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Review
. 2021 Oct;37(5):383-393.
doi: 10.1159/000515910. Epub 2021 Apr 29.

Targeting the Intestinal Barrier to Prevent Gut-Derived Inflammation and Disease: A Role for Intestinal Alkaline Phosphatase

Florian Kühn  1 , Ruifeng Duan  1 , Matthias Ilmer  1 , Ulrich Wirth  1 , Fatemeh Adiliaghdam  2 , Tobias S Schiergens  1 , Joachim Andrassy  1 , Alexandr V Bazhin  1 , Jens Werner  1
Affiliations
Review

Targeting the Intestinal Barrier to Prevent Gut-Derived Inflammation and Disease: A Role for Intestinal Alkaline Phosphatase

Florian Kühn et al. Visc Med. 2021 Oct.

Abstract

Background: Intestinal alkaline phosphatase (IAP) as a tissue-specific isozyme of alkaline phosphatases is predominantly produced by enterocytes in the proximal small intestine. In recent years, an increasing number of pathologies have been identified to be associated with an IAP deficiency, making it very worthwhile to review the various roles, biological functions, and potential therapeutic aspects of IAP.

Summary: IAP primarily originates and acts in the intestinal tract but affects other organs through specific biological axes related to its fundamental roles such as promoting gut barrier function, dephosphorylation/detoxification of lipopolysaccharides (LPS), and regulation of gut microbiota.

Key messages: Numerous studies reporting on the different roles and the potential therapeutic value of IAP across species have been published during the last decade. While IAP deficiency is linked to varying degrees of physiological dysfunctions across multiple organ systems, the supplementation of IAP has been proven to be beneficial in several translational and clinical studies. The increasing evidence of the salutary functions of IAP underlines the significance of the naturally occurring brush border enzyme.

Keywords: Diabetes; Endotoxemia; Gut barrier; Intestinal alkaline phosphatase; Lipopolysaccharides; Metabolic syndrome; Microbiome.

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Conflict of interest statement

The authors have no disclosures or conflicts of interests to report.

Figures

Fig. 1
Fig. 1
Working mechanisms of IAP. High levels of ATP lead to intestinal dysbiosis. IAP can dephosphorylate ATP to other nucleotides and thus regulate the number and diversity of commensal bacteria. LPS causes TLR4 activation which further promotes the release of inflammatory mediators. LPS can transfer through the intercellular space or bind to chylomicrons which leads to more LPS absorption in the context of an HFD. Released inflammatory mediators and absorbed LPS can cause local intestinal inflammation and chronic systemic inflammation. IAP removes 1 of the 2 phosphate groups from LPS and reduces its toxicity; dephosphorylated LPS can still bind to TLR4 but mainly acts as a TLR antagonist, thus inhibiting downstream intracellular signaling. IAP also regulates the levels of intestinal intercellular tight junction proteins (TJP) and their cellular localization and reduces the translocation of LPS.
Fig. 2
Fig. 2
IAP deficiency results in various pathologies/disorders caused by endotoxemia and chronic systemic inflammation. ↓ indicates a decrease, and ↑ indicates an increase, in the parameters. DM, diabetes mellitus.
See this image and copyright information in PMC

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