Table 1.

Fructose in the crosstalk with microbiota in the pathogenesis of NAFLD.

Species	Treatment	Findings	Conclusion	Reference
Mouse	Diet high in saturated fat, fructose, and cholesterol for 8 weeks	F11r−/− mice with defects in intestinal epithelial permeability developed more severe steatohepatitis than control mice.	Diet-induced microbial dysbiosis contribute to the development of NASH.	Rahman et al. (47)
	High fat diet with 10% fructose	Addition of Lactobacillus paracasei reduced expression of inflammatory markers (Tlr4, Nox-4, Tnf-α, MCP-1, IL-4) and number of Kupffer cells, and induced M2-dominant Kupffer cell polarization.	Lactobacillus paracasei attenuates hepatic steatosis with M2-dominant Kupffer cell polarization.	Sohn et al. (48)
	30% fructose in drinking water	Endotoxin levels in portal blood and lipid peroxidation as well as TNF-α expression were significantly increased in fructose-fed mice. Hepatic lipid accumulation was lowered by concomitant treatment with antibiotics.	Fructose increase intestinal translocation of endotoxin leading to liver damage.	Bergheim et al. (49)
	30% fructose in drinking water for 8 weeks	In fructose-fed tlr4 mice, hepatic triglyceride accumulation was significantly reduced by approximately 40% in comparison to fructose-fed wild type mice.	Fructose-induced NAFLD is associated with intestinal bacterial overgrowth and increased intestinal permeability.	Spruss and Bergheim (50)
	Chronic consumption of 30% fructose solution with or without Lactobacillus casei Shirota	Treatment with Lactobacillus casei Shirota attenuated activation of TLR4 signaling.	Treatment with Lactobacillus casei Shirota protects against the onset of fructose-induced NAFLD.	Wagnerberger et al. (51)
	30% fructose solution for 8 weeks	Occludin expression was lowered in the duodenum during fructose feeding without changes in microbiota.	Increased intestinal translocation of microbial components is involved in the onset of fructose-induced NAFLD.	Wagnerberger et al. (52)
	high-fat diet plus 30% fructose solution (HFHF)	HFHF diet promoted changes in intestinal tight-junctions proteins, increased insulin resistance and plasma cholesterol. HFHF increased hepatic Lipocalin 2 (Lcn2) mRNA expression and plasma levels indicating hepatic inflammation.	Diets high in fat and fructose increase the vulnerability to metabolic syndrome-related conditions associated with NAFLD.	de Sousa Rodrigues et al. (7)
	30% fructose solution for 8 weeks with or without Lactobacillus rhamnosus GG	Lactobacillus rhamnosus GG increased number of beneficial bacteria, reduced duodenal IkB protein levels and restored the duodenal tight junction proteins. Portal LPS and hepatic expression of TNF-α, IL-8R and IL-1β was reduced and increase of fat accumulation and alanine-aminotransferase was attenuated.	Treatment with Lactobacillus rhamnosus GG protects against fructose-induced NAFLD.	Ritze et al. (53)
	30% fructose solution for 8 weeks and combination of bile acids chenodeoxycholic acid and cholic acid	The additional treatment with bile acids downregulated hepatic TNF-α, SREBP1, FAS mRNA expression, and lipid peroxidation. Bile acid treatment normalized expression of occludin, markers of Kupffer cell activation, and portal endotoxin levels.	Bile acids prevent fructose-induced hepatic steatosis through mechanisms that protect against the fructose-induced translocation of intestinal bacterial endotoxin	Volynets et al. (38)
	30% fructose solution for 8 weeks with or without concomitantly treatment with metformin (300 mg/kg body weight/day) in drinking water	Chronic consumption of fructose caused a significant increase in hepatic triglyceride and plasma AST levels. This effect was attenuated by metformin, which protected against loss of the tight-junction proteins occludin and zonula occludens-1 in the duodenum, thereby preventing increased translocation of bacterial endotoxin.	Metformin protects the liver from the onset of fructose-induced NAFLD through mechanisms involving its direct effects on hepatic insulin signaling and by altering intestinal permeability and subsequent endotoxin-dependent activation of Kupffer cells.	Spruss et al. (54)
