Abstract

The upstream regulators that initiate early transcriptional responses to intestinal stress remain poorly defined. Here, we used germ-free wild-type, Lao1-knockout (LAO1KO), and Lao1/Il4i1 double-knockout (DKO) mice to determine how two L-amino acid oxidases shape acute transcriptional responses to dextran sulfate sodium (DSS). RNA-sequencing performed 24 h after DSS exposure revealed that Lao1 accounted for 80.1% of DSS-induced transcriptional changes, while Il4i1 contributed an additional 14.7%, collectively accounting for 94.8% of the total response. Pathway analysis revealed that Lao1 was required for inducing oxidative phosphorylation (OXPHOS), ATP synthesis, and RNA splicing, while also driving the suppression of nuclear transport and protein localization pathways. At baseline, Lao1 regulated dicarboxylic acid, folic acid, and pteridine metabolism. In contrast, Il4i1 showed minimal baseline activity but was specifically required during DSS exposure to induce lipid metabolism genes and restrain protein homeostasis responses. These findings identify Lao1 as a primary metabolic regulator of early intestinal stress responses, with Il4i1 providing additional stress-specific control. Together, these enzymes link amino acid oxidation to mitochondrial transcriptional programs during intestinal injury.