The Protective Role of Intestinal Alkaline Phosphatase in Inflammatory Bowel Disease-Associated Non-Alcoholic Fatty Liver Disease

Liu, Y.; Lv, H.; Zhang, H.; Yu, S.; Cao, G.

doi:10.1101/2025.02.11.637679

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bioRxiv · 10.1101/2025.02.11.637679

The Protective Role of Intestinal Alkaline Phosphatase in Inflammatory Bowel Disease-Associated Non-Alcoholic Fatty Liver Disease

Liu, Y.·Lv, H.·Zhang, H.·Yu, S.·Cao, G.

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Abstract

BackgroundInflammatory bowel disease (IBD) is a chronic and progressive inflammatory condition characterized by weight loss as a prominent feature. Non-alcoholic fatty liver disease (NAFLD), typically linked to obesity and metabolic dysregulation, is increasingly recognized as being influenced by the gut-liver axis. Notably, IBD patients exhibit a heightened susceptibility to NAFLD, although the underlying mechanisms remain poorly understood. Intestinal alkaline phosphatase (IAP), an endogenous enzyme, plays a critical role in preventing intestinal bacterial translocation. We hypothesized that IAP may serve as a potential therapeutic agent for mitigating IBD-associated NAFLD. MethodsAn IBD model was established using three cycles of 2% dextran sulfate sodium (DSS) administration. Mice were subsequently treated with L-phenylalanine or IAP. The activity of stool IAP, gut microbiota composition, hepatic lipid accumulation, inflammatory markers, and gut microbiome diversity were assessed. ResultsDSS treatment markedly reduced IAP levels. Suppression of IAP significantly increased gut permeability and exacerbated hepatic inflammation and lipid deposition. Conversely, IAP supplementation restored these parameters, improved gut microbial diversity, and normalized microbiota composition. However, IAP failed to ameliorate hepatic inflammation and lipid accumulation in Toll-like receptor 4 (TLR4) knockout mice. ConclusionDeficiency in endogenous IAP contributes to the onset of NAFLD in the context of IBD. Oral IAP supplementation enhances gut barrier integrity, stabilizes gut microbiota, and prevents NAFLD development in IBD through a TLR4-dependent mechanism.

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Liu, Y., Lv, H., Zhang, H., Yu, S., Cao, G.. 2025-02-12. The Protective Role of Intestinal Alkaline Phosphatase in Inflammatory Bowel Disease-Associated Non-Alcoholic Fatty Liver Disease. https://doi.org/10.1101/2025.02.11.637679

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