Deoxycholic acid enhancement of lymphocyte migration through direct interaction with the intestinal vascular endothelium

Abstract

Background and Aim The small intestine plays a central role in gut immunity, and enhanced lymphocyte migration is involved in the pathophysiology of various enteropathy. Bile acid (BA) is closely related to lipid metabolism and gut microbiota and essential for gut homeostasis. However, the effects of BA on gut immunity have not been studied in detail, especially on the small intestine and lymphocyte migration. Therefore, we aimed to investigate the effect of BA on small intestinal lymphocyte microcirculation. Methods The effect of deoxycholic acid (DCA), taurocholic acid (tCA), or cholic acid (CA) on the indomethacin (IND)‐induced small intestinal enteropathy in mice was investigated. Lymphocyte movements were evaluated after exposure to BA using intravital microscopy. The effects of BA on surface expression of adhesion molecules on the vascular endothelium and lymphocytes through BA receptors were examined in vitro. Results IND‐induced small intestinal enteropathy was histologically aggravated by DCA treatment alone. The expression of adhesion molecules ICAM‐1 and VCAM‐1 was significantly enhanced by DCA. Exposure to DCA increased lymphocyte adhesion in the microvessels of the ileum, which was partially blocked by anti‐α4β1 integrin antibody in vivo. The expression of ICAM‐1 and VCAM‐1 was significantly enhanced by DCA in vitro, which was partially suppressed by the sphingosine‐1‐phosphate receptor 2 (S1PR2) antagonist. The S1PR2 antagonist significantly ameliorated IND‐induced and DCA‐exaggerated small intestinal injury. Conclusion DCA exacerbated IND‐induced small intestinal enteropathy. DCA directly acts on the vascular endothelium and enhances the expression levels of adhesion molecules partially via S1PR2, leading to enhanced small intestinal lymphocyte migration.

Green Extraction of Orange Peel Waste Reduces TNFα-Induced Vascular Inflammation and Endothelial Dysfunction

“…Interestingly, the levels of the bile acid, deoxycholic acid was also significantly reduced by TNF-α treatment and was further suppressed when co-treated with 60 °C OPWE ( Table 2 ). To date, the role of bile acids on endothelial cells remains controversial; while some studies have reported the pro-inflammatory effects of bile acids [ 49 , 50 ], others have demonstrated their vasoprotective effects [ 51 , 52 ]. Specifically, an earlier study reported that bile acids had enhanced adhesion molecule expression in endothelial cells [ 50 ] through oxidative stress and activation of NF-kappaB and p38 signalling pathway [ 49 ].…”

“…To date, the role of bile acids on endothelial cells remains controversial; while some studies have reported the pro-inflammatory effects of bile acids [ 49 , 50 ], others have demonstrated their vasoprotective effects [ 51 , 52 ]. Specifically, an earlier study reported that bile acids had enhanced adhesion molecule expression in endothelial cells [ 50 ] through oxidative stress and activation of NF-kappaB and p38 signalling pathway [ 49 ]. This suggested that elevated levels of bile acids may cause endothelium dysfunction and contribute to the initiation of early events of vascular inflammation [ 49 ].…”

NSAID-Associated Small Intestinal Injury: An Overview From Animal Model Development to Pathogenesis, Treatment, and Prevention

“…Deoxycholic acid (DCA) enhanced ileal lymphocyte migration in part by up-regulating adhesion molecule expression through sphingosine-1-phosphate receptor 2 (S1PR2), and S1PR2 antagonist alleviated indomethacin-induced and DCA-exaggerated small bowel injury ( Shibuya et al, 2021 ). Bile acid receptor S1PR2 may play a proinflammatory role in the intestine.…”

Versatile Triad Alliance: Bile Acid, Taurine and Microbiota

“…The properties of DCA rely on its capacity to activate several carcinogenesis-related cell signaling pathways, including protein kinase C (PLC) [ 250 ], ERK1/2 via the epidermal growth factor receptor [ 255 , 256 , 257 ], β-catenin [ 258 ], JNK1/2 [ 259 ] and activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome [ 260 ]. DCA also induces and exacerbates intestinal inflammation as well as associated dysbiosis [ 261 , 262 , 263 ]. Increased amounts of DCA in the bile of a subset of cholesterol gallstone patients correlate with the abundance of CA 7α-dehydroxylating fecal bacteria.…”