Time Exposure and Fat Mass Reduction Drive Trimethylamine N-Oxide Modulation During a Very-Low-Energy Ketogenic...

Background/Objectives: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite increasingly recognized as a pro-atherogenic factor and a biomarker of cardiometabolic risk. Dietary patterns and adiposity are key modulators of circulating TMAO levels; however, evidence on the impact of very-low-energy ketogenic therapy (VLEKT) on TMAO metabolism, particularly in women with obesity, remains limited. This study aimed to investigate the effects of VLEKT on circulating TMAO concentrations, with specific focus on treatment duration and body composition (BC) changes. Methods: This study included 43 adult women with obesity eligible for VLEKT based on meal replacements. Anthropometric measurements and BC were assessed using standardized protocols and bioelectrical impedance analysis at baseline and post-intervention. Serum TMAO concentrations were quantified by validated HPLC-ESI-MS/MS. Results: After VLEKT, participants exhibited significant reductions in body weight, BMI, waist girth, fat mass (FM), and circulating TMAO levels. Greater reductions in TMAO were observed in women with longer ketogenic exposure and more pronounced FM loss. Changes in TMAO levels correlated negatively with VLEKT duration and positively with FM variations. In multivariate models, treatment duration and FM reduction emerged as independent predictors of TMAO decrease. A Receiver Operating Characteristic (ROC) analysis identified a FM reduction ≥14.25% as the optimal threshold associated with clinically relevant TMAO lowering. Conclusions: VLEKT reduces circulating TMAO levels in women with obesity. This effect appears to be primarily driven by the duration of ketogenic exposure and the magnitude of FM loss, rather than total weight reduction alone, highlighting the relevance of BC-targeted interventions in modulating gut microbiota-derived cardiometabolic risk markers.