Targeting the gut barrier for the treatment of alcoholic liver disease

Abstract

Alcohol consumption remains one of the predominant causes of liver disease and liver-related death worldwide. Intriguingly, dysregulation of the gut barrier is a key factor promoting the pathogenesis of alcoholic liver disease (ALD). A functional gut barrier, which consists of a mucus layer, an intact epithelial monolayer and mucosal immune cells, supports nutrient absorption and prevents bacterial penetration. Compromised gut barrier function is associated with the progression of ALD. Indeed, alcohol consumption disrupts the gut barrier, increases gut permeability, and induces bacterial translocation both in ALD patients and in experimental models with ALD. Moreover, alcohol consumption also causes enteric dysbiosis with both numerical and proportional perturbations. Here, we review and discuss mechanisms of alcohol-induced gut barrier dysfunction to better understand the contribution of the gut-liver axis to the pathogenesis of ALD. Unfortunately, there is no effectual Food and Drug Administration-approved treatment for any stage of ALD. Therefore, we conclude with a discussion of potential strategies aimed at restoring the gut barrier in ALD. The principle behind antibiotics, prebiotics, probiotics and fecal microbiota transplants is to restore microbial symbiosis and subsequently gut barrier function. Nutrient-based treatments, such as dietary supplementation with zinc, niacin or fatty acids, have been shown to regulate tight junction expression, reduce intestinal inflammation, and prevent endotoxemia as well as liver injury caused by alcohol in experimental settings. Interestingly, saturated fatty acids may also directly control the gut microbiome. In summary, clinical and experimental studies highlight the significance and efficacy of the gut barrier in treating ALD.

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…Excessive alcohol consumption causes alcoholic liver disease (ALD), which is characterized by liver steatosis, hepatitis, and cirrhosis. Alcohol drinking disrupts intestinal permeability leading to elevated serum levels of lipopolysaccharide (LPS), which is a bacterial endotoxin causing inflammatory responses . A previous study has analyzed the effects of moderate alcohol drinking on circadian rhythms using 11 daytime workers and 11 nighttime workers.…”

“…Alcohol drinking disrupts intestinal permeability leading to elevated serum levels of lipopolysaccharide (LPS), which is a bacterial endotoxin causing inflammatory responses. 18,19 A previous study has analyzed the effects of moderate alcohol drinking on circadian rhythms using 11 daytime workers and 11 nighttime workers. In this study, all subjects were told to avoid alcohol drinking and have usual sleep schedule for 1 week.…”

Modeling alcoholic liver disease in a human Liver-Chip

“…Moreover, withdrawal from LPS and ethanol for five days did not diminish the oxidative stress or polyploidy, in contrast to the rescuing of the pathology induced by ethanol alone. This suggests that chronic alcohol intake coupled with systemic inflammation worsens the liver damage and may significantly compromise recovery in ALD/ASH, similar to the responses of patients with more advanced disease 84 . In animal experiments administration of antibiotics to reduce endotoxemia or inactivation of Kupffer cells with gadolinium chloride can both prevent liver injury 85 , suggesting that the ALD Liver-Chip model could be useful as a platform to determine human relevancy of proposed mechanisms for new therapeutic approaches.…”

Obesidad y enfermedad hepática grasa no alcohólica en Pediatría.

“…Los niveles de etanol en la sangre se elevan con la dieta rica en azúcar, luego por medio de la enzima alcohol deshidrogenasa hepática, se convierte en acetaldehído, que incluso en pequeñas concentraciones es tóxico para el organismo. La producción de etanol por la microbiota intestinal en pacientes obesos con EHGNA contribuye al desarrollo y progresión de la enfermedad (12,14,15).…”