Patients with Treatment-Requiring Chronic Graft versus Host Disease after Allogeneic Stem Cell Transplantation Have Altered Metabolic Profiles due to the Disease and Immunosuppressive Therapy: Potential Implication for Biomarkers

Abstract

Chronic graft versus host disease (cGVHD) is a common long-term complication after allogeneic hematopoietic stem cell transplantation. The objective of our study was to compare the metabolic profiles for allotransplant recipients and thereby identify metabolic characteristics of patients with treatment-requiring cGVHD. The study included 51 consecutive patients (29 men and 22 women; median age: 44 years, range: 15–66 years) transplanted with peripheral blood stem cells derived from human leukocyte antigen-matched family donors. All serum samples investigated by global metabolomic profiling were collected approximately 1 year posttransplant (median 358 days). Thirty-one of the 51 patients (61%) had cGVHD 1 year posttransplant. The affected organs were (number of patients) liver/bile duct (23), eyes (15), gastrointestinal tract (14), skin (13), mouth (10), lungs (3), and urogenital tract (1). We compared the metabolic profile for patients with and without cGVHD, and a Random Forrest Classification Analysis then resulted in 75% accuracy in differentiating the two groups. The 30 top-ranked metabolites from this comparison included increased levels of bile acids, several metabolites from the cytokine-responsive kynurenine pathway for tryptophan degradation, pro-inflammatory lipid metabolites, phenylalanine and tyrosine metabolites derived from the gut microbial flora, and metabolites reflecting increased oxidative stress. However, nine of these 30 top-ranked metabolites were probably altered due to cyclosporine or steroid treatment, and we therefore did a hierarchical clustering analysis including all 51 patients but only based on the other 21 cGVHD-specific metabolites. This analysis identified three patient subsets: one cluster included mainly patients without cGVHD and had generally low metabolite levels; another cluster included mainly patients with cGVHD (most patients with at least three affected organs) and high metabolite levels, and the last intermediate group including cGVHD patients with limited organ involvement. We conclude that allotransplant recipients with cGVHD have an altered metabolic profile caused both by the disease and its immunosuppressive treatment.

Metabolic Reprogramming—A New Era How to Prevent and Treat Graft Versus Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation Has Begun

“…Patients with cGVHD showed a significantly higher levels of phenylacetate, 3-(4-hydroxyphenyl) lactate, phenylalanine, and tyramine o-sulfate in comparison to patients without cGVHD which could result from altered intestinal microbiota or functions. cGVHD patients in the same study also showed higher levels of biomarkers for proteolysis and accelerated protein catabolism, involving N-acetylserine, N-acetylaspartate, N-acetylasparagine, N-acetylglutamate, and 1-methylhistidine (Reikvam et al, 2017).…”

“…A study conducted by Reikvam and his team suggested altered protein metabolism associated with disturbed redox homeostasis in cGVHD patients, and hierarchical clustering analyses for "oxidative stress" metabolites resulted in two main clusters with high frequency of cGVHD patients in subset showing high levels of these metabolites. These metabolites increased in cGVHD patients were gamma-glutamyl amino acids (e.g., gamma-glutamylglutamate, gamma-glutamyltryptophan, gamma-glutamylphenylalanine, and gamma-glutamylthreonine) and their activity that is critical for recycling and regeneration of the antioxidant glutathione and other oxidative stress markers, considering alpha-tocopherol, cysteine sulfonic acid, and methionine sulfoxide, were also seen in cGVHD patients (Reikvam et al, 2017).…”

“…No studies have been conducted on whole tissue to study their metabolomics reprograming during GVHD pathophysiology. Allotransplant recipients with chronic GVHD (cGVHD) showed an altered serum metabolic profile after one year of transplant which was due to the underlying disease and related immunosuppressive treatment (Reikvam et al, 2017).…”

“…Another study reported altered pretransplant amino acid metabolites in plasma of patients which later developed aGVHD. This alteration involved immunoregulatory branched chain amino acids (leucine, isoleucine and valine); and proinflammatory tyrosine metabolites (p-cresol sulfate, 3-phenylpropionate) produced by the gastrointestinal microbial flora (Reikvam et al, 2017). p-Cresol is soaked up from the intestine and detoxified in the liver by conjugation (sulfatation and glucuronidation), producing p-cresylsulfate and p-cresylglucuronide (de Loor et al, 2005) in serum.…”

Enteral Nutrition in Pediatric Patients Undergoing Hematopoietic SCT Promotes the Recovery of Gut Microbiome Homeostasis

“…Interestingly, Wilmanski et al [41] recently found a connection between the eubiotic GM structure and the host blood metabolic profile. This suggests a possible feedback of the eubiotic GM trajectory in HSCT patients also in terms of the blood metabolome, which has been connected with the GvHD risk [42]. At the compositional level, EN-fed subjects recovered a GM structural layout comparable to the one observed before the transplant starting from 30 days post-HSCT, while in PN patients this end point was never achieved.…”