Baseline gut metagenomic functional gene signature associated with variable weight loss responses following a healthy lifestyle intervention in humans

Recent human feeding studies have shown how the baseline taxonomic composition of the gut microbiome can determine responses to weight loss interventions. However, the functional determinants underlying this phenomenon remain unclear. We report a weight-loss response analysis on a cohort of individuals (N=105) selected from a larger population enrolled in a commercial scientific wellness program, which included healthy lifestyle coaching. Each individual in the cohort had baseline blood metabolomics, blood proteomics, clinical labs, dietary questionnaires, and stool 16S rRNA gene amplicon sequencing data. These individuals also had follow-up data on weight change. We generated additional targeted proteomics data on obesity-associated markers in blood before and after intervention, along with baseline shotgun metagenomics data from stool, for a subset of 25 individuals who showed the most extreme weight change phenotypes. We built linear regression models to identify baseline blood, stool, and dietary features significantly associated with weight loss, independent of age, sex, and baseline body mass index (BMI). Many features were independently associated with baseline BMI, but very few were independently associated with weight loss. Baseline diet was not associated with weight loss and only a single blood analyte was associated with weight loss. However, 31 baseline stool metagenomic functional features, including complex polysaccharide and protein degradation genes, stress-response genes, respiration-related genes, and cell wall synthesis genes, along with gut bacterial replication rates, that were significantly associated with weight loss response after controlling for age, sex, and baseline BMI. Together, these results provide a set of compelling hypotheses for how commensal human gut microbiota may influence weight loss outcomes following healthy lifestyle interventions.