Effect of ursodeoxycholic acid treatment on the altered progesterone and bile acid homeostasis in the mother-placenta-foetus trio during cholestasis of pregnancy

Aim

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intra-uterine and perinatal complications. High concentrations of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial aetiopathogenesis of ICP. The aim of this study was to investigate further the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio.

Method

Using HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by real time quantitative PCR (RT-QPCR) and immunofluorescence.

Results

In ICP, markedly increased concentrations of bile acids (tauroconjugates > glycoconjugates >> unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced concentrations in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS concentrations. ABCG2 mRNA abundance was increased in placentas from ICP patients vs. controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2.

Conclusion

UDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on concentrations of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high concentrations of bile acids and PMS during ICP.     

Analysis of mononuclear cell infiltrate and cytokine production in murine autoimmune gastritis

BACKGROUND & AIMS: Murine autoimmune gastritis, induced by day-3 thymectomy, is characterized by cellular infiltrates and circulating autoantibodies to gastric hydrogen/potassium adenosine triphosphatase. The aim of this study was to analyze the cellular infiltrates and cytokines in autoimmune gastritis. METHODS: Stomachs and blood samples from day-3 thymectomized BALB/c mice were obtained from 2 to 12 weeks after thymectomy for analysis. RESULTS: At 4 weeks, the gastritic infiltrates were composed of macrophages and CD4+ T cells, accompanied by major histocompatibility complex class II expression on gastric epithelial cells. Mucosal B cells, scant at 4 weeks, were abundant at 8 weeks, coincident with the peaking of autoantibodies to gastric hydrogen/potassium adenosine triphosphatase. CD8+ T cells increased marginally during the 12 weeks. Mononuclear cells from diseased stomachs transferred gastritis to nu/nu recipients. At 4 weeks, interleukins 2, 3, 5, 6, and 10; interferon gamma; tumor necrosis factor alpha; and granulocyte-macrophage colony-stimulating factor were detected in gastritic mucosa, but interleukin 4 was not. CONCLUSIONS: The early lesion of autoimmune gastritis is composed of macrophages and CD4+ T cells with major histocompatibility complex class II expression in gastric epithelial cells. Autoantibody production is a late event. Our results are consistent with a lesion mediated by CD4+ T cells producing a mix of Th1- and Th2-type cytokines. (Gastroenterology 1996 Jun;110(6):1791-802)     

Claudins: unlocking the code to tight junction function during embryogenesis and in disease

Gupta IR, Ryan AK. Claudins: unlocking the code to tight junction function during embryogenesis and in disease. Claudins are the structural and molecular building blocks of tight junctions. Individual cells express more than one claudin family member, which suggests that a combinatorial claudin code that imparts flexibility and dynamic regulation of tight junction function could exist. Although we have learned much from manipulating claudin expression and function in cell lines, loss‐of‐function and gain‐of‐function experiments in animal model systems are essential for understanding how claudin‐based boundaries function in the context of a living embryo and/or tissue. These in vivo manipulations have pointed to roles for claudins in maintaining the epithelial integrity of cell layers, establishing micro‐environments and contributing to the overall shape of an embryo or tissue. In addition, loss‐of‐function mutations in combination with the characterization of mutations in human disease have demonstrated the importance of claudins in regulating paracellular transport of solutes and water during normal physiological states. In this review, we will discuss specific examples of in vivo studies that illustrate the function of claudin family members during development and in disease.     

Influence of diets containing high and low risk factors for colon cancer on early stages of carcinogenesis in human flora-associated (HFA) rats

Germ-free rats colonised with a human intestinal flora were fed diets containing high risk (HR) or low risk (LR) factors for colorectal cancer, and putative biomarkers were evaluated in the colonic mucosa; (i) proliferation, (ii) 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci and (iii) DMH-induced DNA damage. The HR diet was high in fat (45% of calories) and low in calcium and fibre, reflecting levels characteristic of typical western diets. The LR diet was low in fat (<5% of calories), and high in calcium and fibre. The nutrient/energy ratio of the two diets were similar. Mucosal crypt cell proliferation, assessed after microdissection, was higher on the LR diet (mean number of mitoses per crypt was 2.65 on the LR diet, and 1.62 on the HR diet; P < 0.05). Aberrant crypt foci (ACF) were assessed in the mucosa 12 weeks after DMH treatment. On the HR diet there were significantly more small ACF with 1 and 2 crypts per focus, but fewer ACF with 3, 5 and 7 or more crypts per focus. There was no significant difference in total ACF or the total number of crypts. The effect of diet on DNA damage in the colon was assessed in vivo by the comet assay. Animals were fed a HR or LR diet for 12 weeks before treatment with DMH or saline. For carcinogen-treated animals, DNA damage was significantly higher in colon cells from animals on the HR diet. On the LR diet both DNA damage and the induction of small ACF were reduced despite an increase in cell proliferation. The increase in large ACF on the LR diet may be attributable to elevated crypt cell proliferation possibly increasing crypt fission rates.