title: Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome.
abstract: Indole, which is produced from l-tryptophan by commensal bacteria expressing tryptophanase, not only is an important intercellular signal in microbial communities, but also modulates mucosal barrier function and expression of pro- and anti-inflammatory genes by intestinal epithelial cells. Here, we hypothesized that decreased urinary excretion of 3-indoxyl sulfate (3-IS), the major conjugate of indole found in humans, may be a marker of gut microbiota disruption and increased risk of developing gastrointestinal (GI) graft-versus-host-disease. Using liquid chromatography/tandem mass spectrometry, 3-IS was determined in urine specimens collected weekly within the first 28 days after allogeneic stem cell transplantation (ASCT) in 131 patients. Low 3-IS levels within the first 10 days after ASCT were associated with significantly higher transplant-related mortality (P = .017) and worse overall survival (P = .05) 1 year after ASCT. Least absolute shrinkage and selection operator regression models trained on log-normalized counts of 763 operational taxonomic units derived from next-generation sequencing of the hypervariable V3 region of the 16S ribosomal RNA gene showed members of the families of Lachnospiraceae and Ruminococcaceae of the class of Clostridia to be associated with high urinary 3-IS levels, whereas members of the class of Bacilli were associated with low 3-IS levels. Risk factors of early suppression of 3-IS levels were the type of GI decontamination (P = .01), early onset of antibiotic treatment (P = .001), and recipient NOD2/CARD15 genotype (P = .04). In conclusion, our findings underscore the relevance of microbiota-derived indole and metabolites thereof in mucosal integrity and protection from inflammation.
authors.affiliation: Department of Hematology and Oncology, Internal Medicine III, University Medical Center, Regensburg, Germany;
authors.forename: Daniela
authors.initials: D
authors.lastname: Weber
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Regensburg, Germany;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.affiliation: Institute of Clinical Microbiology and Hygiene and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hiergeist
authors.affiliation: Institute of Clinical Microbiology and Hygiene and.
authors.forename: Josef
authors.initials: J
authors.lastname: Koestler
authors.affiliation: Institute of Clinical Microbiology and Hygiene and.
authors.forename: André
authors.initials: A
authors.lastname: Gessner
authors.affiliation: Department of Orthopedic Surgery, University Medical Center, Regensburg, Germany; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Weber
authors.affiliation: Department of Hematology and Oncology, Internal Medicine III, University Medical Center, Regensburg, Germany;
authors.forename: Joachim
authors.initials: J
authors.lastname: Hahn
authors.affiliation: Department of Hematology and Oncology, Internal Medicine III, University Medical Center, Regensburg, Germany;
authors.forename: Daniel
authors.initials: D
authors.lastname: Wolff
authors.affiliation: Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Stämmler
authors.affiliation: Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spang
authors.affiliation: Department of Hematology and Oncology, Internal Medicine III, University Medical Center, Regensburg, Germany;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Herr
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Regensburg, Germany;
authors.forename: Katja
authors.initials: K
authors.lastname: Dettmer
authors.affiliation: Department of Hematology and Oncology, Internal Medicine III, University Medical Center, Regensburg, Germany;
authors.forename: Ernst
authors.initials: E
authors.lastname: Holler
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D056148:Chromatography, Reverse-Phase; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D005838:Genotype; D006086:Graft vs Host Disease / Q000235:genetics / Q000382:microbiology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007200:Indican / Q000652:urine*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D016016:Proportional Hazards Models; D011446:Prospective Studies; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D007200:Indican