Toward revision of antimicrobial therapies in hematopoietic stem cell transplantation: target the pathogens, but protect the indigenous microbiota

Abstract

Host microbiota plays important roles in providing colonization resistance to pathogens and instructing development and function of the immune system. Antibiotic treatments intended to target pathogens further weaken the host defenses and may paradoxically increase the risk of systemic infections. This consequence is especially problematic in patients undergoing hematopoietic stem cell transplantation, where the mucosal defenses are already weakened by the conditioning regimens. This review discusses the roles that indigenous microbiota plays in protecting the host and maintaining immune homeostasis. In addition, we highlight possible strategies that are being developed to allow targeted antimicrobial therapy against pathogens, while minimizing the harm to indigenous microbiota.

Fig 1

Overview of the roles of microbiota after HCT. (A) During steady state, the gut microbiota is kept compartmentalized from the host by a number of mechanisms, including the thick inner mucus in the colon fortified with antimicrobial peptides and secreted immunoglobulin. Microbiota-derived products provide trophic signals to the epithelium and promote development of noninflammatory elements of the immune system. Potentially pathogenic microbes (pathobionts) are constrained by the multiple mechanisms, including intense competition for nutrients. (B) Myeloablative regimens used to condition patients for HCT have toxic effects on the intestinal epithelium and the mucosal immune system. However, repair is facilitated by healthy microbiota-derived trophic signals. (C) Broad-spectrum antibiotics disrupt the normal microbial community structure of gut microbiota and lead to expansion of pathobionts, which are more likely to be antibiotic-resistant and more able to translocate across the compromised gut barrier leading to blood-borne infections. Loss of trophic microbiota-derived signals also limits repair of the epithelial barrier and the mucosal immune system. (D) Loss of mutualist microbiota and greater abundance of pathobionts results in altered signaling to the developing immune system and rise of an inflammatory host response leading to GVHD. HCT, hematopoietic stem cell transplantation; GVHD, graft-vs-host disease.

Fig 2

Deleterious effect of antibiotics in a model of xenogeneic GVHD. Human mononuclear cells from peripheral blood were injected intravenously into NOD/SCID/γc−/− mice, 20 × 10⁶ cells per animal. Some of the mice (n = 20) were given ampicillin (1 mg/mL), clindamycin (1 mg/mL), vancomycin 1 mg/mL, and cefoperazone (0.5 mg/mL) in their drinking water. Control mice did not receive antibiotics (n = 10). The animals were monitored for diarrhea and weight loss and sacrificed when weight decreased 30% from the starting weight. The antibiotics in drinking water alone without the cell injection did not cause weight loss. The shown experiment is representative of 3 independent experiments. GVHD, graft-vs-host disease; PBMC, peripheral blood mononuclear cells.