Calorie restriction improves metabolic state independently of gut microbiome composition: a randomized dietary intervention trial

BACKGROUND: The gut microbiota has been suggested to play a significant role in the development of overweight and obesity. However, the effects of calorie restriction on gut microbiota of overweight and obese adults, especially over longer durations, are largely unexplored. METHODS: Here, we longitudinally analyzed the effects of intermittent calorie restriction (ICR) operationalized as the 5:2 diet versus continuous calorie restriction (CCR) on fecal microbiota of 147 overweight or obese adults in a 50-week parallel-arm randomized controlled trial, the HELENA Trial. The primary outcome of the trial was the differential effects of ICR versus CCR on gene expression in subcutaneous adipose tissue. Changes in the gut microbiome, which are the focus of this publication, were defined as exploratory endpoint of the trial. The trial comprised a 12-week intervention period, a 12-week maintenance period, and a final follow-up period of 26 weeks. RESULTS: Both diets resulted in $\sim$5% weight loss. However, except for Lactobacillales being enriched after ICR, post-intervention microbiome composition did not significantly differ between groups. Overall weight loss was associated with significant metabolic improvements, but not with changes in the gut microbiome. Nonetheless, the abundance of the Dorea genus at baseline was moderately predictive of subsequent weight loss (AUROC of 0.74 for distinguishing the highest versus lowest weight loss quartiles). Despite the lack of consistent intervention effects on microbiome composition, significant study group-independent co-variation between gut bacterial families and metabolic biomarkers, anthropometric measures, and dietary composition was detectable. Our analysis in particular revealed associations between insulin sensitivity (HOMA-IR) and Akkermansiaceae, Christensenellaceae, and Tanerellaceae. It also suggests the possibility of a beneficial modulation of the latter two intestinal taxa by a diet high in vegetables and fiber, a