Su1588 Helicobacter Hepaticus Infection Promotes Hepatitis and Foci of Cellular Alteration in Farnesoid X Receptor (FXR) Deficient Mice

ABSTRACTObjectiveThe gut microbiota (GM) can have complicated and often undetermined interactions with the function of many organs in the body. GM is altered in a variety of liver diseases, but the significance of such changes on the liver disease is still unclear. Hepatic autophagy deficiency causes liver injury accompanied with cholestasis. Here, we investigated the impact of such hepatic changes on GM and in turn the effect of gut dysbiosis on liver injury.DesignFecal microbiota from mice with liver-specific loss of autophagy-related gene 5 (Atg5), Atg5Δhep mice, were analyzed by 16S sequencing. Antibiotics (ABX) was used to modulate GM in mice. Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice over-expressing FGF15 gene, or given a fibroblast growth factor receptor 4 (FGFR4) inhibitor.ResultsThe composition of GM was significantly changed with a notable increase of BA-metabolizing bacteria in Atg5Δhep mice, leading to a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs in the intestine, which markedly activated ileal FXR with an increased expression of FGF15. ABX or cholestyramine treatment exacerbated liver injury and ductular reaction, and decreased FGF15 expression, whereas modulating FGF15 signaling altered liver phenotypes in the autophagy-deficient mice.ConclusionGut dysbiosis can remedy liver injury in Atg5Δhep mice through the FXR-FGF15 signaling. Antibiotics use in the condition of liver injury may have unexpected adverse consequences via the gut-liver axis.SHORT SUMMARYWhat is already known about this subject?Gut microbiota (GM) can be altered during hepatic pathogenesis.GM are involved in bile acid (BA) metabolism.Autophagy deficiency in the liver disrupts BA homeostasis and causes cholestatic injury.What are the new findings?Deficiency of autophagy in the liver causes alteration of GM, which leads to a higher proportion of BA-metabolizing bacteria.GM contribute to the activation of ileal farnesoid X receptor (FXR) and a higher expression of fibroblast growth factor 15 (FGF15) in autophagy deficient condition in the liver, which is associated with decreased levels of conjugated BAs and increased levels of unconjugated BAs in the intestine.Manipulations that lead to GM alteration, intestinal BA signaling, or FGF15 signaling can all modulate the liver phenotype.BA and GM together can act as a sensor to liver injury to trigger FGF15-mediated protective mechanism.How might it impact on clinical practice in the foreseeable future?These findings indicate that gut dysbiosis in the scenario of liver disease can be beneficial, suggesting cautions should be exercised in the use of antibiotics during specific liver diseases.If antibiotics need to be used in patients with liver diseases it may be beneficial to enhance the FXR-FGF15 feedback signaling to retain the protective effect of GM.

Download Full-text

Ectonucleoside Triphosphate Diphosphohydrolase Type 5 (Entpd5)-Deficient Mice Develop Progressive Hepatopathy, Hepatocellular Tumors, and Spermatogenic Arrest

Veterinary Pathology ◽

10.1354/vp.08-vp-0201-r-am ◽

2009 ◽

Vol 46 (3) ◽

pp. 491-504 ◽

Cited By ~ 27

Author(s):

R. Read ◽

G. Hansen ◽

J. Kramer ◽

R. Finch ◽

L. Li ◽

...

Keyword(s):

Cellular Proliferation ◽

Hepatocellular Adenoma ◽

Oval Cell ◽

Soluble Enzyme ◽

Wild Type ◽

Genetic Inactivation ◽

Cellular Alteration ◽

Low Incidence ◽

Proliferation Of Hepatocytes ◽

Deficient Mice

Ectonucleoside triphosphate diphosphohydrolase type 5 (ENTPD5, also CD39L4) is a soluble enzyme that hydrolyzes purine nucleoside diphosphates. Genetic inactivation of ENTPD5 in mice ( Entpd5-/-) resulted in 2 major histopathologic lesions: hepatopathy and aspermia. The hepatopathy was progressive and characterized by centrilobular hepatocyte hypertrophy, oval cell proliferation, bile staining of Kupffer cells, and hepatocyte degeneration with increasing incidence and severity of degenerative lesions, development of multiple foci of cellular alteration, and hepatocellular neoplasia with age. Greatly increased proliferation of hepatocytes in young adult as well as aged Entpd5-/- mice was demonstrated by Ki67 immunohistochemistry and 5î-bromo-3î-deoxyuridine incorporation. Of 15 Entpd5-/- mice between 44 and 69 weeks of age, all showed foci of cellular alteration in the liver, and at least 6 of 15 developed hepatocellular carcinoma (HCC), hepatocellular adenoma, or both. Significantly, none of these lesions were observed in 13 wild-type Entpd5++ littermates. These findings, combined with the historically low incidence (about 5%) of HCC in mice up to 2 years of age with the same genetic background, strongly suggest that loss of Entpd5 promotes hepatocellular neoplasia in mice. In humans, ENTPD5 has been found to be identical to the PCPH proto-oncogene, and dysregulation of this gene has been demonstrated in some human cancers. This mouse model could contribute to the understanding of the influence of ENTPD5/PCPH on cellular proliferation and neoplasia.

