sodium-taurodeoxycholate and Intestinal-Diseases

Intestinal barrier integrity may be disrupted in many conditions allowing for bacterial invasion and ensuing systemic illness. We investigated the efficacy and mechanism of bile salts in protecting the intestinal mucosa integrity after injury through stimulation of cell proliferation and an increased resistance to apoptosis.. Over 7 days, wild-type C57Bl/6J and Nr1h4(tm1Gonz)/J (farnesoid X receptor [FXR] knockout) male mice received either liquid rodent chow alone (for control animals) or with added 50 mg/kg per day of taurodeoxycholic acid (TDCA; for experimental animals). On day 6, all mice received 10 mL/kg of lipopolysaccharide intraperitoneally. On day 7, small intestines were harvested. After immunohistochemistry with hematoxylin and eosin, activated caspase-3, and 5-bromo2'-deoxy-uridine (BrdU), mean proliferating and apoptotic cells were determined with light microscopy. In vitro, FXR proteins were immunoblotted from cultured cells after exposure to TDCA. FXR expression was then inhibited in the presence and absence of TDCA. Intestinal epithelial proliferation along with c-Myc and FXR protein expressions were determined.. C57Bl/6J mice exhibited significant mucosal enterocyte proliferation and decreased mucosal enterocyte apoptosis when provided with supplemental TDCA in their diet. Inhibition of FXR, both in vivo and in vitro, prevented the bile salt-induced enterocyte proliferation and resistance to apoptosis. TDCA exposure stimulated nuclear translocation of FXR resulting in increased expression of c-Myc.. A diet supplemented with bile salts, especially in patients who have decreased luminal bile salt, may prove beneficial and therapeutic in critical illness where intestinal injury is part of the spectrum.

Topics: Animals; Bile Acids and Salts; Biopsy, Needle; Carrier Proteins; Caspase 3; Dietary Supplements; Disease Models, Animal; Immunohistochemistry; Intestinal Absorption; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Random Allocation; Receptors, Cytoplasmic and Nuclear; Reference Values; Taurodeoxycholic Acid

Mechanisms by which hydrophobic bile salts cause tissue changes below their critical micellar concentration (CMC, 1-2mM) and above (4-8mM) remain poorly understood. In this study, rat colonic mucosa was exposed to different concentrations of taurodeoxycholate (TDC), t-butyl-hydroperoxide (t-BH) or glutathione ester with or without pre-incubation with 2mM TDC. Exposure to 2mM TDC was associated with 10% higher tissue levels of total glutathione (GSH, basal values: 33.7+/-3.3 nmol/mg prot). With TDC 8mM, GSH decreased to 16.4+/-2.3 nmol/mg prot (P<0.05), oxidized glutathione (GSSG) increased by 60% (P<0.05), glutathione peroxidase (GSH-Px) and reductase activities were threefold increased, protein carbonyls fourfold increased, protein sulfhydrils decreased by 78%, lactate dehydrogenase (LDH) and GSSG release in the incubation medium were sixfold higher. In 2mM TDC pre-treated tissues, the subsequent incubation with 8mM TDC induced a lower loss of tissue GSH, and a lower release of LDH and GSSG. Pre-incubation with 2mM TDC partly protected against t-BH toxicity, while glutathione ester protected against 8mM TDC toxicity. In conclusion, TDC exposure causes opposite effects depending on CMC: induction of antioxidant protective systems including glutathione system (pre-conditioning effect) was observed with TDC below CMC, oxidative damages pointing to decreased mucosal detoxification potential with above CMC.

Topics: Animals; Cholagogues and Choleretics; Glutathione; Intestinal Diseases; Intestinal Mucosa; Ischemic Preconditioning; L-Lactate Dehydrogenase; Male; Micelles; Oxidation-Reduction; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Sulfhydryl Compounds; Taurodeoxycholic Acid