Fructose is one of the key dietary catalysts in the development of non-alcoholic fatty liver disease (NAFLD). NAFLD comprises a complex disease spectrum, including steatosis (fatty liver), non-alcoholic steatohepatitis, hepatocyte injury, inflammation, and fibrosis. It is also the hepatic manifestation of the metabolic syndrome, which covers abdominal obesity, insulin resistance, dyslipidemia, glucose intolerance, or type 2 diabetes mellitus. Commensal bacteria modulate the host immune system, protect against exogenous pathogens, and are gatekeepers in intestinal barrier function and maturation. Dysbalanced intestinal microbiota composition influences a variety of NAFLD-associated clinical conditions. Conversely, nutritional supplementation with probiotics and preobiotics impacting composition of gut microbiota can improve the outcome of NAFLD. In crosstalk with the host immune system, the gut microbiota is able to modulate inflammation, insulin resistance, and intestinal permeability. Moreover, the composition of microbiota of an individual is a kind of fingerprint highly influenced by diet. In addition, not only the microbiota itself but also its metabolites influence the metabolism and host immune system. The gut microbiota can produce vitamins and a variety of nutrients including short-chain fatty acids. Holding a healthy balance of the microbiota is therefore highly important. In the present review, we discuss the impact of long-term intake of fructose on the composition of the intestinal microbiota and its biological consequences in regard to liver homeostasis and disease. In particular, we will refer about fructose-induced alterations of the tight junction proteins affecting the gut permeability, leading to the translocation of bacteria and bacterial endotoxins into the blood circulation.

This data points out the necessity of functional Nrf2 for fetal and placental growth. A deficiency in Nrf2 signaling may negatively affect nutrient transfer capacity which is then no longer able to meet fetal growth demands.

The intake of excess dietary fructose most often leads to non-alcoholic fatty liver disease (NAFLD). Fructose is metabolized mainly in the liver and its chronic consumption results in lipogenic gene expression in this organ. However, precisely how fructose is involved in NAFLD progression is still not fully understood, limiting therapy. Lipocalin-2 (LCN2) is a small secreted transport protein that binds to fatty acids, phospholipids, steroids, retinol, and pheromones. LCN2 regulates lipid and energy metabolism in obesity and is upregulated in response to insulin. We previously discovered that LCN2 has a hepatoprotective effect during hepatic insult, and that its upregulation is a marker of liver damage and inflammation. To investigate if LCN2 has impact on the metabolism of fructose and thereby arising liver damage, we fed wild type and Lcn2−/− mice for 4 or 8 weeks on diets that were enriched in fructose either by adding this sugar to the drinking water (30% w/v), or by feeding a chow containing 60% (w/w) fructose. Body weight and daily intake of food and water of these mice was then measured. Fat content in liver sections was visualized using Oil Red O stain, and expression levels of genes involved in fat and sugar metabolism were measured by qRT-PCR and Western blot analysis. We found that fructose-induced steatosis and liver damage was more prominent in female than in male mice, but that the most severe hepatic damage occurred in female mice lacking LCN2. Unexpectedly, consumption of elevated fructose did not induce de novo lipogenesis or fat accumulation. We conclude that LCN2 acts in a lipid-independent manner to protect the liver against fructose-induced damage.

Lipocalin 2 (LCN2) mediates key roles in innate immune responses. It has affinity for many lipophilic ligands and binds various siderophores, thereby limiting bacterial growth by iron sequestration. Furthermore, LCN2 protects against obesity and metabolic syndrome by interfering with the composition of gut microbiota. Consequently, complete or hepatocyte-specific ablation of the Lcn2 gene is associated with higher susceptibility to bacterial infections. In the present study, we comparatively profiled microbiota in fecal samples of wild type and Lcn2 null mice and show, in contrast to previous reports, that the quantity of DNA in feces of Lcn2 null mice is significantly lower than that in wild type mice (p < 0.001). By using the hypervariable V4 region of the 16S rDNA gene and Next-Generation Sequencing methods, we found a statistically significant change in 16 taxonomic units in Lcn2-/- mice, including eight gender-specific deviations. In particular, members of Clostridium, Escherichia, Helicobacter, Lactococcus, Prevotellaceae_UCG-001 and Staphylococcus appeared to expand in the intestinal tract of knockout mice. Interestingly, the proportion of Escherichia (200-fold) and Staphylococcus (10-fold) as well as the abundance of intestinal bacteria encoding the LCN2-sensitive siderphore enterobactin (entA) was significantly increased in male Lcn2 null mice (743-fold, p < 0.001). This was accompanied by significant higher immune cell infiltration in the ileum as demonstrated by increased immunoreactivity against the pan-leukocyte protein CD45, the lymphocyte transcription factor MUM-1/IRF4, and the macrophage antigen CD68/Macrosialin. In addition, we found a higher expression of mucosal mast cell proteases indicating a higher number of those innate immune cells. Finally, the ileum of Lcn2 null mice displayed a high abundance of segmented filamentous bacteria, which are intimately associated with the mucosal cell layer, provoking epithelial antimicrobial responses and affecting T-helper cell polarization.

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