Experiments On Biledeprived Rats

We designed experiments for the clarification of this question in vivo. Because rats do not have gallbladders, it was possible to produce bile deficiency by the cannulation of the common bile duct. With this technique we successfully produced a chronic bile deficiency, which was suitable for the study of endotoxin absorption from the gastrointestinal tract. We favoured the hypothesis that in healthy animals orally given endotoxin, or the endotoxin released from Gram-negative bacteria within the gastrointestinal tract, did not cause clinical symptoms because bile acids which are present in the gut on a permanent basis, will take apart the endotoxin molecule due to the detergent action. Non-toxic small fractions are produced which are adsorbed by protein molecules present in the gut. It was anticipated on this basis that bile deficiency was necessary for the development of entero-endotoxaemia. This hypothesis has been proven experimentally in rats [16,17], Endotoxin labelled with tritium or radioactive chromium was not absorbed in normal animals after oral application [18]. No clinical symptoms were produced by such treatment. In contrast, if such endotoxin was given to rats having a bile fistula for 1-2 weeks, which led to bile acid deficiency, the animals succumbed to endotoxin shock (Table I). It was possible to detect radioactive endotoxin in the blood of these animals (by the measurement of 3H and 51Cr activity), and we could sensitise such animals further to endotoxin by treatment with lead acetate [19]. These experiments revealed that bile deficiency is required for the absorption of endotoxin from the gastrointestinal tract. In further experiments we treated the endotoxin with sodium deoxycholate prior to oral application to rats having bile fistulas. Complete protection was observed even when the rats had been sensitised to endotoxin by treatment with lead acetate (Table II). Identical results were obtained when bile was used from rats, pigs and cows for the restoration of missing bile acids. Such treatment prevented the development of endotoxin shock [6]. The ligation of the bile duct in rats increased the blood cholesterol, bile acid and bilirubin levels, as shown in Table III.

These experiments provided proof for the role of bile acids in host defence against endotoxin, and indicated that bile deficiency leads to the absorption of intestinal endotoxin, both of which have clinical significance. Other investigators confirmed our results in animal experiments and also in clinical situations (endotoxaemia of patients suffering from bile duct occlusion and

Table II Sodium deoxycholate prevents deaths due to endotoxin in rats with bile fistula and lead acetate sensitisation.

Group Treatment Death ratio (dead/total)

2 Bile fistula + LPS ( 10 mg per os 0 hr) 5/6 + lead acetate (5 mg iv + 3 hr)

3 Bile fistula + sodium deoxycholate (40 mg per os) 2/6 + LPS (10 mg per os)

* Died of intercurrent bile peritonitis.

Table III The effect of ligation of the common bile duct in rats on serum bile acid, cholesterol, lipoprotein and bilirubin levels.

Intact

Li gated

Glycocholic acid (|rmol/l) (n = 15) Glycodeoxicholic acid (junol/l) (n = Cholesterol (mmol/1) (n = 15) HDL (mmol/1) (n = 15) LDL (mmol/1) (n = 15) Bilirubin (umol/1) (n = 15) Bilirubin D (¡jmol/1) (n = 14)

1.4 ±0.84 2.1 ±0.79 2.26 ± 0.34 0.55 ±0.16 .36 ± 0.42 7.0 ± 1.22 4.4 ± 1.30

45.5 ±43.45 7.36 ±5.68 3.5 ± 0.30 0.58 ±0.18 2.69 ± 1.04 115.00 ±89.67 45.00 ±34.41

icterus), see for example Bailey [20], Cahill [21] and later Gaffin [22], It was found that the treatment of patients suffering from icterus with bile acids prior to surgery prevented the impairment of renal function and the development of renal deficiency [21-24], Our experimental observations made it possible to prevent a severe clinical disease. It seems obvious that this beneficial effect of bile acids is based on the physico-chemical, surface-active, detergent action. Our results support the hypothesis that the inactivation of endotoxin in the gastrointestinal tract by bile acids is due to the detergent action [25], For this reason we studied other detergents in addition to sodium deoxycholate that are present in the bile of various animal species. Our goal was to find out whether or not they are capable of detoxifying endotoxin by fractionation of the molecule.

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