Microbiota transplantation may not be as advantageous as dietary interventions in the treatment of NAFLD
Nonalcoholic fatty liver disease (NAFLD) refers to a common disorder characterised by an excessive accumulation of fat in the liver that begins from a mild steatosis to nonalcoholic steatohepatitis (NASH), that left untreated can lead to fibrosis, cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is multifactorial including diet, environment and the gut microbiota that is involved in the regulation of energy homeostasis, synthesis of triglycerides, lipoprotein synthesis, bile acid homeostasis and bacterial-derived toxins or virulence factors. There are few therapeutic strategies for the treatment of NAFLD and the most effective is represented by diet modification in terms of fat and sugar intake combined with physical activity. The international guidelines suggest a reduction of calories intake, saturated and trans fatty acids and fructose, while a consumption of omega-3 polyunsaturated fatty acids (PUFA) is highly recommended for the treatment of NAFLD.
In this promising study, Mitsinikos and colleagues evaluate the impact in mice of different diets on the progression of NAFLD and how the microbiota is shaped. Moreover, they compare the dietary intervention with the effect of microbiota transplantation to assess if manipulating the microbiota may be effective for the treatment of NAFLD.
Three different diets were developed: the NAFLD-inducing diet (NAF) made of high fat, cholesterol and fructose was used to induce a disease similar to human NAFLD (increased steatosis, liver inflammation and elevated liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels), the other two diets respectively a high-fat/high-fiber diet (HFF) and a low-fat/low-fiber diet (LFF) were used for dietary intervention. After treating the mice for 6 weeks with NAF diet, they switched to HFF or LFF or maintained on NAF for 6 more weeks. Both dietary interventions showed amelioration in NAFLD progression, in particular HFF diet was able to reduce liver steatosis and fibrosis and ALT level, while LFF-fed mice showed a complete resolution of liver pathology and a significant reduction in AST and ALT levels. Moreover, pro-inflammatory cytokines such as TNF-alfa and IL-6 were reduced in homogenized liver tissue of HFF- and LFF-fed mice. These data suggest how a dietary intervention high in fibers (even in the presence of high saturated fat) or low in fats and fibers reverse hepatic steatosis and reduce inflammation in the liver. The latter is not unexpected as the effect of the NAF diet can be reserved upon fat removal. However, these results indicate that high fibers can be beneficial even in the presence of fat and fructose.
Modulating the diet, the first actor affected is the microbiota. In order to evaluate changes in the bacterial population of examined groups, 16s rRNA sequencing on ileal and fecal samples was performed. NAF- and HFF-fed mice showed a Firmicutes-dominant microbiome, whereas LFF-fed mice had a significant increase in Actinobacteria and Bacteroidetes. These results show that although in dietary intervention the steatosis was resolved, the microbiota profile of each group had its own characteristics.
The authors were also interested in understanding the diet-educated microbiota potentiality to reverse steatosis or inflammation independently from the interventional diet itself. After treating the mice with a cocktail of antibiotics, they performed a cecal microbiota transplantation from mice previously fed with the dietary interventions or maintained on NAF. The results showed no improvement of steatosis: AST and ALT levels in the serum were as high as in NAF-fed mice and pro-inflammatory cytokines levels were not reduced. Microbiota transplantation failed to resolve NAFLD in the absence of the dietary factors that play a crucial role in shaping the microbiota.
To conclude, both dietary interventions high in fibers or low in fats and fibers, have demonstrated a reversal of NAFLD by a resolution of steatosis and liver inflammation accompanied by evident changes in the microbiota. However, when microbiota was transplanted in recipient mice, it was not able to confer protection from NAFLD, suggesting that fecal microbiota transplantation (FMT) may not be sufficient as a potential therapeutic strategy for the treatment of NAFLD in the absence of a continued dietary intervention.