Immune modulatory mechanisms of Oncostenum bojerianum extracts during Clostridium difficile infection in mice

Activation of peroxisome proliferator-activated receptor (PPAR) γ has proven beneficial for the treatment of several inflammatory diseases. However, current drugs targeting PPAR result in significant adverse side effects. Therefore, the development of novel and safer anti-inflammatory therapies is important. This project aimed to discover new natural constituents from ethnomedicinal plants that target PPARγ and to systematically elucidate the mechanisms of action underlying their anti-inflammatory activities. From a screen of 200 plant extracts, we identified more than 50 that activate PPARγ, with a high predominance in Oncostenum species. The anti-inflammatory properties of two O. bojerianum extracts were further tested in a mouse model of Clostridium difficile infection, which resulted in a detectable improvement in disease activity, weight loss, colonic inflammatory lesions, and increased levels of colonic IL-10-producing CD4+ T cells. Oral treatment with Oncostemum extracts increased PPARγ and PPARa activity and elevated transcriptional expression of their responsive genes. Bioassay-guided fractionation studies in combination with in silico molecular screening, identified the resorcinol family as the PPARγ-activating compounds contained in the extracts. Characterizing the modulation of cellular and molecular signatures by resorcinols at the sites of inflammation will translate natural products discovery into the development of safer and more efficacious host-targeted immune therapeutics for infectious and immune-mediated diseases.