Gut Inflammation, the Microbiome and Tryptophan/Serotonin Metabolism during Bone Marrow Transplant Article Swipe

Background: Tryptophan is an essential amino acid, necessary for protein synthesis. Tryptophan can be metabolized down one of two pathways to produce serotonin (5-HT) or kynurenine, and the relative activity of the two pathways is driven by interactions with microbiota (Figure 1). Serotonin exists in two largely separate compartments, central and peripheral. Ninety percent of peripheral serotonin comes from metabolism of tryptophan in the gut and influences platelet activation, gluconeogenesis, intestinal motility and immunity. We hypothesized that loss of diversity of the microbiome during transplant might dysregulate tryptophan metabolism and worsen gut inflammation. Methods: We collected serum, urine and fecal samples at baseline and day 14 for 40 patients who received allogeneic HSCT. Metabolite quantification was performed by NMR. Serotonin levels in serum and fecal specimens of the same cohort, plus an additional 18 patients with Fanconi Anemia (FA), were measured using a Serotonin ELISA kit from Enzo Life Sciences. Results: Tryptophan increased in stool (P = .0069) and urine (P = .0001) during transplant in our initial cohort of 40 patients (Figure 2). Similarly, serum serotonin (normal range 50-220 ng/mL) increased from baseline to day 14 (249.5 ng/mL v. 355.9 ng/mL, P = .3858). Risk factor analysis revealed the highest elevations in serum serotonin were in FA patients. We analyzed 18 additional FA patients and found baseline serum serotonin similar to non-FA patients. A nearly 10-fold increase in serum serotonin is seen by day 14 in FA patients (mean 2669.3 ng/mL, P < .0001) (Figure 3). We then tested serum serotonin levels in 7 patients who received the same t-cell depleted grafts as FA patients, but did not have FA, and did not see an increase at day 14. Stool serotonin decreased during transplant in non-FA (474.7 ng/mL v. 222.3 ng/mL, P = .0005) and FA patients (347.5 ng/mL v. 104.1 ng/mL, P = .0008). Similarly, serum kynurenine also decreased during BMT in both non-FA (P = .006) and FA patients (P = .081).Figure 3Patients with Fanconi Anemia (n = 24, orange) display a marked increase in serum serotonin (P < .0001) during transplant. Patients without FA (n = 35, blue) demonstrate a decrease in serum serotonin during transplant (P = .0024). Note logarithmic scale.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusions: Serotonin decreases after transplant in a majority of patients, and may alter gastric motility, worsen gut inflammation and impair immunity. Unexpectedly, we found a marked increase in serum serotonin that appears specific for FA patients, suggesting a differential response to stress. Children with FA commonly have a low BMI, which may reflect chronic elevation of peripheral serotonin, known to reduce appetite and impact gluconeogenesis.