Akkermansia muciniphila Ameliorates Acetaminophen-Induced Liver Injury by Regulating Gut Microbial Composition and Metabolism.

The gut microbiota drives individual sensitivity to excess acetaminophen (APAP)-mediated hepatotoxicity. It has been reported that the bacterium Akkermansia muciniphila protects hosts against liver disease via the liver-gut axis, but its therapeutic potential for drug-induced liver injury remains unclear. In this study, we aimed to investigate the effect of A. muciniphila on APAP-induced liver injury and the underlying mechanism. Administration of A. muciniphila efficiently alleviated APAP-induced hepatotoxicity and reduced the levels of serum alanine aminotransferase (ALT) and aspartate transaminase (AST). A. muciniphila significantly attenuated APAP-induced oxidative stress and the inflammatory response, as evidenced by restoration of the reduced glutathione/oxidized glutathione (GSH/GSSG) balance, enhanced superoxide dismutase (SOD) activity, reduced proinflammatory cytokine production, and alleviation of macrophage and neutrophil infiltration. Moreover, A. muciniphila maintained gut barrier function, reshaped the perturbed microbial community and promoted short-chain fatty acid (SCFA) secretion. The beneficial effects of A. muciniphila were accompanied by alterations in hepatic gene expression at the transcriptional level and activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results suggested that A. muciniphila could be a potential pretreatment for APAP-induced liver injury. IMPORTANCE Our work revealed that A. muciniphila attenuated APAP-induced liver injury by alleviating oxidative stress and inflammation in the liver, and its hepatoprotective effect was accompanied by activation of the PI3K/Akt pathway and mediated by regulation of the composition and metabolic function of the intestinal microbiota. This finding suggested that the microbial community is a non-negligible impact on drug metabolism and probiotic administration could be a potential therapy for drug-induced liver injury.

Western Diet Aggravated Carbon Tetrachloride-Induced Chronic Liver Injury by Disturbing Gut Microbiota and Bile Acid Metabolism.

SCOPE: The high-fat, high-sucrose, and low-fiber Western diet (WD) is popular in many countries and affects the onset and progression of many diseases. This study is aimed to explore the influence of the WD on chronic liver disease (CLD) and its possible mechanism. METHODS AND RESULTS: C57BL/6 mice are given a control diet (CD) or WD and CLD is induced by intraperitoneally injecting carbon tetrachloride (CCL4 ) twice a week for 8 weeks. The WD aggravated CCL4 -induced chronic liver injury, as evidenced by increased serum transaminase levels, worsened hepatic inflammatory response, and fibrosis. Gut microbiota is disturbed in mice treated with CCL4 +WD (WC group), manifested as the accumulation of Fusobacteria, Streptococcaceae, Streptococcus, Fusobacterium, and Prevotella and the depletion of Firmicutes, Lachnospiraceae, and Roseburia. Additionally, increased hepatic taurocholic acid in the WC group activated sphingosine-1-phosphate receptor 2, which is positively correlated with hepatic fibrosis and inflammation parameters. Mice in the WC group have higher fecal primary bile acid (BA) levels and lower fecal secondary/primary BA ratios. Serum FGF15 levels are also elevated in the WC group, which is positively correlated with hepatic inflammation. CONCLUSION: WD accelerates the progression of CLD which is associated with changes in the gut microbiota and BA metabolism.

Lactobacillus rhamnosus Granules Dose-Dependently Balance Intestinal Microbiome Disorders and Ameliorate Chronic Alcohol-Induced Liver Injury.

As the functions of Lactobacilli become better understood, there are increasing numbers of applications for Lactobacillus products. Previously, we have demonstrated that Lactobacillus rhamnosus GG (LGG) can prevent alcoholic liver injury. LGG granules were produced by fluid bed granulation with a media composed of starch, skimmed milk powder, whey powder, microcrystalline cellulose and maltose, and LGG fermented liquid that comprised 30-50% of the total weight. We found LGG granules dose-dependently protected against chronic alcoholic liver disease. When alcohol was consumed for 8 weeks with LGG treatment during the last 2 weeks, we demonstrated that the dose dependence of LGG granules can improve alcohol-induced liver injury through decreasing the levels of lipopolysaccharide and tumor necrosis factor-α in serum and prevent liver steatosis by suppressing triglyceride, free fatty acid, and malondialdehyde production in liver. Alcohol feeding caused a decline in the number of both Lactobacillus and Bifidobacterium, with a proportional increase in the number of Clostridium perfringens in ileum, and expansion of the Gram-negative bacteria Proteobacteria, Campylobacterales, and Helicobacter in cecum. However, LGG granule treatment restored the content of these microorganisms. In conclusion, LGG granule supplementation can improve the intestinal microbiota, reduce the number of gram-negative bacteria, and ameliorate alcoholic liver injury.

Type 3 cytokines in liver fibrosis and liver cancer.

The type 3 cytokines IL-17 and IL-22 play a crucial, well synchronized physiological role in wound healing and repairing tissue damage due to infections or injury at barrier surfaces. These cytokines act on epithelial cells to induce secretion of early immune mediators, recruitment of inflammatory cells to the site of injury, and to trigger tissue repair mechanisms. However, if the damage persists or if these cytokines are dysregulated, then they contribute to a number of inflammatory pathologies, autoimmune conditions and cancer. The liver is a multifunctional organ that plays an essential role in metabolism, detoxification, and immune surveillance. It is also exposed to a variety of pathogens, toxins and injuries. Over the past decade, IL-17 and IL-22 have been implicated in various aspects of liver inflammation. IL-17 is upregulated in chronic liver injury and associated with liver disease progression. In contrast, IL-22 was shown to be hepatoprotective during acute liver injury but exhibited inflammatory effects in other models. Furthermore, IL-22 and IL-17 are both associated with poor prognosis in liver cancer. Finally, the regulatory mechanisms governing the physiological versus the pathological role of these two cytokines during acute and chronic liver injury remain poorly understood. In this review, we will summarize the current state of knowledge about IL-17 and IL-22 in wound healing during acute and chronic liver injury, their contribution to pathogenesis, their regulation, and their role in the transition from advanced liver disease to liver cancer.

[Intestinal microflora in rats under the conditions of a chronic toxic lesion of the liver]. / Mikroflora kishechnika krys v usloviiakh khronicheskogo toksicheskogo porazheniia pecheni.

Intestinal microflora in healthy rats and its changes under the conditions of experimental chronic toxic hepatitis were studied. The study revealed that in intact animals the microflora of the small intestine was represented by bacteria of the genera Escherichia, Enterobacter, Moraxella, Alcaligenes, Staphylococcus, Streptococcus. Bacteria of the genera Escherichia, Enterobacter, Moraxella, Alcaligenes, Staphylococcus, Corynebacterium and Clostridium were isolated from the large intestine. No bacteria were found in the systemic blood, the contents of the portal vein, as well as in the liver parenchyma and the mesenterial lymph nodes. As the result of dysbiosis induced by the introduction of kanamycin and in chronic hepatitis caused by carbon tetrachloride the sharp decrease in the species composition of microbial communities (up to 2-3 species) in the small intestine and was observed along with penetration of bacteria into the blood stream, the mesenterial lymph nodes and the liver parenchyma. The tendency towards the restoration of the quantitative and qualitative microflora composition was noted following administration into experimental animals of bactisubtil and amixin--an inductor of interferonogenesis.