The Protective Effects of Live and Pasteurized Akkermansia muciniphila and Its Extracellular Vesicles against HFD/CCl4-Induced Liver Injury

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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.

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Cytoscape: a software environment for integrated models of biomolecular interaction networks.

Paul Shannon, Andrew Markiel, Owen Ozier … (2003)

Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.

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limma powers differential expression analyses for RNA-sequencing and microarray studies

Matthew E. Ritchie, Belinda Phipson, Di Wu … (2015)

limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.

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Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study

Clara Depommier, Amandine Everard, Céline Druart … (2019)

Metabolic syndrome is characterized by a constellation of comorbidities that predispose individuals to an increased risk of developing cardiovascular pathologies as well as type 2 diabetes mellitus (T2DM) 1 . The gut microbiota is considered as a new key contributor involved in the onset of obesity-related disorders 2 . In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated T2DM, or hypertension 3–8 . As the administration of A.muciniphila has never been investigated in humans, we conducted a randomized double-blind placebo-controlled pilot study in overweight/obese insulin resistant volunteers, 40 were enroled and 32 completed the trial. The primary endpoints were on safety, tolerability and metabolic parameters (i.e., insulin resistance, circulating lipids, visceral adiposity, body mass). The secondary outcomes were the gut barrier function (i.e., plasma lipopolysacharrides (LPS) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 1010 bacteria either alive or pasteurized A.muciniphila for 3 months was safe and well tolerated. Compared to the Placebo, pasteurized A.muciniphila improved insulin sensitivity (+28.62±7.02%, P=0.002), reduced insulinemia (-34.08±7.12%, P=0.006) and plasma total cholesterol (-8.68±2.38%, P=0.02). Pasteurized A.muciniphila supplementation slightly decreased body weight (-2.27±0.92kg, P=0.091) as compared to the Placebo group, and fat mass (-1.37±0.82kg, P=0.092) and hip circumference (-2.63±1.14cm, P = 0.091) as compared to baseline. After 3 months of supplementation, A.muciniphila reduced the levels of relevant blood markers of liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (NCT02637115) shows that the intervention was safe and well-tolerated and that the supplementation with A.muciniphila improves several metabolic paramaters.

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Author and article information

Contributors

Seyed Davar Siadat:

ORCID: https://orcid.org/0000-0002-6892-5603

Mohammad Reza Zali

Jennifer M. Auchtung: Role: Editor

Journal

Journal ID (nlm-ta): Microbiol Spectr

Journal ID (iso-abbrev): Microbiol Spectr

Journal ID (publisher-id): spectrum

Title: Microbiology Spectrum

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Electronic): 2165-0497

Publication date (Electronic, pub): 22 September 2021

Publication date (Electronic, collection): Sep-Oct 2021

Publication date PMC-release: 22 September 2021

Volume: 9

Issue: 2

Electronic Location Identifier: e00484-21

Affiliations

[a ] Microbiology Research Center, Pasteur Institute of Irangrid.420169.8, , Tehran, Iran

[b ] Mycobacteriology and Pulmonary Research Department, Pasteur Institute of Irangrid.420169.8, , Tehran, Iran

[c ] Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

[d ] Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran

[e ] Systems Biomedicine Unit, Pasteur Institute of Irangrid.420169.8, , Tehran, Iran

[f ] Department of Basic Sciences, School of Veterinary Medicine, Shiraz Universitygrid.412573.6, , Shiraz, Iran

[g ] Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

[h ] Taleghani Hospital, Department of Pathology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

[i ] Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

[j ] Experimental Therapy Unit, Laboratory of Oncology, Giannina Gaslini Children’s Hospital, Genoa, Italy

University of Nebraska-Lincoln

Author notes

Citation Keshavarz Azizi Raftar S, Ashrafian F, Yadegar A, Lari A, Moradi HR, Shahriary A, Azimirad M, Alavifard H, Mohsenifar Z, Davari M, Vaziri F, Moshiri A, Siadat SD, Zali MR. 2021. The protective effects of live and pasteurized Akkermansia muciniphila and its extracellular vesicles against HFD/CCl4-induced liver injury. Microbiol Spectr 9:e00484-21. https://doi.org/10.1128/Spectrum.00484-21.

Author information

Shahrbanoo Keshavarz Azizi Raftar https://orcid.org/0000-0002-4492-6716

Seyed Davar Siadat https://orcid.org/0000-0002-6892-5603

Article

Publisher ID: 00484-21 Publisher ID: spectrum.00484-21

DOI: 10.1128/Spectrum.00484-21

PMC ID: 8557882

PubMed ID: 34549998

SO-VID: c041444e-f0c4-4ff1-bbca-3abe34190f4a

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

History

Date received : 7 June 2021

Date accepted : 4 August 2021

Page count

supplementary-material: 1, Figures: 7, Tables: 1, Equations: 0, References: 90, Pages: 24, Words: 14407

Funding

Funded by: SBUMS | Research Institute for Gastroenterology and Liver Diseases (دانشگاه علوم پزشکی و خدمات بهداشتی، درمانی), FundRef https://doi.org/10.13039/501100015693;

Award ID: RIGLD 1017

Award Recipient : Mohammad Reza Zali

Funded by: Pasteur Institute of Iran (IPI), FundRef https://doi.org/10.13039/501100010679;

Award ID: B-9428

Award Recipient : Seyed Davar Siadat

Custom metadata

cover-date September/October 2021

Keywords: akkermansia muciniphila,liver fibrosis,extracellular vesicles,hepatic stellate cells,intestinal bacteria

Data availability:

Keywords: akkermansia muciniphila, liver fibrosis, extracellular vesicles, hepatic stellate cells, intestinal bacteria

The Protective Effects of Live and Pasteurized Akkermansia muciniphila and Its Extracellular Vesicles against HFD/CCl4-Induced Liver Injury

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Bacterial extracellular vesicles

Most cited references 89

Cytoscape: a software environment for integrated models of biomolecular interaction networks.

limma powers differential expression analyses for RNA-sequencing and microarray studies

Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study

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