The Gut-Liver Axis and NAFLD: Clarifying the Link

William F. Balistreri, MD


December 11, 2013

In This Article

The Influence of Diet

The mechanism of this interrelationship is elucidated by the observation that the gut microbial community of genetically obese mice has great capacity to harvest and store energy from the diet. Turnbaugh and colleagues[7] defined this as an "obesity-associated gut microbiome," enriched with Firmicutes. This trait can be transmitted by transplanting the microbial community into germ-free mice.[8]

Further studies by this group of investigators documented that acquisition of this specific gut microbial composition is linked to long-term dietary habits.[9,10] Specifically, in animal models, a high-fat, high-sugar diet alters the composition of the gut microflora; obese mice harbor more Firmicutes and fewer Bacteroidetes, with the result that more calories are absorbed.[11]

Specific components of the diet may also exert an influence; for example, consumption of added refined carbohydrates alters the microbiota. Intake of fructose-containing beverages by overweight adults leads to increased lipid synthesis, impaired insulin sensitivity, and increased visceral adiposity -- all predisposing factors for NAFLD.[12]

Fructose consumption was found to be higher in individuals with NAFLD than in age-matched and body mass index (BMI)-matched controls.[13] In an investigation of the relationship between fructose consumption and disease severity in individuals with NAFLD, after controlling for age, sex, BMI, and total calorie intake, daily fructose consumption was associated with lower steatosis grade but higher fibrosis stage and increased hepatic inflammation and hepatocyte ballooning.[13]

These results identified a readily modifiable environmental risk factor that might ameliorate disease progression in patients with NAFLD. In fact, moderate reduction in intake of fructose- or sugar-sweetened beverages improved BMI and reduced intrahepatic fat accumulation in overweight or obese children.[14,15,16]

The mechanism of fructose-induced steatosis is related to endotoxin exposure. The role of endotoxin in contributing to steatosis was clarified by studies that documented that antibiotics protected against fructose-induced hepatic lipid accumulation in mice.[17] Further studies indicate that fructose alters the gut flora, which in turn increases gut permeability, thereby increasing bacterial lipopolysaccharide and gut endotoxin exposure.[18] This leads to increased TLR4 activation and increased TNF production, which results in systemic inflammation and, therefore, liver injury.


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