aGvHD

Gut microbiota dynamics in relation to the development of aGvHD in pediatric patients following allogeneic hematopoietic cell transplantation

Gut microbiota (GM) composition has been correlated with the onset of acute graft-versus-host disease (aGvHD), however, experimental observations are still few, mainly involving cohorts of adult patients. In the current scenario where fecal microbiota transplantation has been used as a pioneer therapeutic approach to treat steroid-refractory aGvHD, there is an urgent need to expand existing observational studies of the GM dynamics in hematopoietic stem cell transplantation (HSCT).

Allogeneic HSCT (allo-HSCT) is a therapeutic option for many patients with high-risk hematopoietic malignancies and hematological disorders. However, the success of the procedure is often hindered by a process in which donor-derived T cells recognize host healthy tissue as non-self, causing an immune-mediated complication which are instrumental in determining ill health and mortality of patients. An association between aGvHD and the GM has long been hypothesized2,3 due to the ever-increasing evidence of the involvement of the GM in the regulation of the human immune system functionality.4

Elena Biagi from the University of Bologna, Italy, and colleagues, published findings in the journal BMC Medical Genomics on a study exploring the GM trajectory in 36 pediatric HSCT recipients in relation to aGvHD onset.1

Patients and methods

  • N = 36 (male n = 20, female n = 16)
  • Stools were collected at three-timepoints: before HSCT, at time of engraftment and > 30 days following HSCT
  • Protocol was approved by the University of Bologna Ethics Committee (ref. number 19/2013/U/Tess)
  • Changes in the GM phylogenetic structure were studied by 16S rRNA gene Illumina sequencing and phylogenetic assignation
  • Inclusion criterion was the availability of a pre-HSCT fecal sample and of at least two samples collected after HSCT
  • 5 out of 36 patients received intravenous levofloxacin5 to the complete neutrophil recovery
  • All patients observed complete fasting beginning from the onset of oral mucositis or diarrhea with the administration of parenteral nutrition until the day of engraftment
  • Conditioning regimen: n = 32 patients received a myeloablative busulfan (or treosulfan)-based conditioning regimen, n = 3 patients received total body irradiation-based conditioning regimen, and n = 1 patient received a non-myeloablative preparative regimen with cyclophosphamide/fludarabine
  • Antiviral and antifungal prophylaxis was administered from day −1 and +2 respectively
  • Antibiotic empiric therapy, with piperacillin/tazobactam or ceftazidime, was given in case of neutropenic fever in 29/36 cases
  • N = 7 cases received antibiotic therapy at the beginning of the neutropenic phase independently from the onset of fever, and n = 4 cases received a cephazolin/piperacillin tazobactam-based anti-streptococcal prophylaxis before the engraftment phase

Dr. Biagi and her team presented a longitudinal observation of microbiota dynamics in pediatric patients undergoing HSCT for a variety of hematological diseases. Despite the complexity of the study in terms of possible confounding variables (i.e. chemotherapy, antibiotics, proton-pump inhibitors, and hospitalization), it was possible to detect a signature of the future development of aGvHD in the GM composition before HSCT.

The researchers indicated that children developing gut aGvHD had a dysbiotic GM layout before HSCT occurred. This assumed aGvHD predisposing ecosystem state was characterized by firstly a reduced diversity, and secondly, the team identified a lower Blautia content, as well as an increase in Fusobacterium abundance. Dr. Biagi and her team found a specific GM signature before HSCT predictive of subsequent gut aGvHD occurrence. The data may open the way to a GM-based stratification of the risk of developing aGvHD in children undergoing HSCT, potentially useful also to identify patients benefiting from prophylactic fecal transplantation.

References

  1. Biagi Eet al. Early gut microbiota signature of aGvHD in children given allogeneic hematopoietic cell transplantation for hematological disorders. BMC medical genomics. 2019 Dec;12(1):49. DOI: 10.1186/s12920-019-0494-7
  2. Murphy Set al. Role of gut microbiota in graft-versus-host disease. Leuk Lymphoma. 2011;52:1844–56. DOI: 10.3109/10428194.2011.580476
  3. Zeiser R. et al. Pathogenesis of acute graft-versus-host disease: from intestinal microbiota alterations to donor T cell activation. Br J Haematol. 2016;175:191–207. DOI: 10.1111/bjh.14295
  4. Round J.L. et al. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;9:313–23. DOI: 1038/nri2515
  5. Bucaneve Get al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005; 353:977–87. DOI:10.1056/NEJMoa044097
  6. Simms-Waldrip T.R. et al. Antibiotic-induced depletion of anti-inflammatory clostridia is associated with the development of graft-versus-host disease in pediatric stem cell transplantation patients. Biol Blood Marrow Transplant. 2017;23:820–9. DOI:1016/j.bbmt.2017.02.004
  7. Ríos-Covián D. et al. Intestinal short-chain fatty acids and their link with diet and human health. Front Microbiol. 2016;7:185. DOI: 3389/fmicb.2016.00185
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