Chorioamnionitis induces hepatic inflammation and time-dependent changes of the enterohepatic circulation in the ovine fetus.

Chorioamnionitis, inflammation of fetal membranes, is an important cause of preterm birth and a risk factor for the development of adverse neonatal outcomes including sepsis and intestinal pathologies. Intestinal bile acids (BAs) accumulation and hepatic cytokine production are involved in adverse intestinal outcomes. These findings triggered us to study the liver and enterohepatic circulation (EHC) following intra-amniotic (IA) lipopolysaccharide (LPS) exposure. An ovine chorioamnionitis model was used in which circulatory cytokines and outcomes of the liver and EHC of preterm lambs were longitudinally assessed following IA administration of 10 mg LPS at 5, 12 or 24h or 2, 4, 8 or 15d before preterm birth. Hepatic inflammation was observed, characterized by increased hepatic cytokine mRNA levels (5h - 2d post IA LPS exposure) and increased erythropoietic clusters (at 8 and 15 days post IA LPS exposure). Besides, 12h after IA LPS exposure, plasma BA levels were increased, whereas gene expression levels of several hepatic BA transporters were decreased. Initial EHC alterations normalized over time. Concluding, IA LPS exposure induces significant time-dependent changes in the fetal liver and EHC. These chorioamnionitis induced changes have potential postnatal consequences and the duration of IA LPS exposure might be essential herein.

Influence of CD8 T cell priming in liver and gut on the enterohepatic circulation.

BACKGROUND & AIMS: The enterohepatic circuit of T cells may be responsible for the development of autoimmune liver disease. We employed transgenic mice to characterize phenotype and migration patterns of CD8 T cells activated in liver and gut. METHODS: We studied the migration of antigen-specific CD8 T cells primed in liver or gut after transfer in wild-type mice or mice that express ovalbumin in liver or gut. We performed transcriptome analysis of these two distinct T cell populations and confirmed our findings by flow cytometry. RESULTS: Specific migration patterns were induced by activation of CD8 T cells in gut or liver. Gut-activated CD8 T cells expressed α4ß7 and CCR9 and migrated to the gut and to the liver. Liver-activated T cells expressed integrins α4, α6, ß1, α4ß7 as well as CD62L, Ly6C, and neuropilin-1 and retained the capability to re-circulate through lymph nodes. Presence of the antigen increased retention of both types of activated T cells in the liver, but migration of liver-activated T cells to the gut was prohibited. CONCLUSIONS: CD8 T cells primed in the liver in vivo are not capable of migrating to the gut, implying that the enterohepatic circuit of CD8 T cells is in fact a one-way road from the gut to the liver. Priming of CD8 T cells in the liver results in a distinct phenotype with attributes of central memory cells and induces a unique homing pattern. Gut-primed T cells preferentially home to the liver, in principle enabling them to induce autoimmune liver disease.

Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease.

Primary sclerosing cholangitis is strongly linked to inflammatory bowel disease, but any model to explain the development of primary sclerosing cholangitis must take into account the fact that it usually runs a course independent from inflammation in the bowel, illustrated by the fact that this disease can develop many years after proctocolectomy. Thus, liver disease can develop in the absence of a diseased colon and cannot be explained solely by release of toxic factors from the inflamed gut. We propose the existence of an enterohepatic circulation of lymphocytes, whereby some mucosal lymphocytes generated in the gut during active inflammatory disease subsequently persist as longlived memory cells capable of recirculation through the liver. Under the right conditions, these dual-homing lymphocytes might become activated in the liver resulting in hepatic inflammation that is independent from inflammation in the gut. Recent reports that some lymphocyte homing-receptors are shared by the liver and gut provide a molecular basis for this hypothesis and explain the distribution of extraintestinal disease in inflammatory bowel disease.