Role of DUOX2 in shaping the intestinal microbiota and effects on inflammation, cancer and metabolic disease

• Applicant: Privatdozent Felix Sommer, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432682190

The intestinal microbiota contributes to several aspects of host physiology, e.g. by providing nutrients from the diet, but also poses a potential infection danger. Reactive oxygen species (ROS) have antibiotic properties and therefore eukaryotes employ ROS as protective component of innate immunity. However, excessive ROS-production can also damage host tissues. The main ROS producing enzymes belong to the NADPH oxidase (NOX) family and within the intestine Duox2 is the most highly expressed member of the NOX family. Intestinal epithelial cells (IECs) express DUOX2 and pathogenic infection, but also the normal microbiota elevate Duox2 expression. Due to its potential antimicrobial effects, here we aim to investigate whether DUOX2 shapes the intestinal microbiota and thereby affects intestinal inflammation or metabolism. To this end, we will employ our recently generated IEC-DUOX2 mice, which lack DUOX2 specifically in IECs. In preliminary experiments, we found that under basal conditions loss of DUOX2-produced ROS alters the microbiota, for example enriching for the anti-inflammatory commensal Akkermansia muciniphila or reducing several Bacteroidetes taxa associated with energy extraction. Furthermore, we will test whether the altered microbiota in IEC-DUOX2 mice confers differential disease susceptibility under inflammatory or dietary challenge. Finally, we will investigate which microbial factors induce DUOX2 in IECs. These experiments combine classical techniques including expression analysis and conditional gene knockout with state-of-the-art methodology such as culture-independent microbial profiling and metagenomics in the mouse model. Together, this project promises to yield important insights into host-microbiota interactions that might be used to develop novel therapeutic strategies to treat chronic inflammation, cancer and metabolic diseases.

• DFG Programme: Research Grants