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Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis
Published on: February 10, 2015
Host miRNA-21 promotes liver dysfunction by targeting small intestinal Lactobacillus in mice
André A Santos1, Marta B Afonso1, Ricardo S Ramiro2
1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa , Lisbon, Portugal.
Abstract:
New evidence shows that host-microbiota crosstalk can be modulated via endogenous miRNAs. We have previously reported that miR-21 ablation protects against liver injury in cholestasis. In this study, we investigated the role of miR-21 in modulating the gut microbiota during cholestasis and its effects in liver dysfunction. Mice lacking miR-21 had reduced liver damage and were protected against small intestinal injury as well as from gut microbiota dysbiosis when subjected to bile duct ligation surgery. The unique microbiota profile of miR-21KO mice was characterized by an increase in Lactobacillus, a key microbiome genus for gut homeostasis. Interestingly, in vitro incubation of synthetic miR-21 directly reduced Lactobacillus load. Moreover, supplementation with Lactobacillus reuteri revealed reduced liver fibrosis in acute bile duct-ligated mice, mimicking the protective effects in miR-21 knockout mice. D-lactate, a main product of Lactobacillus, regulates gut homeostasis that may link with reduced liver fibrosis. Altogether, our results demonstrate that miR-21 promotes liver dysfunction through direct modulation of the gut microbiota and highlight the potential therapeutic effects of Lactobacillus supplementation in gut and liver homeostasis.
Insights
MicroRNA-21 (miR-21) promotes liver dysfunction by altering gut microbiota. Supplementing with Lactobacillus reuteri protects against liver injury and fibrosis, highlighting a potential therapeutic strategy.
Area of Science:
- Microbiology
- Molecular Biology
- Hepatology
Background:
- Host-microbiota interactions are crucial for health and disease.
- Endogenous microRNAs (miRNAs) can modulate these interactions.
- Previous work indicated miR-21 ablation protects against cholestatic liver injury.
Purpose of the Study:
- To investigate the role of miR-21 in gut microbiota modulation during cholestasis.
- To determine the effect of miR-21 on liver dysfunction in cholestasis.
- To explore the therapeutic potential of Lactobacillus supplementation.
Main Methods:
- Utilized miR-21 knockout (miR-21KO) mice subjected to bile duct ligation (BDL) surgery.
- Analyzed gut microbiota composition and liver/intestinal injury.
- Performed in vitro incubation of synthetic miR-21 with Lactobacillus and in vivo supplementation with Lactobacillus reuteri.
Main Results:
- miR-21KO mice exhibited reduced liver and small intestinal injury, and protected against gut microbiota dysbiosis post-BDL.
- miR-21KO mice showed an increase in Lactobacillus, a genus vital for gut homeostasis.
- In vitro miR-21 reduced Lactobacillus load; Lactobacillus reuteri supplementation mimicked miR-21KO protective effects against liver fibrosis.
Conclusions:
- miR-21 promotes liver dysfunction by directly modulating the gut microbiota composition.
- Lactobacillus, particularly Lactobacillus reuteri, plays a protective role in cholestasis-induced liver injury and fibrosis.
- Lactobacillus supplementation represents a potential therapeutic avenue for restoring gut and liver homeostasis.
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