Adenosine in Intestinal Epithelial Barrier Function

Abstract

At the intestinal front, several lines of defense are in place to resist infection and injury, the mucus layer, gut microbiome and strong epithelial junctions, to name a few. Their collaboration creates a resilient barrier. In intestinal disorders, such as inflammatory bowel disease (IBD), barrier function is compromised, which results in rampant inflammation and tissue injury. In response to the destruction, the intestinal epithelium releases adenosine, a small but powerful nucleoside that functions as an alarm signal. Amidst the chaos of inflammation, adenosine aims to restore order. Within the scope of its effects is the ability to regulate intestinal epithelial barrier integrity. This review aims to define the contributions of adenosine to mucus production, microbiome-dependent barrier protection, tight junction dynamics, chloride secretion and acid-base balance to reinforce its importance in the intestinal epithelial barrier.

Keywords: IBD; acid–base balance; adenosine; chloride secretion; inflammation; microbiome; mucus; tight junctions.

Figure 1

The diverse mechanisms of adenosine production. Abbreviations: adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenylate kinase-1 (AK1), adenosine deaminase (AD), nicotinamide adenine dinucleotide (NAD+), adenosine diphosphate ribose (ADPR), cytosolic 5′-nucleotidase (cyto-5′NT), S-adenosylhomocysteine hydrolase (SAHH), S-adenosylhomocysteine (SAH). Created with BioRender.com, accessed on 13 February 2024.

Figure 2

Regulation of adenosine levels across the plasma membrane is facilitated by concentrative nucleoside transporters (CNTs): CNT2 and CNT3 and equilibrative nucleoside transporters (ENTs): ENT1, ENT2, ENT4. CNTs transport adenosine into the intracellular space by coupling to sodium ions (Na⁺) and hydrogen ions (H⁺). ENTs are bidirectional and shuttle adenosine across the plasma membrane with its concentration gradient. Created with BioRender.com, accessed on 13 February 2024.

Figure 3

The canonical signaling pathways associated with adenosine receptor activation. Abbreviations: A1 adenosine receptor (A1AR), A2A adenosine receptor (A2AAR), A2B adenosine receptor (A2BAR), A3 adenosine receptor (A3AR), Gs α-subunit (Gs), Gi α-subunit (Gi), Gq α-subunit, adenylyl cyclase (AC), adenosine triphosphate (ATP), cyclic-AMP (cAMP), protein, protein kinase A (PKA), phospholipase C (PLC), inositol 1,4,5-triphosphate (IP3), diacylglycerol (DAG), protein kinase C (PKC), calcium (Ca²⁺), endoplasmic reticulum (ER). Created with BioRender.com, accessed on 13 February 2024.

Figure 4

Extracellular adenosine is increased during intestinal inflammation. A key contributing factor to the development of intestinal inflammation is intestinal barrier dysfunction. Barrier dysfunction is associated with an altered microbiome composition (1), bacterial infiltration (2), impaired cell junctions (3), loss of the mucus layer (4) and acidification (5). Collectively, these induce and exacerbate intestinal inflammation. This contributes to the release of ATP from injured cells, which is converted to the alarm molecule adenosine. Created with BioRender.com, accessed on 13 February 2024.

Figure 5

The protective effects of A2BAR signaling on intestinal barrier function. When activated by extracellular adenosine, A2BAR promotes potent downregulation of inflammation (1) and barrier resealing through PKA-phospho-VASP signaling (2). This is accompanied by cAMP-dependent Cl⁻ secretion from intestinal epithelial cells and water movement into the intestinal lumen, which may contribute to mucus hydration and pathogen flushing (3). Evidence also exists to suggest A2BAR signaling may restore the mucus layer by upregulating Muc2 expression (4). Abbreviations: A2B adenosine receptor (A2BAR), Gs α-subunit (Gs), adenylyl cyclase (AC), adenosine triphosphate (ATP), cyclic-AMP (cAMP), protein, protein kinase A (PKA), vasodilator-stimulated phosphoprotein (VASP), water (H₂O), chloride ion (Cl⁻), mucin 2 (MUC2). Created with BioRender.com, accessed on 13 February 2024.