	Sugar- and fat-rich Western-style diet (WSD) for 12 weeks plus fructose-supplemented water (30%)	Fructose intake increased endotoxin translocation, induced a loss of mucus thickness in the colon (246%) and reduced defensin expression in the ileum and colon. Microbiota analysis revealed that fructose increased the Firmicutes/Bacteroidetes ratio.	The consumption of a WSD or high fructose differentially affects gut permeability and microbiome. Fructose, especially when combined with a WSD, results in pronounced gut barrier dysfunction.	Volynets et al. (55)
	30% fructose solution, a high-fat diet, or a combination of both for 8 and 16 weeks	The combined diet induced development of hepatic steatosis and progression to steatohepatitis. Bacterial endotoxin levels in portal plasma increased, while levels of the tight junction protein occludin and zonula occludens-1 were reduced in the duodenum of all treated groups after 8 and 16 weeks.	Chronic intake of fructose and/or fat lead to the development of NAFLD over time which is associated with an increased translocation of bacterial endotoxin.	Sellmann et al. (56)
	Normal diet and high fat diet (HFD) with or without fructose for 16 weeks	Livers of mice fed with HFD and fructose showed a higher infiltration of lymphocytes and a lower inflammatory profile of Kupffer cells than livers of mice fed with the HFD without fructose. In the resulting dysbiosis, fructose specifically prevented the decrease of mouse intestinal bacteria in HFD-fed mice and increased Erysipelotrichi, independently of fat amount.	Fructose induces dysbiosis which is modulated by the presence of dietary fat. Combined diet of fat and fructose prevents fat-induced activation of Kupffer cells.	Ferrere et al. (57)
	High fat (40%)/high fructose (10%) diet with or without Lactobacillus paracasei supplementation for 10 weeks	Hepatic fat deposition, serum ALT level, and urinary 51Cr-EDTA clearance were significantly lower when mice received L. paracasei. The probiotics caused lower expression of TLR4 protein and mRNA for TNF-α, IL-4, MCP-1, PPAR-γ, and PPAR-α. The activation of Kupffer cells was lowered by L. paracasei.	Lactobacillus paracasei attenuates hepatic steatosis and Kupffer cell activation during progression of NASH.	Sohn et al. (48)
Rat	Diet enriched in fat and fructose	The diet induced a marked (i) increase in A. muciniphila in cecal microbiota, (ii) dramatic changes in the colon mucosa-associated microbiota, with a significant decrease in total bacteria, Clostridium leptum, Bacteroides/Prevotella and Lactobacillus/Leuconostoc, (iii) decreased expression of claudin-1, and (iv) increased expression of Tnf-α and Tlr4.	Diets enriched in fructose reduce bacterial colonization, lead to dysbiosis, increase numbers of mucin-degrading bacteria, and provoke inflammation in colon mucosa, thereby supporting NAFLD progression.	Jegatheesan et al. (58)
	Fructose-rich diet in combination with antibiotics for 8 weeks	After 4 weeks of treatment, fructose-fed rats exhibited higher values of fasting plasma insulin and homeostatic model assessment (HOMA) index. Antimicrobial therapy prevented diet-induced decrease of ileal occludin expression, increase of hepatic transaminases, lipid oxidation, and increase myeloperoxidase activity in ileum, liver, and visceral white adipose tissue. Similarly, quantities of portal TNF-α and LPS, as well as ileal TNF-α were induced by fructose. Fructose increased levels of plasma and hepatic triglycerides, irrespectively of antimicrobial treatment. Fructose increased oxidative damage to mitochondrial lipids and proteins, together with a significant decrease in antioxidant activity, while antibiotic treatment reversed all of these effects. A diet-dependent increase in Coprococcus and Ruminococcus was prevented by antibiotics.	Fructose promotes alterations in the gut microbiota profile triggering inflammation and metabolic dysregulation in the gut, liver, and visceral white adipose tissue. These obesity-related features can be experimentally reversed by treatment with antibiotics.	Crescenzo et al. (59)
