Abstract
ABSTRACTAkkermansia 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.
Highlights
Akkermansia muciniphila, as a member of the gut microbiota, has been proposed as a next-generation probiotic
The meta-analysis performed on data sets comparing mRNA levels in mice with CCL4-induced liver injury to those in controls shows that the expression of eight genes, including tumor necrosis factor alpha (TNF-a), Toll-like receptor (TLR)-2, TLR-4, transforming growth factor beta (TGF-b), alpha smooth muscle actin (a-SMA), platelet-derived growth factor (PDGF), tissue inhibitor of metalloproteinases (TIMP1), and collagen type 1 alpha 1 (Col1a1) in liver, are closely related to fibrosis and were differentially expressed, with a P value of,0.05 by the Mann-Whitney method
extracellular matrix (ECM) regulator genes involved in tissue fibrosis and inflammation (TGF-b, a-SMA, PDGF, TIMP1, and Col1a1) were significantly overexpressed in the fibrosis group compared to those in healthy control (HC) mice (P, 0.0001)
Summary
Akkermansia muciniphila, as a member of the gut microbiota, has been proposed as a next-generation probiotic. MicrobiolSpectrum.asm.org 1 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 ameliorated by different A. muciniphila treatments. Chronic liver disease (CLD) refers to liver dysfunction as a consequence of progressive destruction and regeneration of liver tissue, which can lead to fibrosis and hepatic carcinoma with high mortality rates [1]. It is known that fibrosis is a wound-healing process that activates hepatic stellate cells (HSCs) following exposure to chronic stimuli and persistent inflammation; this results in the overexpression of the extracellular matrix (ECM) and a collagen-rich tissue that replaces the natural parenchyma of the liver [4]. CLD affects other tissues through interstitial communication between the liver, gut, adipose, and kidney tissues [7, 8]
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