Antibiotic Treatment of Acute Graft vs. Host Disease: Stop Killing the Good Bacteria

Hematopoietic stem cell transplantation (HSCT) has been used for many years to treat various malignant and nonmalignant conditions. However, the high-dose conditioning regimen prior to stem cell transplant can lead to major organ injury and dysfunction as well as life-threatening infection and bleeding. In addition, engraftment of stem cells may induce the multi-organ inflammatory disorder called acute graft-versus-host disease (GVHD) making post-transplant management complex. Stem cell transplantation can be performed with cells from a family member or an unrelated volunteer. However, the likelihood of obtaining donors who are immunologically matched with the recipient is only 25%. Therefore, the pool of potential donors has been expanded to include related or unrelated donors who are partially matched with the recipient. These donors are referred to as allogeneic donors. By including these donors,  >95% of all patients who require HSCT are able to receive this treatment.

Myeloablative conditioning has been a prerequisite for performing hematopoietic stem cell transplantation. The process involves destroying the recipient’s bone marrow to allow for engraftment, proliferation, and differentiation of the healthy hematopoietic stem cells.  Unfortunately, there is mounting evidence to show that pre-transplant conditioning damages the gut and other tissues. Damage to the intestine is thought to play an important role in the initiation and amplification of acute GVHD.  Recent studies show that injury to the intestinal tract plays an important role in the development of acute GVHD by facilitating the translocation of intestinal bacteria and/or their constituents (e.g. lipopolysaccharides, pathogen-associated molecular patterns) into gut tissue and systemic circulation where they activate innate immune cells and trigger a cytokine storm. Indeed, bacterial infections are major complications following HSCT.

These observations have prompted clinicians to investigate the potential protective effects of antibiotic administration before and/or after myeloablative conditioning and HSCT. Some studies suggest that antibiotic administration to mice or humans undergoing HSCT attenuates the onset and/or severity of acute GVHD. Other studies report that administration of certain antibiotics may exacerbate acute GVHD-induced intestinal tissue damage as well as increase mortality by damaging bacterial colonies that maintain intestinal epithelial cell viability and mucosal barrier function.

In light of this, Texas Tech University Health Sciences Center researchers: Brianyell McDaniel Mims, Josue Enriquez, Kathryn Furr, and Professor Matthew Grisham sought to investigate whether the administration of certain antibiotics would affect the onset and/or severity of acute GVHD in lymphopenic mice not subjected to myeloablative pre-transplant conditioning. The original research article is now published in the journal PLoS ONE. Dr. Andrea Pires dos Santos from Purdue University, Yava Jones-Hall from Texas A&M University, Scot Dowd from MR DNA in Texas contributed to the study.

The research team hypothesized that in the absence of intestinal mucosal barrier disruption, commensal bacteria would play little or no role in the onset and/or severity of acute GVHD. To test their hypothesis, the authors used a mouse model of acute GVHD that does not require pre-transplant conditioning.

The authors found that treating lymphopenic mice with a mix of two non-absorbable, broad spectrum antibiotics (Vancomycin and Neomycin) before and after the adoptive transfer of allogenic CD4⁺ T cells exacerbated T-cell mediated bone marrow failure and spleen hypoplasia. Antibiotic-treated mice exhibited more severe anemia and monocytopenia as well as more extensive reductions in BM- and spleen-residing T cells, myeloid cells and NK cells when compared to untreated mice engrafted with allogeneic T cells. Antibiotic-induced exacerbation of BM and spleen damage correlated with a dramatic reduction in fecal bacterial diversity, marked loss of beneficial anaerobic bacteria and remarkable expansion of potentially pathogenic bacteria.

The authors concluded that continuous administration of antibiotics could worsen acute GVHD-induced tissue damage by reducing the populations of potentially protective, anaerobic bacteria and/or by promoting the expansion of antibiotic-resistant pathogens and pathobionts. Given the reported findings of Professor Matthew Grisham and co-authors, it will be important to identify specific antibiotics that can eradicate detrimental bacteria while retaining beneficial, anaerobic bacteria.