Modifying macronutrients is superior to microbiome transplantation in treating nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver injury and liver transplantation in Western countries. The pathogenesis of NAFLD includes overnutritionassociated metabolic syndrome or the improper consumption of dietary macro-and micronutrients that either support or prevent disease development. This altered nutrient landscape has been linked to shifts within the gut microbiota which can exacerbate liver pathology and the progression of NAFLD. Treatment goals for NAFLD target lifestyle and dietary modifications that restrict calories and adjust macronutrient content. It is not well understood how different macronutrients alter the microbiota and whether the diet-educated microbiota contribute to the resolution of disease. We fed mice a diet high in fat, cholesterol and fructose for 6 weeks and then in two different arms of the study, intervened with either a diet high in saturated and polyunsaturated fats and fiber or low in fats and fiber. In a second set of experiments, we performed microbiota transplants using cecal contents from mice fed one of the intervention diets to assess whether the diet-educated microbiota could impact clinical outcomes in mice fed a NAFLD-inducing diet. Pathology, steatosis, ALT/AST levels, and liver cytokine levels were measured as primary outcomes. We found that despite different microbiota compositions, both of the intervention diets reversed the progression of NAFLD and dampened inflammation. In contrast, transplantation of cecal contents from the intervention diet-fed mice to mice receiving a NAFLD-inducing diet was unable to prevent disease progression, and, in some cases, worsened disease. These data underscore the importance of dietary modifications to treat NAFLD and caution against the use of microbiota transplantation in the absence of dietary and lifestyle modifications.

The role of the microbiome in liver disease

“…The exact mechanisms of FMT are not fully understood and there are probably multiple routes of beneficial effects, e.g., through microbial modulation of the phageome, or activation of the bile-acid–FXR–FGF-19 pathway [33]. FMT affected liver DNA methylation in patients with MASLD [34], indicating an epigenetic regulatory effect of microbiota on genes relevant for metabolism. FMT from lean healthy donors to obese patients with type 2 diabetes mellitus led to reduced LDL and liver stiffness, when combined with lifestyle interventions [35].…”

Faecal Microbiota Transplantation, Paving the Way to Treat Non-Alcoholic Fatty Liver Disease

“…This improvement can be explained by changes in GM that increase butyrate levels and reduce pro-inflammatory factors (i.e., IL-1, IL-6 or TNFα), promoting an anti-inflammatory microenvironment [ 74 ]. However, Mitsinikos et al showed that FMT may not be as advantageous as dietary modifications, given that FMT from mice receiving dietary interventions to rats with NASH did not improve histological activity [ 98 ].…”