Infection‑associated bile acid disturbance contributes to macrophage activation in patients with cirrhosis.

Abstract

Cirrhosis impairs macrophage function and disrupts bile acid homeostasis. Although bile acids affect macrophage function in patients with sepsis, whether and how the bile acid profile is changed by infection in patients with cirrhosis to modulate macrophage function remains unclear. The present study aimed to investigate the changes in the bile acid profile of patients with cirrhosis and infection and their effects on macrophage function. Serum was collected from 20 healthy subjects, 18 patients with cirrhosis and 39 patients with cirrhosis and infection. Bile acid profiles were detected using high‑performance liquid chromatography‑triple time‑of‑flight mass spectrometer. The association between bile acid changes and infection was analysed using receiver operating characteristic (ROC) curves. Infection‑altered bile acids were used in combination with lipopolysaccharides (LPS) to stimulate RAW264.7/THP‑1 cells in vitro. The migratory capacity was evaluated using wound healing and Transwell migration assays. The expression of Arg‑1, iNOS, IκBα, phosphorylated (p‑)IκBα and p65 was examined with western blotting and immunofluorescence, Tnfα, Il1b and Il6 mRNA was examined with RT‑qPCR, and CD86, CD163 and phagocytosis was measured with flow cytometry. The ROC curves showed that decreased hyodeoxycholic acid (HDCA) and deoxycholic acid (DCA) levels were associated with infection. HDCA or DCA combined with LPS enhanced the phagocytic and migratory ability of macrophages, accompanied by upregulation of iNOS and CD86 protein expression as well as Tnfα, Il1b, and Il6 mRNA expression. However, neither HDCA nor DCA alone showed an effect on these phenotypes. In addition, DCA and HDCA acted synergistically with LPS to increase the expression of p‑IκBα and the intranuclear migration of p65. Infection changed the bile acid profile in patients with cirrhosis, among which the reduction of DCA and HDCA associated most strongly with infection. HDCA and DCA enhanced the sensitivity of macrophage function loss to LPS stimulation. These findings suggested a potential role for monitoring the bile acid profile that could help manage patients with cirrhosis and infection.