Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in western countries both in children and adults. Metabolic dysregulation associated with gut microbial dysbiosis may influence disease progression from hepatic steatosis to inflammation and subsequent fibrosis. Using a multi-omics approach, we profiled the oral and fecal microbiome and plasma metabolites from 241 predominantly Latino children with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFL), and controls. Children with more severe liver pathology were dysbiotic and had increased gene content associated with lipopolysaccharide biosynthesis and lipid, amino acid and carbohydrate metabolism. These changes were driven by increases in Bacteroides and concomitant decreases of Akkermansia, Anaerococcus, Corynebacterium, and Finegoldia. Non-targeted mass spectrometry revealed perturbations in one-carbon metabolism, mitochondrial dysfunction, and increased oxidative stress in children with steatohepatitis and fibrosis. Random forests modeling of plasma metabolites was highly predictive of non-alcoholic steatohepatitis (NASH) (97% accuracy) and hepatic fibrosis, steatosis and lobular inflammation (93.8% accuracy), and can differentiate steatohepatitis from simple steatosis (90.0% accuracy). Multi-omics predictive models for disease and histology findings revealed perturbations in one-carbon metabolism, mitochondrial dysfunction, and increased oxidative stress in children with steatohepatitis and fibrosis. These results highlight the promise of non-invasive biomarkers for the growing epidemic of fatty liver disease.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in western countries both in children and adults (Lazo et al, 2013)
The non-alcoholic steatohepatitis (NASH) (N = 21) group was slightly older with a median age of 13 years (p = 0.008)
All subjects with NASH were Latinos with a median ALT of 122 U/L, significantly higher than the non-alcoholic fatty liver (NAFL) group and control groups
Summary
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in western countries both in children and adults (Lazo et al, 2013). NAFLD is a multi-factorial condition that is intimately linked to obesity and insulin resistance. This metabolic imbalance leads to an excessive accumulation of hepatic fat resulting in non-alcoholic fatty liver (NAFL). In the setting of lipid-laden hepatocytes, fatty acid metabolites cause oxidative stress and a cascade of necroinflammation and fibrosis leading to NASH (Neuschwander-Tetri, 2010). These pathologic processes are being identified in childhood and progress during adulthood. Non-invasive methods identifying NASH antecedents in childhood provide opportunities to intervene while avoiding confounding factors introduced by aging, alcohol use, concomitant medications, and comorbidities
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