Sepsis and cholestasis: the in vitro effects of bacterial products on ¹⁴C‐taurocholate uptake by isolated rat hepatocytes

Abstract

ABSTRACT‐ Bacterial endotoxins are known to be an important cause of cholestasis, yet not all organisms that cause cholestasis produce endotoxins. In order to determine whether bacterial products other than endotoxins may be involved in the cholestatis process, 14C‐taurocholate (TC) uptake by isolated rat hepatocytes was measured in the presence of mid‐log, stationary and mid‐death phase bacterial broth supernatants from eight common bacterial pathogens. The results were then correlated with a quantitative assessment of endotoxin production by each organism. Supernatants from Haemophilus influenzae, Pseudomonas aeruginosa and Klebsiella pneumonia demonstrated a striking inhibitory effect on bile salt uptake (77.2 ± 6.7, 46.9 ± 6.5 and 32.9 ± 7.1% maximum inhibition of 14C‐TC uptake, respectively) when compared to sterile broth controls. Streptococcus faecalis (Enterococcus), Escherichia coli, Staphylococcus aureus and Bacteroides fragilis products, on the other hand, had relatively minor effects (12.3 ± 5.2, 12.0 ± 7.5, 8.4 ± 6.7 and < 5.0% inhibition respectively), while those from Proteus mirabilis had an intermediate effect (18.5 ± 8.3% inhibition). Bile salt efflux rates (16.0 ± 2.7 and 25.1 ± 4.2 nmol/min/106 hepatocytes, mean ± SEM) were similar in bacteria demonstrating marked uptake inhibition (Haemophilus influenzae, Pseudomonas aeruginosa) when compared to those with only minor inhibitory effects (Staphylococcus aureus, Bacteroides fragilis) (14.3 ± 1.1 and 18.4 ± 2.6 nmol/min/106 hepatocytes, respectively, p > 0.05). 14C‐TC uptake inhibition did not correlate with the amount of endotoxin produced by each organism (r = 0.251). The results of this study indicate that bacteria produce a factor other than endotoxin that significantly inhibits bile salt uptake by isolated rat hepatocytes. It is conceivable that this factor not only contributes to the cholestasis caused by endotoxin‐producing organisms but could also play an important role in the cholestasis caused by infection with non‐endotoxin producing bacteria.

Neonatal sepsis presenting as a choledochal cyst

“…Klebsiella pneumonia has also been reported by others as a cause for sepsis induced cholestasis in neonates and premature infants (15,16). The mechanisms for cholestasis may not be limited to bacterial endotoxins and other bacterial products as have been suggested (17). Minuk et al (17) showed in a rat model that not all Gram‐negative bacteria caused transport inhibition, and there was no correlation between endotoxin concentrations and inhibition of bile acid uptake.…”

“…The mechanisms for cholestasis may not be limited to bacterial endotoxins and other bacterial products as have been suggested (17). Minuk et al (17) showed in a rat model that not all Gram‐negative bacteria caused transport inhibition, and there was no correlation between endotoxin concentrations and inhibition of bile acid uptake. It is evident that endotoxin not only affects bile transport but also plays a role in hepatocyte injury (18).…”

Acute Osteomyelitis Presenting As Cholestatic Jaundice

“…4 Although cholestatic jaundice is more commonly associated with gram negative bacteraemia, it is also known to occur with gram positive bacteraemia. [14][15][16] Histologically the most prominent finding in bacteraemic patients with jaundice is intrahepatic cholestasis. In addition, Kupffer cell hyperplasia, portal mononuclear cell infiltrates, focal hepatocyte dropout and steatosis have been described.…”

Staphylococcus aureus MnhF Mediates Cholate Efflux and Facilitates Survival under Human Colonic Conditions

“…challenge to the gut microflora; in humans, the liver secretes up to 1 liter of bile per day into the intestines (38). Furthermore, molecules secreted by bacteria, including S. aureus, during infection are an important cause of metabolic cholestasis, an inability of hepatocytes to produce bile (39). Bile is a complex cocktail composed principally of bile salts, phospholipids, cholesterol, proteins, and bilirubin (40).…”