This is the first investigation on fecal microbiota profiles that are specifically associated with cardio-metabolic abnormalities belonging to MS, IR and low-grade inflammation in patients with obesity. On the other hand, we confirmed differences in fecal bacterial richness and composition between young individuals with obesity and healthy age-matched normal-weight subjects. Indeed, we found increased representation of some microbial markers, i.e. Streptococcus and Lachnospiraceae, and reduced one of some others, i.e. Bacteroides spp., Barnesiellaceae and Oscillospira in the group of individuals with obesity as compared to controls [23].
With regard to signatures that were specific of each metabolic abnormality, we found a reduced bacterial richness, that is characteristic of many inflammatory conditions [24, 25], prevalently in patients with more severe IR but also higher DBP suggesting that the close pathogenic link between IR and hypertension can be mediated by the gut microbiota dysbiosis and passes through a condition of enhanced inflammation [5, 26, 27].
We found some microbial taxa that inhabit the gut ecosystem with low abundance (i.e. the Gemellaceae) to be associated with metabolic abnormalities. In general, few microbial taxa dominate almost all types of human-associated samples, while the majority of them are present in low abundance and represent a kind of “rare biosphere” [28]. Nevertheless, in our sample rare taxa seemed to contribute significantly to the diversity of the host’s microbiome and hence to the health to disease balance.
We found significant associations of microbial taxa with metabolic abnormalities. In brief, we found an increase of Clostridiaceae and Clostridium in patients with high blood pressure as already seen in the CARDIA (Coronary Artery Risk Development in Young Adults) study [26]. Nonetheless, in our series, Clostridium was more abundant also in NGT patients as compared with those with IGT, suggesting a not clear role in the obesity context.
We found also an over representation of Lachnospiraceae, Gemellaceae and Turicibacter in patients with low-levels of HDL-C. A previous study in individuals either with normal or high cholesterol found a statistically significant correlation between Turicibacter and low levels of HDL-C [29]. Gemellaceae were also associated with high count of WBCs. The Gemellaceae family is present in the gut microbiota with a low relative abundance in different disease conditions characterized by an inflammatory status [30, 31].
The increased representation of Lachnospiraceae in patients with low-levels of HDL-C and severe obesity confirmed the close connection of this taxa with severe obesity and altered lipid metabolism [32].
Parabacteroides and Bacteroides caccae were highly represented in patients with low levels of fasting glucose. The treatment of obese high-fat diet (HFD)-fed mice with P. distasonis was effective to reduce weight gain, hyperglycemia, and hepatic steatosis in the animals owing likely to the dramatically altered bile acid profile and increased gut levels of succinate [33]. As to the B. caccae, it seems playing a dualistic role in the gut being a beneficial inhabitant or an opportunistic pathogen. Indeed, it was found in the gut microbiota of normal weight adolescents [23] as well as in patients with inflammation as appraised by high WBC count [34, 35].
Furthermore, the P. distasonis together with the Oscillospira was associated with a low MS risk score, suggesting the former may serve as marker of a relatively healthy metabolic profile of obesity. Oscillospira has also been related to a healthy metabolic profile consisting of high HDL-cholesterol and low systolic and diastolic blood pressure, fasting glucose and triglycerides in large cohort study [36].
On the contrary, the Coriobacteriaceae were associated with a high risk score for the metabolic syndrome. In a murine model of streptozocin-induced diabetes, a study demonstrated a beneficial effect of Coriobacteriaceae in the amelioration of the glucose metabolism following the Roux-en-Y gastric bypass. [37].
Coprococcus and H. parainfluenzae were more abundant in patients with low IR. In literature, it has been reported that representation of both bacteria is associated with the amelioration of the IR in HFD-high sucrose mice [38] and the glucose tolerance status in humans [39].
There was also an abundance of Bacteroides ovatus and Enterobacteriaceae in children with IGT. The Enterobacteriaceae is a family belonging to the phylum Proteobacteria that has been found over represented, with an undoubted causative role, in patients T2D [40, 41]. Its abundance seems depending on the diet. Indeed, Proteobacteria were found increased in European children who consumed a calorie-dense, high-fat, low-fiber diet as compared with children from Burkina Faso who were low-fat, high-fiber consumers [42]. Furthermore, the representation of a specific Proteobacteria, the Betaproteobacteria, was found positively correlated with plasma glucose levels in adults with different degree of glucose tolerance [40].
In our series, low levels of triglycerides were associated to the presence of F. prausnitzii that is regarded as marker of a healthy gut. A study on HFD fed mice demonstrated the significant reduction of triglycerides in mice following the oral administration of F. prausnitzii [43].
We are aware of bias in the present investigation: small-size and metabolic heterogeneous sample of patients with obesity and normal-weight controls; cross-sectional design; no use of gold standard techniques to estimate IR; no estimation of microbiome metabolites that are known to cause inflammation, IR and CVD.
Nonetheless, the present study can be deemed as a pilot methodological investigation to open the way at the identification of specific fecal microbiota signatures of metabolic abnormalities even in the population of adolescents in which the diagnosis of MS is not univocally recognized. Indeed, in keeping with the recommendations of the European Childhood Obesity working group on MS [44], we categorized our patients on percentile distributions of metabolic abnormalities. Drawbacks of this study could be overcome by a multi-center cohort investigation with characterization of host inflammation and host and microbiome metabolites.
In conclusion, in young individuals with obesity, we observed reduced heterogeneity in groups with higher propensity to the metabolic syndrome and pro-inflammatory conditions. We also identified single fecal taxa, in some cases rare taxa, that were relatively over abundant in relation to a specific metabolic abnormality, i.e. impaired glucose tolerance or high white blood cell count. On top, findings hint that microbiota signatures can be informative on the risk of incident metabolic syndrome.
Finally, our study provided insight to dissect phenotype heterogeneity of a complex disease and this methodological approach might be replicated in other multifactorial heterogeneous conditions, i.e. the autism spectrum disorder, in which microbiota plays a pivotal role.