Presented by: Jianan Zhang
Colon inflammation and colitis-induced colon tumorigenesis show a gradually increasing incidence with patient age. Due to the complicated genetic and environmental factors involved, however, there are currently no targeted therapeutic approaches available to reduce colon inflammation. Furthermore, the molecular mechanisms involved in how gut microbiota influence colon inflammation are poorly understood. Here we report that microbial β-glucuronidase (GUS) enzymes act as a therapeutic target to reduce colon inflammation in mice. We find that pharmacological inhibition of microbial GUS enzyme using UNC 10201652 abolishes dextran sodium sulfate (DSS)-induced colon inflammation in a dose-dependent manner. Inhibitor-treated mice show increased the colon length, decreased infiltration of immune cells (CD45+ cells, CD45+F4/80+ cells and CD45+ Gr1+ cells), decreased the inflammatory gene expression (Tnf- α, Il-6, Il-17, Il-23 and Tlr-4), and increased tight junction gene expression (Muc3 and Occludin) in colon. Furthermore, 16S rRNA sequencing reveals that inhibition of GUS altered the alpha diversity and the dysbiotic composition of gut microbiota caused by DSS, with changes in the abundance of Actinobacteria, Proteobacteria, Bacteroidetes and Firmicutes taxa. Overall, these results support the conclusion that microbial GUS enzymes could be a potential therapeutic target for the prevention and/or treatment of colon inflammation.
Funded by NIH grants GM135218 and GM137286 (MRR).
Funded by interdisciplinary faculty research award from the University of Massachusetts
Amherst, USDA NIFA 2019-67017-29248 and 2020-67017-30844, and USDA/ Hatch MAS00556