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.
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.
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) (Pinteraction < 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 % (β [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 low-protein diet.
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.
Your institute does not have access to this article
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Turnbaugh PJ, Gordon JI. The core gut microbiome, energy balance and obesity. J Physiol. 2009;587:4153–8.
Jumpertz R, Le DS, Turnbaugh PJ, Trinidad C, Bogardus C, Gordon JI, et al. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am J Clin Nutr. 2011;94:58–65.
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31.
Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457:480–4.
Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488:178–84.
Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541–6.
Wang J, Thingholm LB, Skieceviciene J, Rausch P, Kummen M, Hov JR, et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet. 2016;48:1396–406.
Turpin W, Espin-Garcia O, Xu W, Silverberg MS, Kevans D, Smith MI, et al. Association of host genome with intestinal microbial composition in a large healthy cohort. Nat Genet. 2016;48:1413–7.
Bonder MJ, Kurilshikov A, Tigchelaar EF, Mujagic Z, Imhann F, Vila AV, et al. The effect of host genetics on the gut microbiome. Nat Genet. 2016;48:1407–12.
Hur KY, Lee MS. Gut microbiota and metabolic disorders. Diabetes Metab J. 2015;39:198–203.
Pokusaeva K, Fitzgerald GF, van Sinderen D. Carbohydrate metabolism in Bifidobacteria. Genes Nutr. 2011;6:285–306.
Sanchez B, Delgado S, Blanco-Miguez A, Lourenco A, Gueimonde M, Margolles A. Probiotics, gut microbiota, and their influence on host health and disease. Mol Nutr Food Res. 2017;61:1600240.
Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, et al. Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet. 2004;74:1111–20.
Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, et al. Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet. 2008;82:57–72.
Mathieson I, Lazaridis I, Rohland N, Mallick S, Patterson N, Roodenberg SA, et al. Genome-wide patterns of selection in 230 ancient Eurasians. Nature. 2015;528:499–503.
Field Y, Boyle EA, Telis N, Gao Z, Gaulton KJ, Golan D, et al. Detection of human adaptation during the past 2000 years. Science. 2016;354:760–4.
Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Jarvela I. Identification of a variant associated with adult-type hypolactasia. Nat Genet. 2002;30:233–7.
Manco L, Dias H, Muc M, Padez C. The lactase -13910C>T polymorphism (rs4988235) is associated with overweight/obesity and obesity-related variables in a population sample of Portuguese young adults. Eur J Clin Nutr. 2017;71:21–24.
Hartwig FP, Horta BL, Smith GD, de Mola CL, Victora CG. Association of lactase persistence genotype with milk consumption, obesity and blood pressure: a Mendelian randomization study in the 1982 Pelotas (Brazil) Birth Cohort, with a systematic review and meta-analysis. Int J Epidemiol. 2016;45:1573–87.
Almon R, Alvarez-Leon EE, Serra-Majem L. Association of the European lactase persistence variant (LCT-13910 C > T polymorphism) with obesity in the Canary Islands. PLoS ONE. 2012;7:e43978.
Corella D, Arregui M, Coltell O, Portoles O, Guillem-Saiz P, Carrasco P, et al. Association of the LCT-13910C>T polymorphism withobesity and its modulation by dairy products in a Mediterranean population. Obesity (Silver Spring). 2011;19:1707–14.
Kettunen J, Silander K, Saarela O, Amin N, Muller M, Timpson N, et al. European lactase persistence genotype shows evidence of association with increase in body mass index. Hum Mol Genet. 2010;19:1129–36.
Albuquerque D, Nobrega C, Manco L. The lactase persistence -13910C>T polymorphism shows indication of association with abdominal obesity among Portuguese children. Acta Paediatr. 2013;102:e153–157.
Malek AJ, Klimentidis YC, Kell KP, Fernandez JR. Associations of the lactase persistence allele and lactose intake with body composition among multiethnic children. Genes Nutr. 2013;8:487–94.
Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2007;50:2374–83.
Schroeder BO, Backhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med. 2016;22:1079–89.
Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med. 2009;360:859–73.
de Souza RJ, Bray GA, Carey VJ, Hall KD, LeBoff MS, Loria CM, et al. Effects of 4 weight-loss diets differing in fat, protein, and carbohydrate on fat mass, lean mass, visceral adipose tissue, and hepatic fat: results from the POUNDS LOST trial. Am J Clin Nutr. 2012;95:614–25.
de Clercq NC, Groen AK, Romijn JA, Nieuwdorp M. Gut microbiota in obesity and undernutrition. Adv Nutr. 2016;7:1080–9.
Szilagyi A, Shrier I, Heilpern D, Je J, Park S, Chong G, et al. Differential impact of lactose/lactase phenotype on colonic microflora. Can J Gastroenterol. 2010;24:373–9.
Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500:585–8.
Russell WR, Gratz SW, Duncan SH, Holtrop G, Ince J, Scobbie L, et al. High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health. Am J Clin Nutr. 2011;93:1062–72.
Duncan SH, Lobley GE, Holtrop G, Ince J, Johnstone AM, Louis P, et al. Human colonic microbiota associated with diet, obesity and weight loss. Int J Obes (Lond). 2008;32:1720–4.
Chen J, Wang R, Li XF, Wang RL. Bifidobacterium adolescentis supplementation ameliorates visceral fat accumulation and insulin sensitivity in an experimental model of the metabolic syndrome. Br J Nutr. 2012;107:1429–34.
Takahashi S, Anzawa D, Takami K, Ishizuka A, Mawatari T, Kamikado K, et al. Effect of Bifidobacterium animalis ssp. lactis GCL2505 on visceral fat accumulation in healthy Japanese adults: a randomized controlled trial. Biosci Micro Food Health. 2016;35:163–71.
The authors thank all of the participants in the study for their dedication and contribution to the research.
The study is supported by NIH grants from the National Heart, Lung, and Blood Institute (HL071981, HL034594, HL126024), the National Institute of Diabetes and Digestive and Kidney Diseases (DK091718, DK100383, DK078616), the Boston Obesity Nutrition Research Center (DK46200), and United States–Israel Binational Science Foundation Grant 2011036. LQ was a recipient of the American Heart Association Scientist Development Award (0730094N). YH was a recipient of a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) and the Overseas Research Fellowship from the JSPS. The sponsors had no role in the design or conduct of the study.
YH contributed to the study concept and design, analysis and interpretation of data, drafting and revising the manuscript, statistical analysis, and study supervision. WM, DS, and YZ contributed to the analysis and interpretation of data, and drafting and revising the manuscript. CMC, GAB, and FMS contributed to acquisition of data, interpretation of data, and drafting and revising the manuscript. LQ contributed to the study concept and design, acquisition of data, analysis and interpretation of data, drafting and revising the manuscript, statistical analysis, and funding and study supervision. All authors were involved in the writing and revising of the manuscript and approved the final version of this article. LQ had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis.
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
About this article
Cite this article
Heianza, Y., Sun, D., Ma, W. et al. Gut-microbiome-related LCT genotype and 2-year changes in body composition and fat distribution: the POUNDS Lost Trial. Int J Obes 42, 1565–1573 (2018). https://doi.org/10.1038/s41366-018-0046-9
Nature Reviews Endocrinology (2020)
Lessons Learned from the POUNDS Lost Study: Genetic, Metabolic, and Behavioral Factors Affecting Changes in Body Weight, Body Composition, and Cardiometabolic Risk
Current Obesity Reports (2019)