Gut Microbiota Alterations in Normal Weight Obesity and Their Association with Cardiometabolic Diseases: Results from Two Independent Cohort Studies

Background: Human studies have linked altered gut microbiota profiles and host obesity. However, gut microbiota alterations in normal weight obesity (NWO) and whether these alterations were associated with cardiometabolic diseases (CMD) remain unclear. We aimed to investigate gut microbiota alterations in NWO and their potential associations with CMD risk in two independent cohorts.Methods: Our NWO-CMD mortality analysis included 168,099 adults with normal BMI from two large open-access databases, while our NWO-gut microbiota study involved 3,620 and 1,847 adults with normal body mass index (BMI) from two independent cohorts: the WELL-China cohort and the Lanxi cohort. NWO was defined as having a normal BMI (18.5 kg/m2-23.9 kg/m2) but an excess percent body fat (≥ 25% in men and ≥ 35% in women). The 16S rRNA gene sequencing method was used to measure the diversity and relative abundance of gut microbiota. The primary outcome was cardiometabolic diseases including hypertension, diabetes, metabolic syndrome, and dyslipidemia.Findings: NWO is associated with 26% (95% CI: 7% to 41%) higher risk of CMD mortality. The NWO group exhibited reduced α-diversity and altered gut microbial compositions. Seven genera were consistently observed to be associated with NWO in both two cohorts. Among them, five (Fusobacterium, Ruminococcus gnavus group, Ruminococcus torques group, Christensenellaceae_R7_group, and Coprococcus) have been previously linked to obesity, while the other two (Phascolarctobacterium and Clostridia_UCG-014) were minimally reported. Furthermore, the NWO-related gut microbiome was associated with an elevated risk of CMD, including hypertension, dyslipidemia, and metabolic syndrome.Interpretation: These two independent cohorts provided reliable evidence that NWO has obesity-like yet distinct gut microbiota features, that potentially contribute to heightened cardiometabolic risks in adults with normal BMI.Funding: This work was funded by the Amway (China) Foundation, the Cyrus Tang Foundation, the China Medical Board (CMB), and the Hsun K. Chou Fund of the Zhejiang University Education Foundation. Declaration of Interest: The authors declare that they have no competing interests.Ethical Approval: The WELL-China cohort study protocol received approval from the Institutional Review Boards of Zhejiang University, China (No. ZGL201507-3) and Stanford University, USA (IRB-35020). The Lanxi Cohort study protocol obtained approval from the Ethics Committee of the School of Public Health, Zhejiang University (No: ZGL2012-12), China. Written informed consent was obtained from all study participants.