A carbohydrate-restricted diet has been emerging as an effective dietary intervention for non-alcoholic fatty liver disease (NAFLD) in humans. NAFLD is the most prevalent form of liver disease in western countries, affecting an estimated up to 30% of the population and has been reported to be an independent risk factor for increased mortality related to cardiovascular and liver diseases. However, the mechanisms involved in how this diet may benefit patients with NAFLD are not fully understood.

A recent study, led by Dr. Jan Borén from the Department of Molecular and Clinical Medicine at the University of Gothenburg and Sahlgrenska University Hospital (Gothenburg, Sweden), has found that metabolic benefits of a carbohydrate-restricted diet in obese NAFLD patients may involve shifts in gut microbiota composition.

The researchers performed an intervention with an isocaloric low-carbohydrate diet with increased protein content (<30 g of carbohydrates and an average of 3,115 kcal per day) for 14 days in 10 obese subjects with NAFLD and used multi-omics to investigate its effects on host metabolism and the gut microbiota. Whole-genome shotgun sequencing of faecal samples obtained from participants at baseline and at 1, 3, 7, and 14 days allowed investigation of the impact of the dietary intervention on the gut microbiome.

Reduced carbohydrate consumption improved liver lipid metabolism and reduced inflammation in obese subjects with NAFLD. Although the researchers reported only minor weight loss at the end of the study, magnetic resonance spectroscopy showed a significant reduction in liver fat in all the individuals that was apparent since the first day after the start of the diet intervention. Beyond reductions of liver fat, marked reductions of other cardiometabolic risk factors -including very-low density lipoprotein (VLDL)-triglycerides, fasting plasma triglyceride concentrations and plasma apolipoprotein C-III, which is an inhibitor of VLDL clearance- were also detected. Besides this, reduced carbohydrate consumption decreased plasma concentrations of the inflammatory markers interleukin-6 and tumour necrosis factor alpha and plasma concentrations of the peptide hormone fibroblast growth factor 21 (FGF21) -a novel metabolic regulator that has been reported to be increased in subjects with NAFLD and that correlates with hepatic fat content, which suggests it could be used as a diagnostic marker for NAFLD.

The effects of reduced carbohydrate consumption on liver fat were paralleled by marked decreases in hepatic de novo lipogenesis and large increases in serum b-hydroxybutyrate concentrations (a marker for mitochondrial b-oxidation). These results suggest that the reduced hepatic lipid accumulation could be related to blunted de novo lipogenesis and increased b-oxidation.

It is also worth mentioning that benefits of the low-carbohydrate diet on liver fat metabolism involved shifts in the gut microbiota composition in NAFLD patients. Major shifts in the gut microbiota occurred after only 1 day of the dietary intervention and stabilized after 1 week on the low-carbohydrate diet. 25 genera and 94 bacterial strains were significantly altered, of which Streptococcus, Lactococcus and Eggerthella were increased; the carbohydrate-degrading bacteria Ruminococcus, Eubacterium, Clostridium and Bifidobacterium were decreased over the study period. Reductions in faecal concentrations of short-chain fatty acids were also observed as a result of decreased carbohydrate fermentation. Previous research has shown that carbohydrate-restricted diets may promote marked shifts in the composition of the gut microbiota and those microbial changes may therefore be involved in the development and progression of NAFLD.

Regarding functional changes in the gut microbiome in response to the dietary intervention, the low-carbohydrate diet promoted microbial shifts toward folate production that is potentially used by humans. Besides this, the low-carbohydrate diet upregulated expression of genes involved in folate-dependent one-carbon metabolism in the liver. However, a causal relationship cannot yet be inferred and other sources of increased circulating folate should be explored: for instance, enhanced dietary folate absorption in the small intestine secondary to the carbohydrate-restricted diet.

Finally, liver transcriptomic analysis on biopsy samples from a second cohort of 7 subjects that followed the low-carbohydrate diet for 7 days showed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways. The significant correlations in 5 individuals between serum folate and liver fat show that folate could play a role in improved liver fat metabolism. However, other metabolites involved in lipid and amino acid metabolism, several of them with antioxidant properties, were also increased during the dietary intervention and therefore could be also involved in the metabolic benefits of the low-carbohydrate diet.

In conclusion, gut microbial shifts after only 1 day of a low-carbohydrate diet may be partially behind the improved lipid metabolism and reduced inflammation in obese NAFLD patients. These results emphasize the need for further research exploring diet-microbiota interactions in the long term for preventing and/or treating NAFLD through targeting the gut microbiome.



Mardinoglu A, Wu H, Bjornson E, et al. An integrated understanding of the rapid metabolic benefits of a carbohydrate-restricted diet on hepatic steatosis in humans. Cell Metab. 2018; 27(3):559-71. doi: 10.1016/j.cmet.2018.01.005.