Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2023

Faecal microbiota transfer reduces acute graft-versus-host disease via IgA and mucin secretion in the gastrointestinal tract (#165)

Yashaswini Janardhanan 1 , Kate L Bowerman 2 3 , Rachel D Kuns 1 , Alika D Collinge 1 , Maximillian Lacour 2 3 , Stuart D Olver 1 , Sumaira Z Hasnain 4 , Motoko Koyama 5 , Philip Hugenholtz 2 3 , Geoffrey R Hill 5 6 , Antiopi Varelias 1 7
  1. Transplantation Immunology, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  2. School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, Australia
  3. Australian Centre for Ecogenomics, School of Chemistry and Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia
  4. Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
  5. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  6. Division of Medical Oncology, University of Washington, Seattle, WA, USA
  7. Faculty of Medicine, University of Queensland, St Lucia, QLD, Australia

Acute graft-versus-host disease (aGVHD) limits the success of allogeneic bone marrow transplantation (alloBMT) to treat haematological malignancies and disorders. aGVHD targeting the gastrointestinal (GI)-tract is commonly lethal due to destruction of the barrier integrity. Low diversity in gut microbiota has been shown to be a predictor of GVHD-related mortality in alloBMT. Clinical studies examining the efficacy of faecal microbiota transplantation (FMT) to reconstitute normal microbiota and reduce GVHD are ambiguous, likely reflecting variable products, modes of delivery and patient cohorts. We thus established a murine model of FMT in alloBMT to interrogate predictors of success. This showed that FMT attenuated aGVHD and improved survival. Gut microbial profiling by 16S rRNA sequencing revealed that while FMT did not restore diversity, the post-transplant community differed between FMT and non-FMT mice. Of the mice which displayed a more robust microbiome shift in response to FMT, discrimination between these responders and non-responders was driven by members of the Muribaculaceae, Lachnospiraceae and Deferribacteraceae families. Confocal microscopy of the GI-tract revealed increased IgA deposition and Muc2 expression in responders after FMT, suggesting immunomodulatory bacteria may improve transplant outcome by invoking IgA and mucin secretion to reinstate barrier integrity. To determine whether host-derived IgA was critical in attenuating GVHD, we transplanted polymeric Immunoglobulin receptor (pIgR) deficient mice which lack the ability to transport IgA across epithelia. Compared to wild-type, pIgR-/- recipients displayed increased aGVHD demonstrating protection by host IgA. Interestingly, patients with GVHD remain chronically IgA-deficient, potentially identifying this as a feed forward mechanism maintaining and amplifying gut GVHD. In sum, we identify protective organisms and downstream immunomodulatory benefits of FMT that will serve as a basis for optimization strategies.