Research ArticleActivated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function

Background & AimsBacterial infections commonly occur in decompensated cirrhosis resulting from bacterial translocation from the intestine. We studied the role of intestinal macrophages and the epithelial barrier in cirrhosis.MethodsForty-four patients with NASH/ASH cirrhosis (decompensated n = 29, compensated n = 15) and nineteen controls undergoing endoscopy were recruited. Serum was obtained and LPS and LBP levels determined. Intestinal macrophages were characterized by flow cytometry, immunohistochemistry, and nitric oxide (NO) production measured in supernatant of cultured duodenal samples. Quantitative RT-PCR was performed on duodenal biopsies assessing 84 inflammatory genes. Protein levels of cytokines/chemokines were assessed in serum and supernatant. The duodenal wall was assessed by electron microscopy, tight junction protein expression determined by RT-PCR, immunohistochemistry, and Western blot and, functional analysis performed by transepithelial resistance measurement and permeability studies.ResultsIncreased plasma LPS, LBP levels and higher numbers of duodenal CD33+/CD14+/Trem-1+ macrophages, synthesizing iNOS and secreting NO were present in decompensated cirrhosis. Upregulation of IL-8, CCL2, CCL13 at the transcriptional level, and increased IL-8, and IL-6 were detected in supernatant and serum in cirrhosis. IL-6 and IL-8 co-localised with iNOS+ and CD68+, but not with CD11c+ cells. Electron microscopy demonstrated an intact epithelial barrier. Increased Claudin-2 was detected by Western blot and immunohistochemistry, while decreased transepithelial resistance and increased duodenal permeability were detected in decompensated cirrhosis.ConclusionsOur study shows the presence of activated CD14+Trem-1+iNOS+ intestinal macrophages, releasing IL-6, NO, and increased intestinal permeability in patients with cirrhosis, suggesting that these cells may produce factors capable of enhancing permeability to bacterial products.

Proposed model of intestinal macrophage activation in ASH/NASH cirrhosis. Following changes in bacterial flora, intestinal macrophage activation occurs. CD14+iNOS+ intestinal macrophages release NO and IL-6. In addition CCL-13, IL-8, and CCL-2/MCP-1 are produced that may attract monocytes from the circulation.120