Indole Propionic Acid Regulates Gut Immunity: Mechanisms of Metabolite-Driven Immunomodulation and Barrier Integrity

Abstract

Indole propionic acid (IPA) is a functional indole derivative produced exclusively by intestinal flora through tryptophan metabolism. Numerous studies have shown that IPA has a variety of beneficial biological functions, including anti-inflammatory and antioxidant effects, immunomodulation, intestinal barrier protection, regulation of intestinal flora composition, and neuroprotection. IPA, as an intestinal microbial metabolite, actively participates in the establishment of intestinal immune homeostasis and positively influences the prevention and control of intestinal diseases, thereby playing an indispensable role in regulating host health. We conducted a comprehensive literature review to explore the synthesis of IPA in vivo, the mechanism of action on intestinal immunity, and the promise of its application in the treatment of related diseases. The physiological and biological effects of IPA were investigated to explore its potential application in future drug discovery. Obviously, IPA plays an important role in intestinal immunity and is effective in the treatment of related diseases. IPA helps regulate intestinal immune cell function, inhibiting inflammatory response and enhancing intestinal barrier function through its effects on the aryl hydrocarbon receptor, the pregnane X receptor, and other related signaling pathways. The development of IPA as a target drug for the treatment of intestinal diseases is promising. Although IPA research is still in the experimental animal model stage, there is growing interest in the many therapeutic applications of IPA and increasing opportunities to further modify IPA for future clinical applications.

Keywords: AhR/PXR; Indole propanoic acid; gut barrier integrity; intestinal immunity; microbiome-derived metabolites.

Fig. 1. Structural formula of indole propionic acid (IPA).

Fig. 2. Image illustrating the biosynthesis of indole propionic acid (IPA) in vivo.

Tryptophan is used to produce IPA in the intestines by enzymes such as aromatic amino acid transaminase (ArAT), phenyllactate dehydrogenase (fldH), enzyme phenylmalate dehydrogenase (fldBC), Acyl coenzyme A (Acyl-CoA), and bacteria such as Prevotella russellii, Peptostreptococcus anaerobius, and Porphyromonas stomatis. IPA acts on multiple organs throughout the body via the blood circulation.

Fig. 3. Indole propionic acid (IPA) regulates the intestinal barrier through Aryl hydrocarbon receptor (AhR)/Pregnane X receptor (PXR).

IPA upregulates the expression of proteins such as Occludin, Claudin-1, Zonula Occludens-1, Mucin 2, and Mucin 4 through activation of AhR. IPA also strengthens the expression of the B3galt5 gene through activation of PXR, inhibits NF-κB signaling, and enhances mucin expression, which in turn maintains the intestinal barrier.

Fig. 4. Indole propionic acid (IPA) regulates intestinal immune cells through Aryl hydrocarbon receptor (AhR)/Pregnane X receptor (PXR).

IPA can regulate the status of Tregs, innate lymphoid cells type 3 (ILC3), Th17 cells, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) via AhR. IPA can inhibit the expression of CD4+/CD25/ Th1 via PXR.

Fig. 5. Indole propionic acid (IPA) affects cytokines through Aryl hydrocarbon receptor (AhR)/Pregnane X receptor (PXR).

IPA regulates immune responses and metabolic pathways, as well as influencing cytokine secretion, by activating the AhR and PXR in intestinal epithelial cells.