Gut-microbiome-related LCT genotype and 2-year changes in body composition and fat distribution: the POUNDS Lost Trial

Background/objectives Gut microbiome regulates host energy metabolism and adiposity. A recent study identified a genome-wide significant variant in the lactase (LCT) gene that determines gut-microbiome abundance. We investigated whether the LCT variant influenced long-term changes in adiposity among overweight and obese individuals. Subjects/methods We included 583 whites with LCT variant rs4988235 (G allele as Bifidobacterium-abundance-increasing allele) who were randomly assigned to one of four weight-loss diets varying in macronutrient contents. Two-year changes in adiposity measures were assessed according to the LCT genotype and weight-loss diets. Results We observed a significant interaction between the LCT genotype and dietary protein intake on changes in whole body total fat mass %, trunk fat %, superficial adipose tissue mass (SAT), visceral adipose tissue mass (VAT), and total adipose tissue mass (TAT) (P-interaction < 0.05 for all). In response to high-protein diet, carrying the G allele of LCT variant rs4988235 was associated with greater reduction of whole body total fat mass % (beta [SE] -0.9 [0.43], P = 0.04), trunk fat % (-1.06 [0.58], P = 0.07), SAT (-0.89 [0.42], P = 0.04), VAT (-0.63 [0.27], P = 0.03), and TAT (-1.69 [0.76], P = 0.03). Conversely, increasing numbers of the G allele tended to be related to less reduction of these outcomes in response to lowprotein diet. Conclusions Long-term improvement of body fat composition and distribution was significantly influenced by the Bifidobacterium- related LCT genotype and dietary protein intake. Overweight and obese individuals with the G allele of LCT variant rs4988235 may benefit improving adiposity by eating a low-calorie, high-protein diet.