Small duct cholangitis induced byn-formyll-methioninel-leucinel-tyrosine in rats

Abstract

Primary sclerosing cholangitis (PSC) frequently accompanies inflammatory bowel diseases. In an attempt to increase our understanding of the pathogenesis of PSC, we studied bile duct changes in rats with colitis which had been given N-formyl L-methionine L-leucine L-tyrosine (fMLT) rectally; fMLT is one of the chemotactic peptides produced by Escherichia coli, and is secreted into the bile by hepatocytes after it enters the portal blood. Transrectal administration of fMLT induced a marked inflammation in the portal triad and mild hepatocyte necrosis on the 4th day. The infiltrating leukocytes in the portal tract were mostly mononuclear cells, which densely infiltrated around the bile ducts. These mononuclear cells appeared to attach to bile duct epithelial cells, and they were more numerous in the smaller bile ducts. Electron microscopy revealed that lymphocytes were in direct contact with bile duct lining cells and that some epithelial cells had degenerated or collapsed. These results suggest that this E. coli-derived peptide may induce cholangitis in the small bile duct through cell-mediated mechanisms. Since these pathologic changes resemble those of the bile duct observed in the early stage of PSC, it can be concluded that bacterial chemotactic peptides may play a role in the pathogenesis of small-duct PSC.

Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis ‐ a pilot study

“…fibrosis). 43,[45][46][47][48] Interestingly, these findings can be mitigated by antibiotic administration and by selective degradation of enteric bacterial components. 25,26 We believe that antibiotics such as metronidazole (effective against anaerobic bacteria) and vancomycin (effective against Gram-positive bacteria) may decrease the biosynthesis of bacterially derived immunoactive molecules and thus mitigate the aberrant (pro-inflammatory, pro-fibrotic) hepatobiliary immune responses and signalling cascades that they may trigger in immunogenetically susceptible individuals.…”

Cutting Edge Issues in Primary Sclerosing Cholangitis

“…A potential link between bacterial components and hepatobiliary inflammation was first substantiated by Chadwick and colleagues who demonstrated that N-formylated chemotactic peptides that are produced by several species of intestinal bacteria undergo enterohepatic circulation and that the levels of these compounds are increased in experimentally induced colitis [61][62][63]. In addition, rectal administration of N-formyl L-methionine L-leucine L-tyrosine in rats with acetate-induced colitis results in a biliary-based inflammation consisting of macrophages and neutrophils in the early stages and subsequently CD4+ and CD8+ T cells [64,65].…”

Atypical p-ANCA in PSC and AIH: A Hint Toward a “leaky gut”?

“…Of note, biliary inflammation may reflect abnormal immune responses to constituents of intestinal microorganisms, which do not necessarily require direct bacterial translocation to the biliary tree or portal circulation. For instance, proinflammatory peptides derived from colonic bacteria were sufficient to induce histological changes resembling PSC in rats with experimental colitis [100,101]. Such peptides trigger inflammation because they stimulate antimicrobial pattern recognition receptors, e.g., Toll-like receptors (TLR).…”