Download Full-text

Probiotic Lactobacillus spp. Diminish Helicobacter hepaticus-Induced Inflammatory Bowel Disease in Interleukin-10-Deficient Mice

Infection and Immunity ◽

10.1128/iai.73.2.912-920.2005 ◽

2005 ◽

Vol 73 (2) ◽

pp. 912-920 ◽

Cited By ~ 99

Author(s):

Jeremy A. Peña ◽

Arlin B. Rogers ◽

Zhongming Ge ◽

Vivian Ng ◽

Sandra Y. Li ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Real Time ◽

Bowel Disease ◽

Interleukin 10 ◽

Helicobacter Hepaticus ◽

Murine Colitis ◽

Tnf Α ◽

Inflammatory Bowel ◽

Deficient Mice ◽

Colitis Model

ABSTRACT Clinical and experimental evidence has demonstrated the potential role of probiotics in the prevention or treatment of inflammatory bowel disease. Probiotic clones with direct immunomodulatory activity may have anti-inflammatory effects in the intestine. We investigated the roles of tumor necrosis factor alpha (TNF-α)-inhibitory Lactobacillus clones with a pathogen-induced murine colitis model. Murine-derived probiotic lactobacilli were selected in vitro for their ability to inhibit TNF-α secretion by Helicobacter hepaticus-stimulated macrophages. Interleukin-10 (IL-10)-deficient mice were treated with probiotic Lactobacillus reuteri in combination with Lactobacillus paracasei and then challenged with H. hepaticus. Ten weeks postinoculation, the severity of typhlocolitis was assessed by histologic examination of the cecocolic region. Intestinal proinflammatory cytokine responses were evaluated by real-time quantitative reverse transcriptase PCR and immunoassays, and the quantities of intestinal H. hepaticus were evaluated by real-time PCR. Intestinal colonization by TNF-α-inhibitory lactobacilli reduced intestinal inflammation in H. hepaticus-challenged IL-10-deficient mice despite similar quantities of H. hepaticus in cocolonized animals. Proinflammatory colonic cytokine (TNF-α and IL-12) levels were lowered in Lactobacillus-treated animals. In this H. hepaticus-challenged IL-10-deficient murine colitis model, lactobacilli demonstrated probiotic effects by direct modulation of mucosal inflammatory responses.

Download Full-text

Excessive bile acid activated NF-kappa B and promoted the development of alcoholic steatohepatitis in farnesoid X receptor deficient mice

Biochimie ◽

10.1016/j.biochi.2015.05.014 ◽

2015 ◽

Vol 115 ◽

pp. 86-92 ◽

Cited By ~ 19

Author(s):

Wei-Bin Wu ◽

Yuan-Yuan Chen ◽

Bo Zhu ◽

Xiao-Min Peng ◽

Song-Wen Zhang ◽

...

Keyword(s):

Bile Acid ◽

Farnesoid X Receptor ◽

Nf Kappa B ◽

Alcoholic Steatohepatitis ◽

Deficient Mice

Download Full-text

Gastroenteritis in NF-κB-Deficient Mice Is Produced with Wild-Type Camplyobacter jejuni but Not with C. jejuni Lacking Cytolethal Distending Toxin despite Persistent Colonization with Both Strains

Infection and Immunity ◽

10.1128/iai.72.2.1116-1125.2004 ◽

2004 ◽

Vol 72 (2) ◽

pp. 1116-1125 ◽

Cited By ~ 114

Author(s):

James G. Fox ◽

Arlin B. Rogers ◽

Mark T. Whary ◽

Zhongming Ge ◽

Nancy S. Taylor ◽

...

Keyword(s):

Immune Surveillance ◽

Adaptive Immune System ◽

Cytolethal Distending Toxin ◽

Helicobacter Hepaticus ◽

Wild Type ◽

System Defect ◽

Gastrointestinal Lesions ◽

Humoral Responses ◽

Deficient Mice

ABSTRACT Campylobacter jejuni continues to be a leading cause of bacterial enteritis in humans. However, because there are no readily available animal models to study the pathogenesis of C. jejuni-related diseases, the significance of potential virulence factors, such as cytolethal distending toxin (CDT), in vivo are poorly understood. Mice deficient in NF-κB subunits (p50−/− p65+/−) in a C57BL/129 background are particularly susceptible to colitis induced by another enterohepatic microaerobe, Helicobacter hepaticus, which, like C. jejuni, produces CDT. Wild-type C. jejuni 81-176 and an isogenic mutant lacking CDT activity (cdtB mutant) were inoculated into NF-κB-deficient (3X) and C57BL/129 mice. Wild-type C. jejuni colonized 29 and 50% of the C57BL/129 mice at 2 and 4 months postinfection (p.i.), respectively, whereas the C. jejuni cdtB mutant colonized 50% of the C57BL/129 mice at 2 p.i. but none of the mice at 4 months p.i. Although the C57BL/129 mice developed mild gastritis and typhlocolitis, they had robust immunoglobulin G (IgG) and Th1-promoted IgG2a humoral responses to both the wild-type strain and the C. jejuni cdtB mutant. In contrast, 75 to 100% of the 3X mice were colonized with both the wild type and the C. jejuni cdtB mutant at similar levels at all times examined. Wild-type C. jejuni caused moderately severe gastritis and proximal duodenitis in 3X mice that were more severe than the gastrointestinal lesions caused by the C. jejuni cdtB mutant. Persistent colonization of NF-κB-deficient mice with the wild type and the C. jejuni cdtB mutant was associated with significantly impaired IgG and IgG2a humoral responses (P < 0.001), which is consistent with an innate or adaptive immune system defect(s). These results suggest that the mechanism of clearance of C. jejuni is NF-κB dependent and that CDT may have proinflammatory activity in vivo, as well as a potential role in the ability of C. jejuni to escape immune surveillance. NF-κB-deficient mice should be a useful model to further study the role of CDT and other aspects of C. jejuni pathogenesis.

Download Full-text