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Background: Alcoholic liver disease (ALD) is exacerbated by disruptions in intestinal microecology and immune imbalances within the gut-liver axis. The present study assesses the therapeutic potential of combining Akkermansia muciniphila (A. muciniphila) with inosine in alleviating alcohol-induced liver injury. Methods: Male C57BL/6 mice, subjected to a Lieber-DeCarli diet with 5% alcohol for 4 weeks, served as the alcoholic liver injury model. Various analyzes, including quantitative reverse transcription polymerase chain reaction (qRT-PCR), ELISA, immunochemistry, 16S rRNA gene sequencing, and flow cytometry, were employed to evaluate liver injury parameters, intestinal barrier function, microbiota composition, and immune responses. Results: Compared to the model group, the A. muciniphila and inosine groups exhibited significantly decreased alanine aminotransferase, aspartate aminotransferase, and lipopolysaccharide (LPS) levels, reduced hepatic fat deposition and neutrophil infiltration, alleviated oxidative stress and inflammation, and increased expression of intestinal tight junction proteins (Claudin-1, Occludin, and ZO-1). These effects were further pronounced in the A. muciniphila and inosine combination group compared to individual treatments. While alcohol feeding induced intestinal dysbiosis and gut barrier disruption, the combined treatment reduced the abundance of harmful bacteria (Oscillibacter, Escherichia/Shigella, and Alistipes) induced by alcohol consumption, promoting the growth of butyrate-producing bacteria (Akkermansia, Lactobacillus, and Clostridium IV). Flow cytometry revealed that alcohol consumption reduced T regulatory (Treg) populations while increasing those of T-helper (Th) 1 and Th17, which were restored by A. muciniphila combined with inosine treatment. Moreover, A. muciniphila and inosine combination increased the expression levels of intestinal CD39, CD73, and adenosine A2A receptor (A2AR) along with enhanced proportions of CD4+CD39+Treg and CD4+CD73+Treg cells in the liver and spleen. The A2AR antagonist KW6002, blocked the beneficial effects of the A. muciniphila and inosine combination on liver injury in ALD mice. Conclusion: This study reveals that the combination of A. muciniphila and inosine holds promise for ameliorating ALD by enhancing the gut ecosystem, improving intestinal barrier function, upregulating A2AR, CD73, and CD39 expression, modulating Treg cells functionality, and regulating the imbalance of Treg/Th17/Th1 cells, and these beneficial effects are partly A2AR-dependent.
RESUMO
Background: Sepsis is a severe and common complication of liver transplantation (LT) with a high risk of mortality. However, effective tools for evaluating its risk factors are lacking. Therefore, this study identified the risk factors of early post-liver transplantation sepsis and established a nomogram. Methods: We analyzed the risk factors of post-liver transplantation sepsis in 195 patients. Patients with infection and a systemic inflammatory response syndrome (SIRS) score ≥ 2 were diagnosed with sepsis. The predictive indicators were screened with the least absolute shrinkage and selection operator (LASSO) and collinearity analyses to develop a nomogram. The prediction performance of the new nomogram model, Sequential Organ Failure Assessment (SOFA) score, and Modified Early Warning Score (MEWS) was compared through assessment of the area under the curve (AUC), decision curve analysis (DCA), net reclassification index (NRI), and integrated discrimination improvement (IDI). Results: The nomogram was based on postoperative heart rate, creatinine concentration, PaO2/FiO2 ratio < 400 mmHg, blood glucose concentration, and international normalized ratio. The AUC of the nomogram, the SOFA score, and MEWS were 0.782 (95% confidence interval CI: 0.716-0.847), 0.649 (95% CI: 0.571-0.727), and 0.541 (95% CI: 0.469-0.614), respectively. The DCA curves showed that the net benefit rate of the nomogram was higher than that of the SOFA score and MEWS. The NRI and IDI tests revealed better predictive performance for the nomogram than SOFA score and MEWS. Conclusion: Heart rate, creatinine concentration, PaO2/FiO2, glucose concentration, and international normalized ratio should be monitored postoperatively for patients at risk of post-liver transplantation sepsis. The nomogram based on the aforementioned risk factors had a better predictive performance than SOFA score and MEWS.
