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Abstract: A role for gut bacteria in the pathogenesis of graft-versus-host disease (GVHD) has been firmly established; however, the role of Candida spp, which form part of the mycobiome, remains unknown. In a homogenous group of patients who underwent allogeneic stem cell transplantation (SCT), we found a significant impact of Candida colonization on the occurrence of acute GVHD. Patients colonized with Candida spp developed significantly more grade II-IV acute GVHD compared with noncolonized patients (50% vs 32%; P = .03), as well as more gastrointestinal (GI)-GVHD (33% vs 19%; P = .05). Colonization with Candida spp was more frequent in patients bearing the loss-of-function polymorphism Y238X, which results in dectin-1 dysfunction, compared with patients with the wild-type allele (73% vs 31%; P = .002). There was no direct effect of dectin-1 dysfunction on acute GVHD, although it did influence the occurrence of GVHD indirectly through Candida colonization. The exact mechanism of GVHD induction by Candida spp colonization of the mucosa is unknown, but the link might prove to be the induction of Th 17/IL-23 responses through activation of pattern recognition receptors by fungal motifs, including β-d-glucan and mannans. These data indicate a role for the mycobiome in the pathogenesis of GVHD and suggest that altering the mycobiome by antifungal drugs can help ameliorate GI-GVHD. In addition, given that the genetic constitution of patients affects susceptibility to both Candida colonization and GVHD, whether identifying gene polymorphisms will facilitate personalized treatment of SCT recipients remains to be determined. [Copyright &y& Elsevier]

Abstract: Dectin-1 plays an important role in antifungal immunity. The dectin-1 Y238X polymorphism, which results in decreased Th17 responses, is associated with increased Candida colonization of stem cell transplantation (SCT) recipients. In this study we found no impact of the polymorphism on the incidence of graft-versus-host disease (GvHD), or on disease-free and overall survival in these SCT recipients. However, patients from patient–donor pairs bearing the wild-type allele who where colonized with Candida had a significant increased incidence of acute GvHD compared to non-colonized patients (OR=2.6, P =0.04). The fact that this was not the case in patients from pairs with the Y238X polymorphism (OR=1.2, ns) suggests that despite increased colonization defective dectin-1 signaling might have prevented an impact of Candida colonization on the incidence of acute GvHD to occur. These are the first human data showing a role for Candida in the pathogenesis of acute GvHD. The mechanism could involve C-type lectin receptor mediated Th17 responses. [Copyright &y& Elsevier]