**Background:** Lysophosphatidic acid (LPA) is a bioactive lipid that promotes atherosclerosis and inflammation. Autotaxin, encoded by the Enpp2 gene, converts lysophosphatidylcholine (LPC) to LPA. Previous work showed that a Western diet (WD) increases unsaturated LPA in the small intestine, which correlates with atherosclerosis. Oxidized phospholipids (OxPLs) in the intestine disrupt the mucus layer, increasing lipopolysaccharide (LPS) levels and systemic inflammation. This study aimed to determine the role of enterocyte-derived autotaxin in WD-induced dyslipidemia, systemic inflammation, and atherosclerosis.
**Methods:** The authors generated Ldlr-/- mice with an intestinal-specific knockout of Enpp2 (iKO) and compared them to control Ldlr-/- mice (Cont.). Mice were fed either a chow diet or a WD for 2 weeks or 5 months. Measurements included: enterocyte Enpp2 expression and autotaxin protein levels; LPA species in enterocytes and plasma; OxPLs in jejunum mucus; gene expression of 19 antimicrobial peptides/proteins; protein levels of key regulators (ATOH1, GFI1, interleukins, lysozyme, MUC2, NOTCH2, DLL4, APOA-I, LBP); LPS levels in mucus and plasma; plasma lipids (total cholesterol, triglycerides, apoA-I); inflammatory markers (IL-6, SAA); and aortic atherosclerosis (en face lesion area, aortic root Oil Red O staining, CD68 macrophage area). Ex vivo experiments tested the effect of OxPLs and the 6F peptide on Enpp2 expression.
**Key Results:** After 2 weeks on WD, enterocyte Enpp2 expression increased in Cont. mice but was markedly reduced in iKO mice (Fig. 1A). Autotaxin protein increased on WD in Cont. but not iKO mice (Fig. 1C). Ex vivo, OxPLs induced Enpp2 expression, which was blocked by the 6F peptide (Supplemental Fig. S4). In enterocytes, WD increased LPA 16:0, 18:1, and 18:2 in Cont. mice; in iKO mice, LPA 16:0 and 18:2 did not increase, and LPA 18:1 increased less (Fig. 2). OxPLs in jejunum mucus increased on WD in Cont. mice but not in iKO mice (Fig. 3). Gene expression of 15 out of 17 antimicrobial peptides/proteins decreased on WD in Cont. mice; iKO mice showed less decrease (Fig. 4A, Supplemental Table S3). Two genes (Lbp, Spp1) increased on WD in Cont. but not iKO mice (Fig. 4B). Protein levels of ATOH1, GFI1, IL-36γ, IL-23, IL-22, MUC2, NOTCH2, and DLL4 were better preserved in iKO mice on WD (Figs. 5-7). Lysozyme and APOA-I decreased similarly in both genotypes (Figs. 6D, 7C). LPS in jejunum mucus increased on WD but much less in iKO mice (Fig. 8). Plasma total cholesterol and triglycerides increased less in iKO mice on WD (Fig. 9A, B). Plasma apoA-I decreased less in iKO mice (Fig. 9C). Plasma LPA levels showed no genotype difference at 2 weeks (Fig. 10), but after 5 months, iKO mice on WD had lower LPA 18:1 and 18:2 (Supplemental Fig. S8). Plasma LBP, LPS, IL-6, and SAA were lower in iKO mice on WD (Figs. 11, 12). After 5 months, iKO mice had significantly less aortic atherosclerosis: percent of aorta with lesions (Fig. 13A), aortic root Oil Red O area (Fig. 13B), and CD68+ macrophage area (Fig. 13C). Plasma LPS levels correlated with atherosclerosis (Supplemental Fig. S9).
**Clinical Implications:** This study demonstrates that enterocyte-derived autotaxin and locally produced LPA are critical mediators of Western diet-induced gut barrier dysfunction, systemic inflammation, and atherosclerosis. Targeting intestinal autotaxin or its downstream LPA signaling could represent a novel therapeutic approach to reduce diet-induced cardiovascular risk. The findings also highlight the importance of the gut-vascular axis in atherosclerosis and suggest that interventions aimed at preserving intestinal antimicrobial defenses may have systemic benefits.