Activation of p38 mitogen-activated protein kinase pathway by lipopolysaccharide aggravates postoperative ileus in colorectal cancer patients

Abstract

Background and aim: Patients undergoing abdominal surgery can develop postoperative ileus (POI). Inflammation of the intestinal muscularis following intestinal manipulation may be caused by displaced bacteria or lipopolysaccharide (LPS). The aim of this study was to investigate the relationship between gut microbiota, LPS, and POI in colorectal cancer (CRC) patients and explore underlying mechanisms of LPS-triggered POI.

Methods: Sixty CRC patients undergoing colorectal resection were included. Bacterial communities from fecal samples were characterized by 16S rRNA gene sequencing, and fecal LPS levels were determined by Limulus amebocyte lysate assay. Mice were used to mechanistically investigate the causal relationship between microbiota, LPS, and POI.

Results: We discovered that CRC patients who developed prolonged POI (PPOI) had a unique pro-inflammatory gut microbial composition during the perioperative period. The highest proportions of Gram-negative bacteria at the genus level were Escherichia-Shigella and Bacteroides; the abundance of Escherichia-Shigella was higher throughout the perioperative period. Fecal LPS levels were significantly higher in patients with PPOI. In mice treated with an antibiotic cocktail, intestinal muscularis inflammation and intestinal dysfunction were significantly improved. Inflammation and dysfunction were significantly reduced in mice treated with polymyxin B, but were worsened by treatment with LPS. Moreover, LPS upregulated p38 phosphorylation in mice, and treatment with an inhibitor of p38 (SB203580) significantly alleviated intestinal inflammation and dysmotility.

Conclusion: Lipopolysaccharide increases intestinal muscularis inflammation via activation of p38 signaling, which aggravates POI. Removing bacterial sources of LPS during the perioperative period is promising for the prophylactic treatment of PPOI.

Keywords: Colorectal cancer; Gut microbiota; Intestinal muscularis inflammation; LPS; Postoperative ileus.