Isoallolithocholic acid ameliorates intestinal inflammation via metabolically reprogrammed macrophages

The bile acid isoallolithocholic acid (isoalloLCA) has been observed to be reduced in patients with inflammatory bowel diseases (IBD). However, its role in the pathogenesis of pediatric IBD remains poorly understood. Here we show evidence that isoalloLCA treatment decreases lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production in blood cells from children diagnosed with IBD. In experimental models of IBD, isoalloLCA alleviates acute intestinal inflammation caused by LPS or dextran sulfate sodium (DSS) and shows therapeutic efficacy in a chronic colitis model using Il10 knockout (Il10^-/-) mice. Within the mucosa of these murine models, isoalloLCA enhances the expression of the regulatory T cell transcription factor Forkhead box P3 (Foxp3), while simultaneously inhibiting ETS2, a critical regulator of inflammatory macrophages in IBD. In bone marrow-derived macrophages (BMDMs), isoalloLCA mitigates LPS-induced inflammation, potentially through the enhancement of mitochondrial reactive oxygen species (mitoROS) production and inhibition of the ETS2-HIF1A/PFKFB3 signaling pathway. Simultaneously, isoalloLCA metabolically reprograms macrophages by enhancing oxidative phosphorylation (OXPHOS) that is linked to anti-inflammatory effects. Our research indicates that metabolic modulation of macrophages amplifies the anti-inflammatory properties of isoalloLCA, thereby revealing a promising therapeutic avenue for addressing pediatric IBD.