Microbiota metabolite phenlyacetylglycine alleviates acute graft-versus-host diseases

Abstract Introduction Acute graft-versus-host diseases (aGVHDs) is one of the most important complications after allogenic hematopoietic stem cell transplantation (allo-HSCT), which significantly reduces the overall survival and lower the quality of life of patients. Gut microbiota and their metabolites have been reported to deeply influence aGVHD occurrence and progression. Thus, our research focuses on the mechanism how gut microbiota-derived phenlyacetylglycine (PAGly) plays a protective role against aGVHD, aiming to explore the novel target for aGVHD treatment. Methods We identified key gut microbiota and its metabolites respectively via metagenomic sequencing and liquid chromatography-mass spectrometry based on haploidentical (haplo)-HSCT aGVHD models. Subsequently, flow cytometry, immunofluorescence and gene knockout mice were used to explore the mechanisms how microbiota-derived metabolite PAGly impacts on aGVHD. Results Haplo-HSCT aGVHD mice exhibited a distinguished gut microbiota profiling with non-aGVHD mice. Especially, Ligilactobacilus and Bacteroides remarkably increased in aGVHD mice with the decline of Parabacteroides and Akkermansia. Moreover, PAGly, an important metabolite involving phenylalanine metabolism, was significantly decreased. Consistently, the decrease of PAGly was also observed in aGVHD patients from our center. After the supplementary of PAGly, the survival of aGVHD mice was strikingly improved with the mitigation of aGVHD-induced ileum and colon injuries. Further, PAGly treated aGVHD mice exhibited the decreased proportion of Th1 cells and CD8+ T cells in intestinal lamina propria. Simultaneously, PAGly acts as a vital role in maintaining the intestinal permeability via the upregulation of claudin1 and occludin. PAGly also downregulated the expression of MHC-II molecules in intestinal epithelium, which helped epithelial cells to avoid the attack of donor T cells. The knockout of β2-adrenergic receptors (ADRb2) both in donor T cells and recipient intestinal epithelium caused the loss of PAGly protective roles. Conclusions Gut microbiota-derived metabolite PAGly protects intestine from aGVHD-induced damage via attenuating intestinal inflammation and maintaining intestinal barrier integrity through the ADRb2 signaling.