Optimized Nutri-Dense meals versus a low-carbohydrate high-fat diet: an exploratory randomized controlled trial

Abstract Micronutrient adequacy, beyond macronutrient balance, may matter for health, yet the effects of low-carbohydrate, high-fat (LCHF) diets on obesity remain unclear. This exploratory three-arm, single-blind randomized controlled trial (N = 300) compared, over 4 weeks, meals optimized to the Japanese Dietary Reference Intakes (DRI; Opti meals, matched macronutrient ratio and 26 micronutrients), a micronutrient-insufficient control diet, and LCHF Opti meals (lower carbohydrate–fat ratio, identical micronutrients). In this partial report, primary outcomes were visceral fat area and salivary cortisol/melatonin, the device-derived streams of that set being reported separately; prespecified secondary outcomes were LDL-cholesterol, systolic/diastolic blood pressure (SBP/DBP), gut microbiota, serum metabolome, and DNA-methylation (DNAm) epigenetic age, analyzed in an exploratory, hypothesis-generating manner. Neither primary outcome differed between groups. LDL-cholesterol decreased in both Opti and LCHF Opti groups versus control, and SBP in the LCHF Opti group. Exploratory analyses showed shifts in gut microbiota and metabolites. In a small subgroup of older male participants (n = 10 per group), the Opti group showed lower PhenoAge, a DNA-methylation measure of biological age linked to mortality risk. Post-hoc machine learning predicted cardiometabolic responders (ROC-AUC 0.71–0.76). DRI-based meals did not outperform the comparators on the primary endpoints; the secondary findings are hypothesis-generating and require confirmation. Clinical Trial Registry number: UMIN000050103, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000056407 (approval: 23/1/2023).