GSE204719
Gut microbiome generated Phenylacetylglutamine from dietary phenylalanine is associated with Crohn's Disease and exacerbates colitis in mouse model possibly via platelet activation
Objectives: To better understand the interplay of diet and gut microbiota in Crohn's disease (CD), taking advantage of a newly-onset treatment naïve CD cohort. We focus on phenylacetylglutamine (PAGln), a diet-derived meta-organismal prothrombotic metabolite.  Design: We collected fecal and serum samples prior to treatment in a newly-onset CD cohort (n=262). Plasma PAGln was quantified using LC-MS/MS. Platelet count and mean platelet volume were determined. Diet was assessed using food-frequency questionnaires. Human platelet rich plasma (n=5-6) was primed with PAGln, P-selectin and CD40L expression were determined after exposure to platelet agonists. Dextran sodium sulfate (DSS)-induced colitis mice (C57BL/6) were given phenylacetylglycine (PAGly, the mouse-prevalent metabolite) or saline, colitis severity and colonic tissue gene expression were examined. Mice (C57BL/6) were given isocaloric high protein and low protein diet for 18 days, followed by DSS administration in water. Plasma PAGly was quantified and colitis severity was examined. Bioinformatic analysis and bacterial culturing were performed to identify the main contributor of PAGln in CD.  Results: Phenylacetylglutamine (PAGln), a meta-organismal prothrombotic metabolite, is associated with CD. PAGln enhanced platelet activation and CD40L expression in platelet rich plasma ex vivo. Administration of PAGly exacerbated colitis in mouse model and upregulated coagulation-related biological processes. Further study revealed that high dietary protein intake and increased abundance of phenylacetic acid (PAA)-producing Proteobacteria mediated by phenylpyruvate decarboxylase act in concert to cause the elevated PAGln levels in CD patients.  Conclusion: Taken together, these results suggest that PAGln is a potential early diagnostic marker and therapeutic target of CD. Overall design: Dextran sodium sulfate (DSS)-induced colitis mice (C57BL/6) were given phenylacetylglycine (PAGly, the mouse-prevalent metabolite) or saline for 9 days. Colonic tissue was collected and sequenced.