Immunosuppressive effects of endotoxins and bile acids in vivo in the rat

Abstract

Cell-mediated immunity is impaired during cholestasis. The aim of this study was to evaluate in vivo the effects on this immune defect of high serum levels of endotoxin and bile acids. Heterotopic cardiac allotransplantations were performed in the DA/Lewis rat combination. Cholestasis, induced by ligation/section of the common bile duct, was responsible for a significant delay in the rejection time (16 +/- 0.5 vs. 7.1 +/- 0.4 days in controls, P < 0.01). Elimination of Gram-negative intestinal bacteria from cholestatic rats by a vancocin/colimycin/tobramycin (VCT) mixture induced a significant reduction in endotoxin levels and a reduction in rejection times (9.5 +/- 1.0 days, P < 0.01) that remained, however, significantly longer than those of controls (P < 0.05). Oral administration of chenodeoxycholic acid in non-cholestatic rats significantly enhanced the serum concentration of total bile acids (60.6 +/- 15.3 mumol L(-1) vs. 17.4 +/- 1.9 mol L(-1) in controls, P < 0.01) and postponed allograft rejection (10.7 +/- 0.6 days, P < 0.01 vs. controls). These data suggest that increased endotoxin level and serum bile acid concentration may play a role in the immunosuppressive effect of cholestasis.

Ursodeoxycholic Acid in Patients With Chronic Heart Failure

“…This finding was highly suggestive that bile acids are able to hold bacterial components back in the intestine. Indeed, application of chenodeoxycholic acid to rats in this study was still associated with significantly reduced plasma LPS levels (12). Because elevated levels of LPS are present in patients with CHF (10), the improvement in post-ischemic blood flow observed in our study may be due to the formation of mixed micelles containing UDCA around LPS.…”

“…This is in line with our findings because leukocyte counts decreased with UDCA treatment compared with placebo. An elegant study was presented by Aouad et al (12), who showed that ligation of the common bile duct in Lewis rats yielded significantly elevated levels of LPS in the bloodstream compared with control animals. This finding was highly suggestive that bile acids are able to hold bacterial components back in the intestine.…”

“…The inhibition of LPS might be clinically more meaningful than targeting single downstream cytokines (9,10). Ursodeoxycholic acid (UDCA), a bile acid used in patients with cholestatic liver diseases, is an interesting candidate in this respect because it appears to be able to form mixed micelles around LPS leading to its detoxification (11,12). UDCA is a physiologic constituent of human bile that has been used in cholestatic liver disease such as primary biliary cirrhosis (13).…”

Obstructive Jaundice, Bacterial Translocation and Interdigestive Small-Bowel Motility in Rats

“…Reduced immune system function and an impaired inflammatory response are key factors in the development of gut-derived infections in obstructive jaundice [25, 29, 30, 31, 32, 33, 34]. Inflammatory and immunological effects of obstructive jaundice contribute to the development of bacterial translocation [8].…”

Immunoprotective Properties of Peptidoglycan Monomer Linked with Zinc in Cholestatic Jaundice

“…Since most of these data suggested that PGM-Zn is an immunostimulator which shares some properties with the lipopolysaccharide (LPS), but has a different mode of action on lymphatic cells, we speculate that there is the possibility that PGM-Zn has, during jaundice, interfered with some LPS-induced pathways. Namely, in cholestatic jaundice in plasma toxic factors like bilirubin, bile acids, endotoxin, α 2 -globulin and abnormal lipoproteins [11]accumulate, which alter Kupffer cell function [17], interfere with the early events at the T cell recognition stage [18]and impair the cell-mediated immunity [19]. This eventually leads to gut barrier failure, systemic endotoxemia and translocation of bacteria and endotoxin to the liver [20], as well as to release of large quantities of mainly proinflammatory cytokines (TNF-α, IL-1, IL-6) from various host cells [21].…”