Intestinal permeability of stem cell transplant patients correlates with systemic acute phase responses and dysbiosis.

Intestinal permeability may correlate with adverse outcomes during hematopoietic stem cell transplantation (HSCT), but longitudinal quantification with traditional oral mannitol and lactulose is not feasible in HSCT recipients due to mucositis and diarrhea. A modified lactulose:rhamnose (LR) assay is validated in children with environmental enteritis. Our study objective was to quantify peri-HSCT intestinal permeability changes using the modified LR assay. The LR assay was administered pretransplant, Day+7 and +30 to 80 pediatric and young adult allogeneic HSCT patients. Lactulose and rhamnose were detected by urine mass spectrometry and expressed as an L:R ratio. Metagenomic shotgun sequencing of stool for microbiome analyses and ELISA analyses of plasma lipopolysaccharide binding protein (LBP), ST2, REG3α, claudin1, occludin, and intestinal alkaline phosphatase were performed at the same timepoints. L:R ratios were increased at Day+7 but returned to baseline at Day+30 in most patients (p=0.014). Conditioning regimen intensity did not affect the trajectory of L:R (p=0.39). Baseline L:R ratios did not vary by diagnosis. L:R correlated with LBP levels (r2= 0.208, p=0.0014). High L:R ratios were associated with lower microbiome diversity (p=0.035), loss of anaerobic organisms (p=0.020) and higher plasma LBP (p=0.0014). No adverse gastrointestinal effects occurred due to LR. Intestinal permeability as measured by L:R ratios after allogeneic HSCT correlates with intestinal dysbiosis and elevated plasma LBP. The lactulose/rhamnose assay is well-tolerated and may identify transplant recipients more likely to experience adverse outcomes.