The role of nutrition and diet in the development of non-alcoholic fatty liver disease (NAFLD) is still not fully understood. In the present study, we determined if dietary pattern and markers of intestinal permeability differ between overweight children with and without NAFLD. In addition, in a feasibility study, we assessed the effect of a moderate dietary intervention only focusing on nutrients identified to differ between groups on markers of intestinal barrier function and health status. Anthropometric data, dietary intake, metabolic parameters, and markers of inflammation, as well as of intestinal permeability, were assessed in overweight children (n = 89, aged 5–9) and normal-weight healthy controls (n = 36, aged 5–9). Sixteen children suffered from early signs of NAFLD, e.g., steatosis grade 1 as determined by ultrasound. Twelve children showing early signs of NAFLD were enrolled in the intervention study (n = 6 intervention, n = 6 control). Body mass index (BMI), BMI standard deviation score (BMI-SDS), and waist circumference were significantly higher in NAFLD children than in overweight children without NAFLD. Levels of bacterial endotoxin, lipopolysaccharide-binding protein (LBP), and proinflammatory markers like interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) were also significantly higher in overweight children with NAFLD compared to those without. Total energy and carbohydrate intake were higher in NAFLD children than in those without. The higher carbohydrate intake mainly resulted from a higher total fructose and glucose intake derived from a significantly higher consumption of sugar-sweetened beverages. When counseling children with NAFLD regarding fructose intake (four times, 30–60 min within 1 year; one one-on-one counseling and three group counselings), neither alanine aminotransferase (ALT) nor aspartate aminotransferase (AST) activity in serum changed; however, diastolic blood pressure (p < 0.05) and bacterial endotoxin levels (p = 0.06) decreased markedly in the intervention group after one year. Similar changes were not found in uncounseled children. Our results suggest that a sugar-rich diet might contribute to the development of early stages of NAFLD in overweight children, and that moderate dietary counseling might improve the metabolic status of overweight children with NAFLD.

(1) Background: The etiology of non-alcoholic fatty liver disease (NAFLD) is multifactorial. Dietary composition has been implicated as a factor modulating intestinal barrier and could affect disease severity. The aim of this study was to evaluate dietary intake and markers of intestinal permeability in patients with NAFLD. (2) Methods: We enrolled 63 patients with NAFLD and compared them to age-matched controls. (3) Results: body mass index (BMI) and leptin to adiponectin ratio—the latter being an indicator of abdominal fat accumulation—correlated with the degree of hepatic steatosis being accompanied with rising levels of fasting insulin. Furthermore, endotoxin plasma levels and markers of inflammation were significantly higher in NAFLD compared to controls and increased with the severity of hepatic steatosis. Despite comparable intake of total energy and macronutrients, intake of fiber was lower in all patients with NAFLD compared to controls and were negatively related to disease severity. (4) Conclusions: Taken together, results of the present study suggest that fiber intake in patients is negatively related to steatosis degree and bacterial endotoxin levels, further suggesting that dietary fiber intake may be a target in NAFLD treatment (NCT: 02366052 and 03482284).

Sodium butyrate (SoB) supplementation has been suggested to attenuate the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined the therapeutic potential of SoB on NAFLD progression and molecular mechanism involved. Eight-week old C57BL/6J mice were pair-fed a fat-, fructose- and cholesterol-rich diet (FFC) or control diet (C). After 8 weeks, some mice received 0.6g SoB/kg bw in their respective diets (C+SoB; FFC+SoB) or were maintained on C or FFC for the next 5 weeks of feeding. Liver damage, markers of glucose metabolism, inflammation, intestinal barrier function and melatonin metabolism were determined. FFC-fed mice progressed from simple steatosis to early non-alcoholic steatohepatitis, along with significantly higher TNFα and IL-6 protein levels in the liver and impaired glucose tolerance. In FFC+SoB-fed mice, disease was limited to steatosis associated with protection against the induction of Tlr4 mRNA and iNOS protein levels in livers. SoB supplementation had no effect on FFC-induced loss of tight junction proteins in the small intestine but was associated with protection against alterations in melatonin synthesis and receptor expression in the small intestine and livers of FFC-fed animals. Our results suggest that the oral supplementation of SoB may attenuate the progression of simple steatosis to steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is by now the most prevalent liver disease worldwide. The non-proteogenic amino acid l-citrulline (L-Cit) has been shown to protect mice from the development of NAFLD. Here, we aimed to further assess if L-Cit also attenuates the progression of a pre-existing diet-induced NAFLD and to determine molecular mechanisms involved. Female C57BL/6J mice were either fed a liquid fat-, fructose- and cholesterol-rich diet (FFC) or control diet (C) for 8 weeks to induce early stages of NASH followed by 5 more weeks with either FFC-feeding +/- 2.5 g L-Cit/kg bw or C-feeding. In addition, female C57BL/6J mice were either pair-fed a FFC +/- 2.5 g L-Cit/kg bw +/- 0.01 g/kg bw i.p. N(ω)-hydroxy-nor-l-arginine (NOHA) or C diet for 8 weeks. The protective effects of supplementing L-Cit on the progression of a pre-existing NAFLD were associated with an attenuation of 1) the increased translocation of bacterial endotoxin and 2) the loss of tight junction proteins as well as 3) arginase activity in small intestinal tissue, while no marked changes in intestinal microbiota composition were prevalent in small intestine. Treatment of mice with the arginase inhibitor NOHA abolished the protective effects of L-Cit on diet-induced NAFLD. Our results suggest that the protective effects of L-Cit on the development and progression of NAFLD are related to alterations of intestinal arginase activity and intestinal permeability.

Being overweight has been identified as the main risk factor for the development of metabolic disorders in adults and children. However, recent studies suggest that normal weight individuals are also frequently affected by metabolic abnormalities with underlying mechanisms not yet fully understood. The aim of the present study was to determine if dietary pattern and markers of intestinal permeability, as well as inflammation, differ between normal weight healthy children and normal weight children suffering from metabolic abnormalities. In total, 45 normal weight children aged 5–9 years were included in the study, of whom nine suffered from metabolic abnormalities. Anthropometric data, dietary intake and markers of inflammation, as well as intestinal permeability, were assessed in fasting blood samples. Neither BMI nor BMI-SDS differed between groups; however, children with metabolic abnormalities had a significantly larger waist circumference (+~5 cm) and a higher leptin to adiponectin ratio. While plasma leptin levels are significantly higher in normal weight children with metabolic abnormalities, neither TNF α nor sCD14, adiponectin, PAI-1 or IL-6 plasma levels differed between groups. Despite similar total calorie and macronutrient intake between groups, mean total fructose and total glucose intake (resulting mainly from sugar sweetened beverages, fruits and sweets) were higher in children with metabolic abnormalities than in healthy children. Time spent physically active was significantly higher in healthy normal weight children whereas time spent physically inactive was similar between groups. Furthermore, bacterial endotoxin levels were significantly higher in the peripheral plasma of normal weight children with metabolic abnormalities than in healthy normal weight children. Our results suggest that metabolic disorders in normal weight children are associated with a high monosaccharide intake and elevated bacterial endotoxin as well as leptin plasma levels, the latter also discussed as being indicative of visceral adiposity.