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The Protective Effects of Live and Pasteurized Akkermansia muciniphila and Its Extracellular Vesicles against
Shahrbanoo Keshavarz Azizi Raftar1,2,3, Fatemeh Ashrafian1,2,4, Abbas Yadegar3
1Microbiology Research Center, Pasteur Institute of Irangrid.420169.8, Tehran, Iran.
Abstract:
Akkermansia muciniphila, as a member of the gut microbiota, has been proposed as a next-generation probiotic. Liver fibrosis is the main determinant of liver dysfunction and mortality in patients with chronic liver disease. In this study, we aimed to determine the beneficial effects of live and pasteurized A. muciniphila and its extracellular vesicles (EVs) on the prevention of liver fibrosis. The response of hepatic stellate cells (HSCs) to live and pasteurized A. muciniphila and its EVs was examined in quiescent, lipopolysaccharide (LPS)-activated LX-2 cells. Liver fibrosis was induced in 8-week-old C57BL/6 mice, using a high-fat diet (HFD) and carbon tetrachloride (CCl4) administration for 4 weeks. The mice were concomitantly treated via oral gavage with three forms of bacteria. The relative expression of different fibrosis and inflammatory markers was assessed in the tissues. Histological markers, serum biochemical parameters, and cytokine production were also analyzed, and their correlations with the relative abundance of targeted fecal bacteria were examined. All A. muciniphila preparations exhibited protective effects against HSC activation; however, EVs showed the greatest activity in HSC regression. Oral gavage with A. muciniphila ameliorated the serum biochemical and inflammatory cytokines and improved liver and colon histopathological damages. The relative expression of fibrosis and inflammatory biomarkers was substantially attenuated in the tissues of all treated mice. The composition of targeted stool bacteria in the live A. muciniphila group was clearly different from that in the fibrosis group. This study indicated that A. muciniphila and its derivatives could successfully protect against HFD/CCl4-induced liver injury. However, further studies are needed to prove the beneficial effects of A. muciniphila on the liver. IMPORTANCE Akkermansia muciniphila, as a member of the gut microbiota, has been proposed as a next-generation probiotic. Liver fibrosis is the main determinant of liver dysfunction and mortality in patients with chronic liver disease. In this study, we aimed to determine the beneficial effects of live and pasteurized A. muciniphila and its extracellular vesicles (EVs) on the prevention of liver fibrosis. The results of the present study indicated that oral administration of live and pasteurized A. muciniphila and its EVs could normalize the fecal targeted bacteria composition, improve the intestinal permeability, modulate inflammatory responses, and subsequently prevent liver injury in HFD/CCl4-administered mice. Following the improvement of intestinal and liver histopathology, HFD/CCl4-induced kidney damage and adipose tissue inflammation were also ameliorated by different A. muciniphila treatments.
Insights
Akkermansia muciniphila and its extracellular vesicles show promise in preventing liver fibrosis by modulating gut bacteria and reducing inflammation. These findings suggest potential therapeutic applications for gut microbiota-based interventions in liver disease.
Area of Science:
- Microbiology and Gut Microbiome Research
- Hepatology and Liver Disease Pathogenesis
- Probiotic and Next-Generation Therapeutic Development
Background:
- Akkermansia muciniphila is recognized as a next-generation probiotic with potential health benefits.
- Liver fibrosis, a significant complication of chronic liver disease, drives liver dysfunction and mortality.
- Understanding the role of gut microbiota in liver fibrosis is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the protective effects of live, pasteurized Akkermansia muciniphila, and its extracellular vesicles (EVs) against liver fibrosis.
- To evaluate the impact of A. muciniphila preparations on hepatic stellate cell (HSC) activation and regression.
- To assess the modulation of fibrosis and inflammatory markers in a mouse model of diet- and toxin-induced liver injury.
Main Methods:
- In vitro assessment of HSC response to A. muciniphila and its EVs in LX-2 cells.
- Induction of liver fibrosis in C57BL/6 mice using a high-fat diet (HFD) and carbon tetrachloride (CCl4).
- Oral gavage administration of live, pasteurized A. muciniphila, or its EVs to treated mice.
- Analysis of liver and colon histology, serum biochemical parameters, cytokine production, and gene expression of fibrosis/inflammatory markers.
- Correlation analysis between fecal bacterial composition and host physiological parameters.
Main Results:
- All A. muciniphila preparations demonstrated protective effects against HSC activation, with EVs showing the most potent HSC regression activity.
- Oral administration of A. muciniphila ameliorated liver and colon histopathological damage, reduced pro-inflammatory cytokines, and improved serum biochemical profiles.
- Significant attenuation of fibrosis and inflammatory biomarkers was observed in the liver tissues of treated mice.
- A distinct difference in targeted fecal bacteria composition was noted between the live A. muciniphila group and the fibrosis group.
- Treatment with A. muciniphila derivatives also led to improvements in HFD/CCl4-induced kidney damage and adipose tissue inflammation.
Conclusions:
- Akkermansia muciniphila and its derivatives effectively protect against high-fat diet/carbon tetrachloride-induced liver injury in mice.
- Oral administration of A. muciniphila normalizes fecal bacterial composition, enhances intestinal barrier function, and modulates inflammatory responses.
- Extracellular vesicles of A. muciniphila show significant potential for HSC regression and liver fibrosis prevention.
- Further research is warranted to fully elucidate the therapeutic benefits of A. muciniphila for liver diseases.
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