	Diet enriched in copper combined with drinking water containing 30% fructose	The abundance of 38 fecal metabolites changed after dietary doses of copper or high fructose. Four SCFAs (valeric acid, butyric acid, isovaleric acid, and isobutyric acid) showed major abundance changes. The bacterial-derived long-chain fatty acid margaric was increased by excessive fructose intake.	Dietary fructose modifies the gut microbiota phylum profile contributing to the metabolic phenotype in NAFLD.	Wei et al. (60)
	60% isonitrogenous fructose diet for 4 weeks	Isonitrogenous fructose diet decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia without altering glucose homeostasis, liver function, or gut permeability.	Fructose provokes dysbiosis and fructose-induced hepatic alterations associated with NAFLD can be blunted by nitrogen supply.	Jegatheesan et al. (46)
	HFD for 5 weeks with or without a synbiotic composed out of Lactobacillus fermentum (CECT5716) and fructooligosaccharides	HFD for 5 weeks caused hepatic steatosis, insulin resistance, endotoxemia, increased production of SCFA, and increased numbers of Bacteroidetes in feces with an augmented Bacteroidetes/Firmicutes ratio. In addition, HFD weakened barrier function with increased LPS plasma levels. Saturation of absorptive mechanisms for fructose increased fructose availability in the distal and dysbiosis. Treatment with the synbiotic prevented some of the pathological effects, improved dysbiosis, and barrier function.	The synbiotic composed of L. fermentum CECT5716 and fructooligosaccharides has beneficial effects in the pathogenesis of HFD-induced metabolic syndrome.	Rivero-Gutiérrez et al. (61)
	70% (w/w) high-fructose diet for 3 weeks with or without oral addition of Lactobacillus curvatus and Lactobacillus plantarum	Fructose increased plasma glucose, insulin, triglycerides, total cholesterol, oxidative stress, liver mass, and liver lipids. Probiotic treatment lowered plasma glucose, insulin, triglycerides, and oxidative stress levels, while liver mass and cholesterol were only reduced at high-doses of probiotics. Probiotic treatment reduced lipogenesis via downregulation of SREBP1, FAS and SCD1 mRNA and increased β-oxidation via upregulation of PPARα and CPT2.	The combined administration of probiotic L. curvatus HY7601 and L. plantarum KY1032 suppress the clinical characteristics of high-fructose-induced metabolic syndrome.	Park et al. (37)
	Fructose-rich diet for 8 weeks combined with oral treatment with either antibiotics or fecal samples from control rats	The fructose-rich diet induced markers of metabolic syndrome, inflammation, oxidative stress and numbers of Coprococcus and Ruminococcus. These effects were reduced by both antimicrobial therapy and fecal treatments.	The development of fructose-induced metabolic syndrome is correlated with variations in the gut content of specific bacterial taxa.	Di Luccia et al. (62)
	10% fructose in drinking water for 6 weeks plus orally administered Juglanin	Juglanin prevented fructose-induced systemic increase of LPS levels, ALT, AST, ALP, and upregulation of TNF-α, IL-1β, IL-6, and IL-18. The flavonol suppressed fructose-feeding-induced activation of signaling pathways related to hepatic injury and inflammation.	Juglanin represses inflammatory responses and apoptosis through TLR4-regulated MAPK/NF-κB and JAK2/STAT3 signaling pathways.	Zhou et al. (63)
Monkey	Chronic ad libitum and short-term calorically controlled consumption of a high-fructose diet	Fructose increased biomarkers of liver damage, endotoxemia, and microbial translocation index.	Fructose rapidly causes liver damage secondary to changes in endotoxemia levels and microbial translocation.	Kavanagh et al. (64)
Human	Fructose feeding study	After 24-h fructose feeding, endotoxin levels in NAFLD adolescents increased after fructose beverages (consumed with meals) as compared to healthy children. Similarly, endotoxin was significantly increased after adolescents consumed fructose beverages for 2 weeks.	Fructose induces low level endotoxemia contributing to pediatric NAFLD.	Jin et al. (65)