Imbalanced gut microbiota predicts and drives the progression of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in a fast-food diet mouse model

Nonalcoholic fatty liver disease (NAFLD) is multifactorial in nature, affecting over a billion people worldwide. The gut microbiome has emerged as an associative factor in NAFLD, yet mechanistic contributions are unclear. Here, we show fast food (FF) diets containing high fat, added cholesterol, and fructose/glucose drinking water differentially impact short- vs. long-term NAFLD severity and progression in conventionally-raised, but not germ-free mice. Correlation and machine learning analyses independently demonstrate FF diets induce early and specific gut microbiota changes that are predictive of NAFLD indicators, with corresponding microbial community instability relative to control-fed mice. Shotgun metagenomics showed FF diets containing high cholesterol elevate fecal pro-inflammatory effectors over time, relating to a reshaping of host hepatic metabolic and inflammatory transcriptomes. FF diet-induced gut dysbiosis precedes onset and is highly predictive of NAFLD outcomes, providing potential insights into microbially-based pathogenesis and therapeutics. HighlightsO_LIGerm-free mice are protected from fast-food diet-induced NAFLD. C_LIO_LIFast-food diets rapidly shift gut microbiota composition and function. C_LIO_LIIncreasing dietary cholesterol exacerbates hepatic inflammation only in SPF mice. C_LIO_LIFast-food diet-induced gut dysbiosis precedes and predicts late-stage NAFLD severity. C_LI