administration of polymyxin affected hemopoietic stem cell kinetics at different stages. The kinetic behavior of hemopoietic stem cells was determined as the in vivo sensitivity to the S phase specific cytostatic drug hydroxyurea. The hydroxyurea kill of bone marrow spleen colony-forming cells diminished not significantly (p less than 0.10) from 14 to 4% after 2 days of polymyxin treatment. Already after 1 day of treatment the hydroxyurea kill of bone marrow progenitor cells forming granulocyte-macrophage colonies in vitro decreased from 29 to 7% (p less than 0.05). It took 8 days of treatment before the hydroxyurea kill of splenic granulocyte-macrophage colonies was found reduced from 53 to 14% (p less than 0.001). The decreased susceptibility of hemopoietic stem cells to hydroxyurea during polymyxin treatment appears to argue for a role of intestinal aerobic gram-negative bacteria in the regulation of hemopoiesis, probably mediated by endotoxin.