Sex-dependent gut microbiota modulation in responders and non-responders with obesity to a multiphase weight-loss dietary intervention

Background Very low-calorie diets (VLCDs) are effective in managing obesity. However, the contribution of gut microbiota dynamics, regarding weight-loss magnitude and sex differences remains unclear. The aim of this study is to investigate the impact of VLCD on metabolic outcomes and gut microbiota composition in individuals with obesity, exploring modulation by weight loss and sex. Methods A 6-month longitudinal intervention was carried out in 109 adults with obesity. Participants were classified as responders (≥ 10% weight loss) or non-responders (< 10% weight loss). Clinical, biochemical, inflammatory and gut microbiota (16S rRNA) parameters were assessed. Results The intervention improved cardiometabolic health, particularly in responders. Only responders showed increased gut microbiota alpha diversity, with a greater increase in women. Several taxa were differentially affected: A kkermansia increased in all participants, and Marvinbryantia and Veillonella were enriched in responders and non-responders, respectively. Sex-specific patterns emerged, with Faecalibacterium enriched in male responders and Roseburia in female non-responders. Microbial taxa were associated with clinical parameters, including links between the Ruminococcus gnavus group and lymphocytes, and between Bilophila or Lachnospiraceae UCG-010 and insulin resistance, with associations varying by weight loss and sex. Conclusions These findings highlight that a VLCD-based intervention improves metabolic and gut microbiota profiles, with effects dependent on weight loss magnitude and sex, highlighting the need to consider sex in personalised nutritional strategies targeting obesity and the gut microbiota. Trial registration: The trial was registered at ClinicalTrials.gov (identifier: NCT06279780) (https://clinicaltrials.gov/study/NCT06279780?term=NCT06279780&rank=1).