Profound Alterations of Intestinal Microbiota following a Single Dose of Clindamycin Results in Sustained Susceptibility to Clostridium difficile-Induced Colitis

Abstract

ABSTRACTAntibiotic-induced changes in the intestinal microbiota predispose mammalian hosts to infection with antibiotic-resistant pathogens.Clostridium difficileis a Gram-positive intestinal pathogen that causes colitis and diarrhea in patients following antibiotic treatment. Clindamycin predisposes patients toC. difficilecolitis. Here, we have used Roche-454 16S rRNA gene pyrosequencing to longitudinally characterize the intestinal microbiota of mice following clindamycin treatment in the presence or absence ofC. difficileinfection. We show that a single dose of clindamycin markedly reduces the diversity of the intestinal microbiota for at least 28 days, with an enduring loss of ca. 90% of normal microbial taxa from the cecum. Loss of microbial complexity results in dramatic sequential expansion and contraction of a subset of bacterial taxa that are minor contributors to the microbial consortium prior to antibiotic treatment. Inoculation of clindamycin-treated mice withC. difficile(VPI 10463) spores results in rapid development of diarrhea and colitis, with a 4- to 5-day period of profound weight loss and an associated 40 to 50% mortality rate. Recovering mice resolve diarrhea and regain weight but remain highly infected with toxin-producing vegetativeC. difficilebacteria and, in comparison to the acute stage of infection, have persistent, albeit ameliorated cecal and colonic inflammation. The microbiota of “recovered” mice remains highly restricted, and mice remain susceptible toC. difficileinfection at least 10 days following clindamycin, suggesting that resolution of diarrhea and weight gain may result from the activation of mucosal immune defenses.