The Gut-liver Axis in Immune Remodeling: New insight into Liver Diseases

Yang, Xinyu; Lu, Di; Zhuo, Jianyong; Lin, Zuyuan; Yang, Modan; Xu, Xiao

doi:10.7150/ijbs.46405

Cited by 66 publications

(63 citation statements)

References 117 publications

(106 reference statements)

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“…Many studies have suggested that chronic inflammation, hepatic fibrosis, and immune activation are associated with the translocation of gut-harboring bacteria [20]. Notably, toll-like receptors (TLRs), specifically TLR9 and TLR7, are overexpressed in HCC [21].…”

Section: Introductionmentioning

confidence: 99%

Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis

Chen

Yadav

Chu

et al. 2021

Cancers

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Sorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-like receptor (TLR)-9 was significantly overexpressed, and that miRNA (hsa-miR-30a-5p) was downregulated in sorafenib-resistant HCC cells, which modulated HCC cell proliferation, oxidative stress, and apoptosis. TLR9 overexpression increased HCC cell proliferation, whereas TLR9 inhibition from hydroxychloroquine (HCQ) decreased HCC cell proliferation, tumor growth, oxidative stress marker (SOD1), and the formation of autophagosome bodies (reduced ATG5 and Beclin-1 expression). Moreover, HCQ treatment reduced epithelial–mesenchymal transition, leading to decreased clonogenicity, migratory ability, and invasiveness. HCQ targeted and reduced the self-renewal capacity phenotype by inhibiting tumorsphere generation. Both in vitro and in vivo results demonstrated the synergistic effect of the HCQ–sorafenib combination on sorafenib-resistant HCC (Huh7-SR) cells, increasing their sensitivity to treatment by modulating TLR9, autophagy (ATG5 and Beclin-1), oxidative stress (SOD1), and apoptosis (c-caspase3) expression and thus overcoming the drug resistance. This study’s findings indicate that TLR9 overexpression occurs in sorafenib-resistant HCC cells and that its downregulation aids HCC suppression. Moreover, HCQ treatment significantly increases sorafenib’s effect on sorafenib-resistant HCC cells.

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Section: Introductionmentioning

confidence: 99%

Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis

Chen

Yadav

Chu

et al. 2021

Cancers

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“…The close link between PSC and IBD points to the "gut–liver" axis as a key player in the pathogenesis of PSC and suggests that the modulation of this axis, including the microbiota, may offer opportunities for future interventions [ 7 , 8 ]. This study shows that the endogenous metabolite, 3-IAld, ameliorated the inflammatory pathology in murine PSC through a primary action on gut mucosal and microbial homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…A functional imbalance in the microbial ecosystem favors epithelial barrier dysfunction and increased intestinal permeability, leading to the translocation of gut-derived products into the portal venous system, with consequent biliary inflammation and liver fibrosis [ 5 , 6 ]. Thus, the “gut-liver axis” has been implicated in the pathogenesis of liver diseases, such as PSC [ 7 , 8 , 9 ]. In the last few years, several studies have tried to deeply characterize the clinical PSC–IBD phenotype, providing insight into PSC pathogenesis that could be exploited to develop innovative therapies.…”

Section: Introductionmentioning

confidence: 99%

Indole-3-Carboxaldehyde Restores Gut Mucosal Integrity and Protects from Liver Fibrosis in Murine Sclerosing Cholangitis

D’Onofrio

Renga

Puccetti

et al. 2021

Cells

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Primary sclerosing cholangitis (PSC) is a long-term liver disease characterized by a progressive course of cholestasis with liver inflammation and fibrosis. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC. According to the “leaky gut” hypothesis, gut inflammation alters the permeability of the intestinal mucosa, with the translocation of gut-derived products that enter the enterohepatic circulation and cause hepatic inflammation. Thus, the administration of molecules that preserve epithelial barrier integrity would represent a promising therapeutic strategy. Indole-3-carboxaldehyde (3-IAld) is a microbial-derived product working at the interface between the host and the microbiota and is able to promote mucosal immune homeostasis in a variety of preclinical settings. Herein, by resorting to a murine model of PSC, we found that 3-IAld formulated for localized delivery in the gut alleviates hepatic inflammation and fibrosis by modulating the intestinal microbiota and activating the aryl hydrocarbon receptor-IL-22 axis to restore mucosal integrity. This study points to the therapeutic potential of 3-IAld in liver pathology.

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“…In recent years, the gut microbiota has received increasing attention because of its central role in host-microbiota interaction and its impact on liver diseases (Yang et al, 2020 ). A healthy gut microbiota can maintain liver metabolism and immune homeostasis.…”

Section: Role Of the Microbiota In The Immune Homeostasis Of The Gut Liver And Liver Diseasementioning

confidence: 99%

Gut Microbiota and Chemical-Induced Acute Liver Injury

Chen

2021

Front. Physiol.

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Background: Drug overdose or chemical exposures are the main causes of acute liver injury (ALI). Severe liver injury can develop into liver failure that is an important cause of liver-related mortality in intensive care units in most countries. Pharmacological studies have utilized a variety of comprehensive chemical induction models that recapitulate the natural pathogenesis of acute liver injury. Their mechanism is always based on redox imbalance-induced direct hepatotoxicity and massive hepatocyte cell death, which can trigger immune cell activation and recruitment to the liver. However, the pathogenesis of these models has not been fully stated. Many studies showed that gut microbiota plays a crucial role in chemical-induced liver injury. Hepatotoxicity is likely induced by imbalanced microbiota homeostasis, gut mucosal barrier damage, systemic immune activation, microbial-associated molecular patterns, and bacterial metabolites. Meanwhile, many preclinical studies have shown that supplementation with probiotics can improve chemical-induced liver injury. In this review, we highlight the pathogenesis of gut microorganisms in chemical-induced acute liver injury animal models and explore the protective mechanism of exogenous microbial supplements on acute liver injury.

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The Gut-liver Axis in Immune Remodeling: New insight into Liver Diseases

Cited by 66 publications

References 117 publications

Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis

Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis

Indole-3-Carboxaldehyde Restores Gut Mucosal Integrity and Protects from Liver Fibrosis in Murine Sclerosing Cholangitis

Gut Microbiota and Chemical-Induced Acute Liver Injury

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