Obesity, and not cardiometabolic health status, drives altered gut microbiome functions in the metabolically unhealthy

Obesity (OB) and cardiometabolic disease are public health epidemics linked to changes in the gut microbiome. However, the overlapping occurrence of OB and cardiometabolic health status (CHS) has made it challenging to differentiate unique microbiome associations with either condition. Here, we sought to replicate previously reported associations between microbiome and OB/CHS in a deeply phenotyped cohort and to differentiate features of gut microbiome function associated independently with OB and CHS. Fecal metagenomes were obtained from 408 deeply phenotyped adults from Colombia. OB was defined by body mass index, waist circumference, and body fat; CHS as healthy or unhealthy according to blood biochemistry and anthropometric data. We found that most previously reported functional associations were unique to OB or were shared by both conditions, with few functional modules uniquely associated with CHS. Consistent with previous studies, we found that metagenome sequence diversity was higher in lean and cardiometabolically healthy participants; we further showed that OB explained a higher proportion of variance in sequence diversity and functional beta-diversity than CHS. Compared to a healthy state, OB and CHS were characterized by reduced fermentative potential and elevated response to oxidative stress, and disease-linked features were mainly contributed by members of the family Enterobacteriaceae. Our results link poor metabolic health with the presence of an inflammatory and oxygenated gut state, consistent across study populations, and suggest that OB is the main driver of microbiome functional differences when CHS is a comorbidity.