Investigation of microbiome-host interactions in intestinal graft-versus-host disease as a clinical relevant condition of microbially triggered immune system modulation.
Hematology, Oncology
Immunology
Final Report Abstract
The healthy gut is inhabited by a diverse community of mostly anaerobic bacteria, and a hallmark of dysbiosis observed in many diseases is the expansion of facultative anaerobes. Enterococci are facultative anaerobes that colonize the intestines of almost every species from insects to mammals comprising < 0.1% of the core gut microbiota in healthy humans. However, the species “E. faecium” and “faecalis are an emerging cause of nosocomial multidrug-resistant infections. This is relevant to immunocompromised patients such as recipients of allo-HCT, a curative-intent therapy for hematological malignancies. Patients with severe GVHD after allo-HCT have poor outcomes with only ~30% long-term survival. Gut microbiota perturbation such as exposure to broad-spectrum antibiotics and a reduction in microbial diversity have been associated with increased transplant-related mortality and lethal GVHD in humans and mice. Enterococci play important roles beyond severe infections. Experiments in gnotobiotic mice revealed that enterococci can exacerbate colitis by stimulating gut dendritic cells and eliciting IFNg immune responses. In the present project, we investigated the expansion of enterococci as a marker of microbiota injury after allo-HCT in several, international patient cohorts and also preclinical models. We observed a high incidence of E. faecium expansion in patients who receive allogeneic hematopoietic-cell-transplantation (allo-HCT) at MSKCC, Duke University, Hokkaido University, Regensburg and Frankfurt University Clinics, which was found to be associated with graft-versus-host disease (GVHD) and increased mortality. Enterococci also expand in mouse intestines after allo-HCT, and exacerbates disease severity in gnotobiotic models. Enterococci expansion in vitro was dependent on lactose, and dietary lactose depletion in mice attenuated its outgrowth and reduced GVHD severity. Allo-HCT patients bearing a lactosenon-absorber genotype were less capable to clear post-antibiotic Enterococcus domination. In the present project, we identified a mechanism in which lactose as a common nutrient can stimulate the expansion of an opportunistic bacterium to exacerbate inflammation.
Publications
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The role of the intestinal microbiota in GvHD. Hematology Education: the education program for the annual congress of the European Hematology Association, 2017; 11(1) 7
Stein-Thoeringer CK, van den Brink MRM
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Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice. Cell Host Microbe. 2018 Apr 11;23(4):447-457
Staffas A, Burgos da Silva M, Slingerland AE, Lazrak A, Bare CJ, Holman CD, Docampo MD, Shono Y, Durham B, Pickard AJ, Cross JR, Stein-Thoeringer CK, Velardi E, Tsai JJ, Jahn L, Jay H, Lieberman S, Smith OM, Pamer EG, Peled JU, Cohen DE, Jenq RR, van den Brink MRM
