Control of GVHD by Probiotics with individual Commensal Bacteria

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Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) can cure a variety of benign and malignant hematopoietic disorders, but graft-versus-host disease (GVHD) remains a significant cause of transplant- related mortality and morbidity. Involvement of the gastrointestinal (GI) tract in the pathogenesis of GVHD has been substantiated by the translation of pre-clinical and clinical studies. The intestinal microbiota consists of a community of diverse microbes that reside in the gut and are critical for the host development, homeostasis, and immune regulation. Emerging evidence suggests that perturbations in the microbiota diversity result in aberrant systemic immune responses as well as pathogen colonization and mucosal invasion, fostering the development of GVHD. A clear rationale exists for targeting the microbiota with the goal to benefit patients after allo-HCT. Several interventional strategies have been explored by means of antibiotics, diet and prebiotics, probiotics, microbial metabolites, and fecal microbial transplantation (FMT). However, the identification of optimal FMT donors and appropriate stool screening for immune compromised patients is of a considerable challenge. Identifying and applying one or more live microorganisms that are safe and effective in improving health of HCT patients are of high merit. In the preliminary studies, we observed that abundance of Barnesiella in gut microbiota was associated with the reduction of GVHD in mice after allo-HCT. Furthermore, administration of a single Barnesiella strain, Barnesiella intestinihominis (BI), was safe and effective in preventing both acute and chronic GVHD in preclinical murine models. Our preliminary studies provide initial support that Barnesiella may be a means of probiotics that could benefit to patients after allo- HCT in the clinic. In fact, BI has been shown to clear of intestinal vancomycin-resistance Enterococcus that positively associates with GVHD severity in patients after allo-HCT. In this proposal, we will extend our exciting preliminary studies by further pursuing two Specific Aims: 1) to define the mechanisms by which BI and its derived metabolites modulate GVHD through maintaining gut homeostasis; 2) to determine the mechanisms by which BI and its derived metabolites modulate GVH/GVL responses through regulating donor T cells. We expect to firmly validate Barnesiella as a safe and efficacious probiotic to prevent and treat GVHD without compromising the GVL effect. Furthermore, we expect to understand the cellular and molecular mechanisms by which Barnesiella regulates microbiota, adaptive immunity, and intestinal barrier functions. If the proposed studies are successfully executed as expected, we will provide a compelling rationale that Barnesiella probiotics can be a therapeutic approach that benefits to patients after allo-HCT.