Distinct Gut Microbiota Profiles in Normal Weight Obesity and Their Association With Cardiometabolic Diseases: Results From Two Independent Cohort Studies

Abstract

Background: Normal weight obesity (NWO) is characterized by excess body fat in individuals with normal body mass index (BMI). This study aimed to investigate gut microbiota alterations in NWO and their potential associations with cardiometabolic diseases (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 5467 adults with normal BMI from two independent cohorts: the WELL-China cohort and the Lanxi cohort. NWO was defined as having a normal BMI (18.5-23.9 kg/m²) but an excess per cent body fat (PBF, ≥ 25% in men and ≥ 35% in women). Normal weight lean was defined as having a normal BMI and normal PBF. The 16S rRNA gene sequencing method was used to analyse gut microbiota data.

Results: The study comprised 3620 (64.0% female, median age 58 years) and 1847 (64.3% female, median age 56 years) participants from the WELL-China and Lanxi cohorts. In our meta-analysis, NWO is associated with 26% (95% CI: 1.07-1.41) higher risk of CMD mortality. Gut microbial analyses indicated that the NWO group exhibited reduced levels of observed species (p = 0.009 and p = 0.013) and Chao 1 index (p = 0.002 and p = 0.002) and altered gut microbial compositions (p = 0.009 and p < 0.001) compared with the NWL group. Seven genera were consistently observed to be associated with NWO in both two cohorts (all Q < 0.25). Among them, five (Fusobacterium, Ruminococcus gnavus group, Ruminococcus torques group, Coprococcus and Christensenellaceae_R7_group) have been previously linked to obesity, while the other two (Phascolarctobacterium and Clostridia_UCG-014) were minimally reported. We also found statistically significant differences in the microbial composition between the NWO group and the obesity group (p = 0.001 and p = 0.001). Furthermore, the NWO-related gut microbiome was associated with an elevated risk of hypertension, dyslipidaemia and metabolic syndrome, the corresponding HR (95% CIs) were 1.11 (1.01-1.22), 1.19 (1.10-1.29) and 1.17 (1.05-1.30) in the WELL-China cohort and 1.14 (1.02-1.27), 1.15 (1.02-1.29) and 1.16 (1.02-1.32) in the Lanxi cohort.

Conclusions: These two large cohorts provided reliable evidence that gut microbiota alterations in NWO resemble those found in obesity, yet also display unique aspects. This distinct microbiota profile may contribute to heightened cardiometabolic risks in adults with normal BMI.

Keywords: Cardiometabolic diseases; Gut microbiota; Independent cohort; Normal weight obesity.

FIGURE 1

NWO and cardiometabolic mortality in US NHANES and UK Biobank. HR (95% CIs) were calculated from Cox proportional hazard models, adjusted for age, sex, race, smoking status, drinking status, physical activity, education attainment and income level. The effect estimates from two cohorts were pooled using random effects meta‐analysis. NHANES, National Health and Nutrition Examination Study; NWO, normal weight obesity. Weight refers to the relative importance of each individual study to the overall results of the meta‐analysis.

FIGURE 2

NWO‐related gut microbial α‐ and β‐diversity alterations in the WELL‐China (A1 and A2) and Lanxi cohorts (B1 and B2). P value for α‐diversity was calculated from the multivariable linear regression model, and adjusted for potential confounding factors (described in the text). Permutational ANOVA (999 permutations) was used to evaluate the P value for β‐diversity. NWL, normal weight lean; NWO, normal weight obesity.

FIGURE 3

NWO‐related gut microbial function and metabolic pathways. Differences in the predicted microbial function between the NWL and NWO groups in the WELL‐China (A) and Lanxi cohorts (B). The differential metabolites between the NWL and NWO groups (C). The metabolic pathway analysis of differential metabolites between the NWL and NWO groups (D).

FIGURE 4

NWO‐related gut microbiota and cardiometabolic risk indicators in the WELL‐China (A1) and Lanxi cohorts (A2). P value was corrected using the Benjamini‐Hochberg false discovery rate (FDR). *FDR‐corrected p < 0.05. CRP, C‐reactive protein; DBP, diastolic blood pressure; HDL, high‐density lipoprotein; LDL, low‐density cholesterol; NWO, normal weight obesity; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; UA, uric acid. Upward arrows indicated the genera enriched in the NWO group, whereas downward arrows indicated the genera depleted in the NWO group.

FIGURE 5

NWO‐microbial index and cardiometabolic diseases. Multivariable linear regression model was used to evaluate the association of NWO‐microbial index (MI) with percent body fat (A), and percent android/gynoid fat (B) in the WELL‐China cohort and Lanxi cohort. Multivariable logistic regression was used to estimate the association of NWO‐MI (per‐SD increase) with CMD risk in the WELL‐China cohort and Lanxi cohort (C). The effect estimates from two cohorts were pooled using random effects meta‐analysis. CMD, cardiometabolic diseases.