Zhendong Mei1,2, Guo-Chong Chen2, Zheng Wang2, Mykhaylo Usyk3, Bing Yu4, Yoshiki Vazquez Baeza5, Greg Humphrey5, Rodolfo Salido Benitez5, Jun Li6, Jessica S Williams-Nguyen7, Martha L Daviglus8, Lifang Hou9, Jianwen Cai10, Yan Zheng1,11, Rob Knight5,12, Robert D Burk2,3,13, Eric Boerwinkle4, Robert C Kaplan2,7, Qibin Qi2,6. 1. State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, China. 2. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA. 3. Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA. 4. Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. 5. Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. 6. Department of Nutrition and Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA. 7. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 8. Institute of Minority Health Research, University of Illinois College of Medicine, Chicago, IL, USA. 9. Institute for Public Health and Medicine, Northwestern University, Chicago, IL, USA. 10. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 11. Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China. 12. Department of Computer Science and Engineering, Jacobs School of Engineering, and Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA. 13. Department of Microbiology and Immunology, and Department of Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Abstract
BACKGROUND: Trimethylamine-N-oxide (TMAO), a diet-derived and gut microbiota-related metabolite, is associated with cardiovascular disease (CVD). However, major dietary determinants and specific gut bacterial taxa related to TMAO remain to be identified in humans. OBJECTIVES: We aimed to identify dietary and gut microbial factors associated with circulating TMAO. METHODS: This cross-sectional study included 3972 participants (57.3% women) aged 18-74 y from the Hispanic Community Health Study/Study of Latinos in the United States. Dietary information was collected by 24-h dietary recalls at baseline interview (2008-2011), and baseline serum TMAO and its precursors were measured by an untargeted approach. Gut microbiome was profiled by shotgun metagenomic sequencing in a subset of participants (n = 626) during a follow-up visit (2016-2018). Logistic and linear regression were used to examine associations of inverse-normalized metabolites with prevalent CVD, dietary intake, and bacterial species, respectively, after adjustment for sociodemographic, behavioral, and clinical factors. RESULTS: TMAO was positively associated with prevalent CVD (case number = 279; OR = 1.34; 95% CI: 1.17, 1.54, per 1-SD). Fish (P = 1.26 × 10-17), red meat (P = 3.33 × 10-16), and egg (P = 3.89 × 10-5) intakes were top dietary factors positively associated with TMAO. We identified 9 gut bacterial species significantly associated with TMAO (false discovery rate <0.05). All 4 species positively associated with TMAO belong to the order Clostridiales, of which 3 might have homologous genes encoding carnitine monooxygenase, an enzyme converting carnitine to trimethylamine (TMA). The red meat-TMAO association was more pronounced in participants with higher abundances of these 4 species compared with those with lower abundance (Pinteraction = 0.013), but such microbial modification was not observed for fish-TMAO or egg-TMAO associations. CONCLUSION: In US Hispanics/Latinos, fish, red meat, and egg intakes are major dietary factors associated with serum TMAO. The identified potential TMA-producing gut microbiota and microbial modification on the red meat-TMAO association support microbial TMA production from dietary carnitine, whereas the fish-TMAO association is independent of gut microbiota.
BACKGROUND: Trimethylamine-N-oxide (TMAO), a diet-derived and gut microbiota-related metabolite, is associated with cardiovascular disease (CVD). However, major dietary determinants and specific gut bacterial taxa related to TMAO remain to be identified in humans. OBJECTIVES: We aimed to identify dietary and gut microbial factors associated with circulating TMAO. METHODS: This cross-sectional study included 3972 participants (57.3% women) aged 18-74 y from the Hispanic Community Health Study/Study of Latinos in the United States. Dietary information was collected by 24-h dietary recalls at baseline interview (2008-2011), and baseline serum TMAO and its precursors were measured by an untargeted approach. Gut microbiome was profiled by shotgun metagenomic sequencing in a subset of participants (n = 626) during a follow-up visit (2016-2018). Logistic and linear regression were used to examine associations of inverse-normalized metabolites with prevalent CVD, dietary intake, and bacterial species, respectively, after adjustment for sociodemographic, behavioral, and clinical factors. RESULTS: TMAO was positively associated with prevalent CVD (case number = 279; OR = 1.34; 95% CI: 1.17, 1.54, per 1-SD). Fish (P = 1.26 × 10-17), red meat (P = 3.33 × 10-16), and egg (P = 3.89 × 10-5) intakes were top dietary factors positively associated with TMAO. We identified 9 gut bacterial species significantly associated with TMAO (false discovery rate <0.05). All 4 species positively associated with TMAO belong to the order Clostridiales, of which 3 might have homologous genes encoding carnitine monooxygenase, an enzyme converting carnitine to trimethylamine (TMA). The red meat-TMAO association was more pronounced in participants with higher abundances of these 4 species compared with those with lower abundance (Pinteraction = 0.013), but such microbial modification was not observed for fish-TMAO or egg-TMAO associations. CONCLUSION: In US Hispanics/Latinos, fish, red meat, and egg intakes are major dietary factors associated with serum TMAO. The identified potential TMA-producing gut microbiota and microbial modification on the red meat-TMAO association support microbial TMA production from dietary carnitine, whereas the fish-TMAO association is independent of gut microbiota.
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