| Summary: | Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family. Inhibition of DPP9 has recently been shown to activate the nucleotide-binding domain leucine-rich repeat 1 (NLRP1) inflammasome. NLRP1 is known to bind nucleic acids with high affinity and directly interact with double stranded RNA, which plays a key role in viral replication. <i>DPP9</i> has also recently emerged as a key gene related to lung-inflammation in critical SARS-CoV-2 infection. Importantly, DPP9 activity is strongly dependent on the oxidative status. Here, we explored the potential role of <i>DPP9</i> in the gastrointestinal tract. We performed transcriptomics analyses of colon (microarray, <i>n</i> = 37) and jejunal (RNA sequencing, <i>n</i> = 31) biopsies from two independent cohorts as well as plasma metabolomics analyses in two independent cohorts (<i>n</i> = 37 and <i>n</i> = 795). The expression of <i>DPP9</i> in the jejunum, colon, and blood was significantly associated with circulating biomarkers of oxidative stress (uric acid, bilirubin). It was also associated positively with the expression of transcription factors (<i>NRF-2</i>) and genes (<i>SOD</i>, <i>CAT</i>, <i>GPX</i>) encoding for antioxidant enzymes, but negatively with that of genes (<i>XDH</i>, <i>NOX</i>) and transcription factors (<i>NF-KB</i>) involved in ROS-generating enzymes. Gene co-expression patterns associated with <i>DPP9</i> identified several genes participating in antiviral pathways in both tissues. Notably, <i>DPP9</i> expression in the colon and plasma was strongly positively associated with several circulating nucleotide catabolites (hypoxanthine, uric acid, 3-ureidopropionic acid) with important roles in the generation of ROS and viral infection, as well as other metabolites related to oxidative stress (Resolvin D1, glutamate-containing dipeptides). Gene-drug enrichment analyses identified artenimol, puromycin, anisomycin, 3-phenyllactic acid, and linezolid as the most promising drugs targeting these <i>DPP9</i>-associated genes. We have identified a novel potential pathogenic mechanism of viral infection in the digestive tract and promising existing drugs that can be repositioned against viral infection.
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