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Multi-Omics Analysis of the Gut-Liver Axis Reveals the Mechanism of Liver Injury in Colitis Mice.

ABSTRACT: Liver injury is a common complication of inflammatory bowel disease (IBD). However, the mechanisms of liver injury development are not clear in IBD patients. Gut microbiota is thought to be engaged in IBD pathogenesis. Here, by an integrated analysis of host transcriptome and colonic microbiome, we have attempted to reveal the mechanism of liver injury in colitis mice. In this study, dextran sulfate sodium (DSS) -induced mice colitis model was constructed. Liver transcriptome showed significant up- and down-regulation of pathways linked to immune response and lipid metabolism, respectively. Whilst the colon transcriptome exhibited dramatic alterations in immune response and pathways associated with cell growth and death. The microbiota of DSS-treated mice underwent strong transitions. Correlation analyses identified genes associated with liver and colon injury, whose expression was associated with the abundance of liver and gut health-related bacteria. Collectively, the results indicate that the liver injury in colitis mice may be related to the intestinal dysbiosis and host-microbiota interactions. These findings may provide new insights for identifying potential targets for the treatment of IBD and its induced liver injury.

SUBMITTER: Zhu L

PROVIDER: S-EPMC8770869 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBased on the gut-liver axis theory, a leaky gut can aggravate liver injury. However, clinical studies suggest that although gut mucosa damage is commonly observed in inflammatory bowel disease (IBD), it seldom leads to severe liver injury. We hypothesize that there is a hepatic barrier in the gut-liver axis, which protects the liver against gut-derived invasive factors.MethodsColitis was induced by dextran sulfate sodium (DSS) in eight different liver injury models in Sprague-Dawley rats. Liver sinusoidal endothelial cell (LSEC) injury was evaluated by a scanning and transmission electron microscope. Neutrophils were depleted by injection of anti-rat polymorphonuclear serum. Two pneumonia models were also induced to investigate the mechanism of neutrophil recruitment and activation. LSECs isolated from rat liver were used to investigate the effect on neutrophil recruitment and activation.ResultsAmong eight liver injury models, DSS colitis had no effect on liver injury in three models with normal LSECs. In the other five models with LSEC rupture, liver injury was significantly exacerbated by colitis, and increased hepatic neutrophil accumulation was observed. When neutrophils were depleted, colitis-induced liver injury was significantly attenuated. In pneumonia, liver injury, and colitis models, the level of CXCL1 correlated with the recruitment of neutrophils in different tissues, while DSS colitis and LSEC injury synergistically contributed to increased CXCL1 expression in the liver. In colitis-induced liver injury, neutrophils were activated in the liver. Injured LSECs showed both structural and functional changes, with significantly increased expression of CXCL1 and TNF-α under the stimulation of lipopolysaccharide (LPS). The combination of gut-derived LPS and LSEC-derived TNF-α led to the activation of neutrophils, characterized by enhanced production of reactive oxygen species, pro-inflammatory cytokines, and the formation of neutrophil extracellular traps.ConclusionLSECs constitute a vitally important barrier in the gut-liver axis, defending the liver against colitis-induced injury. When LSECs are damaged, they can turn into a pro-inflammatory pattern under the stimulation of LPS. LSEC injury and colitis-derived LPS synergistically contribute to the recruitment and activation of hepatic neutrophils. Neutrophils play a pivotal role as a downstream effector in colitis-induced liver injury.

Project description:IntroductionAlthough researchers have done intensive research on depression, its pathogenesis is still not fully explained. More and more evidence suggests that gut microbiota is closely related to the onset of depression; but its specific functional ways are not clearly identified.ObjectivesThe purpose of our work was to find out how the gut microbiota was involved in the onset of depression, and to identify the potential ways to link the gut and brain in mice with depressive-like behaviors (DLB).MethodsWe used the chronic restraint stress (CRS)-induced depression model here. Gut microbiota compositions in fecal samples, lipid metabolism (in fecal, serum and hippocampus samples) and neurotransmitters in hippocampus samples were detected.ResultsWe found that the 7 of 13 differential genera that significantly correlated with DLB belonged to phylum Firmicutes. The differential lipid metabolites in fecal samples mainly belonged to glycerophospholipids (GP) and fatty acids (FA) metabolism, and three important "metabolite type-bacterial taxa" correlated pairs were identified: "FA/GP-Firmicutes", "FA/GP-Akkermansia", and "FA/GP-Bifidobacterium". The key differential lipid metabolites significantly correlated with DLB mainly belonged to FA and GP, and the DLB-related metagenomic genes were consistently enriched in GP metabolism and FA metabolism. Three significantly changed short-chain fatty acids (SCFAs) were significantly correlated with the majority of differential genera. Meanwhile, we found that the differential lipid metabolites in serum and hippocampus samples were mainly mapped into the GP metabolism, and there were four differential neurotransmitters from the tryptophan pathway in hippocampus samples.ConclusionTogether, our findings could provide novel insights into the role of "microbiota-gut-brain" (MGB) axis in depression, and indicate that the gut microbiota might have a vital role in the onset of DLB by affecting the peripheral/central GP metabolism and tryptophan pathway. The "Firmicutes-SCFAs-GP metabolism-Tryptophan pathway" might be a possible way to link the gut and brain in depressed mice.

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Multi-Omics Analysis of the Gut-Liver Axis Reveals the Mechanism of Liver Injury in Colitis Mice.

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