Abstract
Microbiota can exert immunomodulatory effects by short-chain fatty acids (SCFA) in experimental models of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-SCT). Therefore we aimed to analyze the expression of SCFAs sensing G-protein coupled receptor GPR109A and GPR43 by quantitative PCR in 338 gastrointestinal (GI) biopsies obtained from 199 adult patients undergoing allo-SCT and assessed the interaction of GPR with FOXP3 expression and regulatory T cell infiltrates. GPR expression was strongly upregulated in patients with stage II-IV GvHD (p=0.000 for GPR109A, p=0.01 for GPR43) and at the onset of GvHD (p 0.000 for GPR109A, p=0.006 for GPR43) and correlated strongly with FOXP3 and NLRP3 expression. The use of broad-spectrum antibiotics (Abx) drastically suppressed GPR expression as well as FOXP3 expression in patients’ gut biopsies (p=0.000 for GPRs, FOXP3 mRNA and FOXP3+ cellular infiltrates). Logistic regression analysis revealed treatment with Abx as an independent factor associated with GPR and FOXP3 loss. The upregulation of GPRs was evident only in the absence of Abx (p=0.001 for GPR109A, p=0.014 for GPR43) at GvHD onset. Thus, GPR expression seems to be upregulated in the presence of commensal bacteria and associates with infiltration of FOXP3+ T regs, suggesting a protective, regenerative immunomodulatory response. However, Abx, which has been shown to induce dysbiosis, interferes with this protective response.
Highlights
Acute Graft versus host disease is the major cause of transplant-related mortality (TRM) and morbidity following allogeneic stem cell transplantation (SCT)
G-protein coupled receptor (GPR) Expression Correlates With the Severity and Onset of GI-Acute Graft versus host disease (aGvHD)
When we assigned unbiasedly selected serial biopsies based on the determined histological Lerner stage to either aGvHD 0-1 or aGvHD 2-4, we found that patients with higher Lerner stages showed increased GPR expression (Figures 1A, B; p=0.000015 for GPR109A, p=0.008 for GPR43)
Summary
Acute Graft versus host disease (aGvHD) is the major cause of transplant-related mortality (TRM) and morbidity following allogeneic stem cell transplantation (SCT). Preclinical and clinical studies introduced prophylactic use of decontamination as an approach to reduce GvHD [3] and together with the concept of prevention of neutropenic gram-negative infections, antibiotic prophylaxis has become standard of care [4] With the introduction of next-generation sequencing technologies including 16s rRNA, it became evident that the intestinal microbiota is an important modulator of aGvHD. Since 2012, several studies using this technique in experimental [5] and clinical settings [6, 7] reported a strong loss of commensal bacteria (dysbiosis) but no complete decontamination and an association of dysbiosis with the occurrence of GI aGvHD as well as several severe infectious complications following allogeneic SCT. Recent reports suggested that even the reconstitution of commensal bacteria by fecal microbiota transfer (FMT) contributes favorably to the treatment of patients (pts) with steroid-refractory aGvHD [10,11,12]
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