Lactobacillus rhamnosus GG combined with inosine ameliorates alcohol-induced liver injury through regulation of intestinal barrier and Treg/Th1 cells.

BACKGROUND: Intestinal epithelial barrier disruption and bacterial translocation exacerbates the progression of alcoholic liver disease. Lactobacillus rhamnosus GG (LGG), a probiotic, has been shown benefits in chronic liver disease and in regulating gut dysbiosis. Previous studies showed the protective roles of LGG in ethanol-disrupted gut barrier functions and liver injury. Inosine, a metabolite produced by intestinal bacteria, has the anti-inflammatory and immunregulatory functions. In this study, the synergistic effect of LGG and inosine was investigated in a mouse model of alcohol-induced liver disease (ALD). METHODS: Male C57BL/6 mice were fed with a Lieber-DeCarli diet containing 5% alcohol for four weeks to establish a model of alcohol-induced liver injury. LGG or a combination of LGG and inosine were administrated orally to explore a new therapeutic method for alcohol-induced liver disease and to investigate the underlying mechanisms. Liver damage was evaluated by transaminases and pathological changes. Tight junction proteins, composition of the gut microbiome, cytokines, lipopolysaccharides (LPS), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), F4/80+ macrophages, as well as p38, Jun N-terminal kinase (JNK), were determined by qRT-PCR, RNAseq, ELISA, IHC and western blot. Regulatory T (Treg) cells were characterized by positive staining of CD4, CD25 and Foxp3 using flow cytometry. IFN-γ-producing CD4+ T (Th1) cells were examined by intracellular cytokine staining. RESULTS: Alcohol consumption induced elevated liver enzymes, steatosis and inflammation, while LGG combined with inosine treatment was more significant to ameliorate these symptoms compared with LGG alone. When LGG combined with inosine were administered to ALD mice, intestinal microecology significantly improved reflected by intestinal villi and tight junction proteins recovery and the restoration of intestinal flora. Combined therapy inhibited phosphorylation of p38 and JNK to alleviate hepatic inflammation. Moreover, flow cytometry analysis showed that long-term excessive alcohol consumption reduced Tregs population while increased Th1 population, which was restored by a combination of LGG and inosine treatment. CONCLUSIONS: The findings from the study indicate that the combined LGG and inosine treatment ameliorates ALD by improving the gut ecosystem, intestinal barrier function, immune homeostasis and liver injury.

Exploring the risk factors of early sepsis after liver transplantation: development of a novel predictive model.

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.