This article describes how a British Nutrition Foundation Drummond Pump Priming Award was used to develop in vivo proof of concept for increasing colonic propionate as a therapeutic strategy to reduce liver fat in adults with non‐alcoholic fatty disease (NAFLD). An overview of how the gut‐derived short‐chain fatty acids propionate and acetate are taken up and metabolised by the liver is provided, as well as a summary of how acetate may have contrasting effects on hepatic lipid content depending on the metabolic health of the individual. Finally, the article proposes that raising colonic propionate production could interfere with hepatic acetate metabolism and have positive effects on liver fat accumulation in individuals with NAFLD.