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Gut-Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease
Marco Poeta1,2, Luca Pierri3,4, Pietro Vajro5,6
1Pediatrics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana"-University of Salerno, 84081 Baronissi (Salerno), Italy. m.poeta@outlook.it.
Insights
Non-alcoholic fatty liver disease (NAFLD) in children is linked to obesity and insulin resistance. The gut-liver axis, influenced by gut microbiota, plays a key role in NAFLD progression, suggesting new therapeutic targets.
Area of Science:
- Pediatric Gastroenterology
- Hepatology
- Microbiome Research
Background:
- Non-alcoholic fatty liver disease (NAFLD) is prevalent in children, mirroring the global obesity epidemic.
- The pathogenesis is explained by a "multiple-hit" hypothesis, starting with liver lipid accumulation due to obesity and insulin resistance.
- Progression to severe inflammation and fibrosis occurs without lifestyle changes, with the gut-liver axis (GLA) implicated.
Purpose of the Study:
- To elucidate the role of the gut-liver axis (GLA) in pediatric non-alcoholic fatty liver disease (NAFLD) pathogenesis.
- To identify novel therapeutic strategies for NAFLD in children unresponsive to lifestyle modifications.
- To explore the involvement of gut microbiota and farnesoid X receptor in NAFLD.
Main Methods:
- Review and synthesis of current research on the gut-liver axis in pediatric NAFLD.
- Analysis of the "multiple-hit" hypothesis and its relation to gut microbiota and inflammation.
- Investigation of the role of dysbiosis, intestinal permeability, and bacterial translocation.
Main Results:
- Dysbiosis and increased intestinal permeability in the GLA can lead to bacterial translocation and liver inflammation.
- This process promotes the progression from simple steatosis to non-alcoholic steato-hepatitis (NASH).
- Farnesoid X receptor, modulated by gut microbiota-altered bile acids, is a significant factor.
Conclusions:
- Derangements in the gut-liver axis are critical in pediatric NAFLD development and progression.
- Targeting the gut microbiota (e.g., pre/probiotics, fecal transplantation) offers promising therapeutic avenues.
- Modulation of the farnesoid X receptor presents another potential strategy for NAFLD treatment in children.
Abstract:
Non-alcoholic fatty liver disease (NAFLD) is the most frequent type of chronic liver disease in the pediatric age group, paralleling an obesity pandemic. A "multiple-hit" hypothesis has been invoked to explain its pathogenesis. The "first hit" is liver lipid accumulation in obese children with insulin resistance. In the absence of significant lifestyle modifications leading to weight loss and increased physical activity, other factors may act as "second hits" implicated in liver damage progression leading to more severe forms of inflammation and hepatic fibrosis. In this regard, the gut-liver axis (GLA) seems to play a central role. Principal players are the gut microbiota, its bacterial products, and the intestinal barrier. A derangement of GLA (namely, dysbiosis and altered intestinal permeability) may promote bacteria/bacterial product translocation into portal circulation, activation of inflammation via toll-like receptors signaling in hepatocytes, and progression from simple steatosis to non-alcoholic steato-hepatitis (NASH). Among other factors a relevant role has been attributed to the farnesoid X receptor, a nuclear transcriptional factor activated from bile acids chemically modified by gut microbiota (GM) enzymes. The individuation and elucidation of GLA derangement in NAFLD pathomechanisms is of interest at all ages and especially in pediatrics to identify new therapeutic approaches in patients recalcitrant to lifestyle changes. Specific targeting of gut microbiota via pre-/probiotic supplementation, feces transplantation, and farnesoid X receptor modulation appear promising.
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