Dataset Information

The gut microbiome contributes to splenomegaly and tissue inflammation in a murine model of primary biliary cholangitis.

ABSTRACT:

Background

Splenomegaly is not just a consequence of numerous chronic and acute conditions but may also contribute to their severity, due to the interaction of the spleen with the gut microbiome. This study aimed to explore the effect of the gut microbiome on splenomegaly.

Methods

We used p40^-/-IL-2Rα^-/- mice as a murine model of primary biliary cholangitis (PBC) as per our previous study. Splenomegaly was evaluated by spleen weight. Severity of liver inflammation was evaluated by hepatic mononuclear cell (MNCs) number and pathological score. Changes of immune cells in the spleen and liver were detected by flow cytometry. The effects of the gut microbiome on splenomegaly and liver inflammation were observed by combined antibiotic treatment in p40^-/-IL-2Rα^-/- mice.

Results

A proportion of p40^-/-IL-2Rα^-/- mice developed splenomegaly. The results revealed that liver mononuclear cells infiltration, histological scores of hepatic inflammation, and bile duct damage were positively correlated with the degree of splenomegaly. Hepatic CD4⁺ and CD8⁺ T cells numbers were significantly higher in mice with splenomegaly, and this was particularly observed in activated effector memory CD4⁺ T and CD8⁺ T cells. A proportion of some other immune cells including granulocytes, B, natural killer (NK), and CD8⁺ T effector memory cells were also altered in the enlarged spleen. More importantly, administration of quadruple antibiotics to deplete gut microbiota relieved the splenomegaly of p40^-/-IL-2Rα^-/- mice, significantly alleviated liver inflammation, and caused a significant reduction of liver and spleen T cell accumulation and activation; however, single antibiotics did not induce these changes.

Conclusions

Splenomegaly was associated with more severe liver inflammation in our PBC murine model, and this effect was reversed by quadruple antibiotic treatment.

SUBMITTER: Wang CB

PROVIDER: S-EPMC9347057 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

The gut microbiome contributes to splenomegaly and tissue inflammation in a murine model of primary biliary cholangitis.

Wang Cheng-Bo CB Wang Yan Y Yao Yuan Y Wang Jin-Jun JJ Tsuneyama Koichi K Yang Qiong Q Liu Bin B Selmi Carlo C Gershwin M Eric ME Yang Shu-Han SH Lian Zhe-Xiong ZX

Annals of translational medicine 20220501 9

<h4>Background</h4>Splenomegaly is not just a consequence of numerous chronic and acute conditions but may also contribute to their severity, due to the interaction of the spleen with the gut microbiome. This study aimed to explore the effect of the gut microbiome on splenomegaly.<h4>Methods</h4>We used p40<sup>-/-</sup>IL-2Rα<sup>-/-</sup> mice as a murine model of primary biliary cholangitis (PBC) as per our previous study. Splenomegaly was evaluated by spleen weight. Severity of liver inflamm ...[more]

PMID: 35928756

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Project description:Purpose of reviewPrimary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease.Recent findingsPBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses.SummaryPBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.

Dataset Information

The gut microbiome contributes to splenomegaly and tissue inflammation in a murine model of primary biliary cholangitis.

Background

Methods

Results

Conclusions

Publications

The gut microbiome contributes to splenomegaly and tissue inflammation in a murine model of primary biliary cholangitis.

Similar Datasets

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