Diet order affects energy balance in randomized crossover feeding studies that vary in macronutrients but not ultra-processing

BACKGROUND: Crossover studies can induce order effects, especially when they lack a wash-out period. OBJECTIVE: To explore diet order effects on energy balance and food intake between randomized diet order groups in two inpatient crossover studies originally designed to compare within-subject differences in ad libitum energy intake between either minimally processed low carbohydrate (LC) versus low fat (LF) diets or macronutrient-matched diets composed of mostly minimally processed food (MPF) or ultra-processed food (UPF). METHODS: Diet order group comparisons of changes in body weight, body composition, and differences in energy expenditure, and food intake were assessed over four weeks in 20 adults randomized to either the LC followed immediately by the LF diet (LC→LF) or the opposite order (LF→LC) as well as 20 adults randomized to either the MPF followed by UPF (MPF→UPF) diets or the opposite order (UPF→MPF). RESULTS: Subjects randomized to LC→LF lost 2.9 ± 1.1 kg more body weight (p < 0.001) and 1.5 ± 0.6 kg more body fat (p = 0.03) than the LF→LC group likely because the LC→LF group consumed 922 ± 304 kcal/d less than the LF→LC group (p = 0.0024). Reduced energy intake in LC→LF vs LF→LC was driven by the last two weeks (−1610 ± 306 kcal/d; p<0.00001) perhaps due to carryover effects of gut adaptations over the first two weeks arising from large differences in the mass of food (1295 ± 209 g/d; p<0.00001) and fiber intake (58 ± 5 g/d; p<0.00001). There were no diet order effects on ad libitum energy intake, body weight, or body composition change between UPF→MPF versus MPF→UPF groups. CONCLUSIONS: Diet order influences daily ad libitum energy intake, body weight change, and fat change within the context of a 4-week crossover inpatient diet study varying in macronutrients, but not varying in extent and purpose of processing. FUNDING SOURCES: Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health CLINICAL TRIAL REGISTRATION: NCT03407053 and NCT03878108