In this cross-sectional study, we identified dysbiosis of gut microbiota and microbial biomarkers correlated with the development and progress of obesity among children. The α-diversity of gut microbiota in OB + high-cIMT children and OB + non-cIMT children was decreased compared with the normal group. Christensenellaceae_R-7_group, UBA1819, Family_XIII_AD3011_group, and unclassified_o__Bacteroidales had moderate to high ability in discriminating OB + non-cIMT and OB + high-cIMT group from the normal group.
Emerging evidence among adults has shown that the dysbiosis of gut microbiota was associated with metabolic diseases such as obesity, diabetes, and cardiovascular diseases (30–32). Previous studies showed that the community diversity of gut microbiota was lower among children with type 1 diabetes or combined with other CVD risk factors, such as elevated blood pressure, compared with normal controls (33–35). However, the associations between gut microbiota and subclinical CVD among children have been less reported. To the best of our knowledge, we innovatively found that the overall gut microbial community diversity of gut microbiota was lower among children with OB + high-cIMT compared with OB + non-cIMT and normal controls. Our findings suggest that the high diversity of gut microbiota might be a preventive in the progress of obesity (i.e, OB + high-cIMT).
We identified that the relative abundance of phylum Proteobacteria and genus Lachnoclostridium was the highest among OB + high-cIMT children followed by those with OB + non-cIMT and normal ones, while Alistipes showed an opposite trend. Studies based on animals and adults similarly reported that the relative abundance of Proteobacteria was positively associated with obesity and its related metabolic disorder (36). Consistent with our results among children, Alistipes can be considered as an important protective biomarker for CVD and metabolic syndrome among Chinese adults (37, 38). In contrast, American studies among 54 subjects have suggested that Alistipes were associated with an increased BP (39). The discrepancy may be due to differences in sample size, age and sex distribution, ethnic groups, and different dietary patterns (40). Moreover, a large population-based cohort based on the TwinsUK registered adult twins showed that Lachnoclostridium was positively correlated with visceral fat and increased the risk of cardiometabolic diseases (41, 42). Our findings add to the existing evidence and suggest that Proteobacteria, Alistipes, and Lachnoclostridium might contribute to the development of obesity combined with cardiovascular damage among children.
We found that the relative abundance in genus Christensenellaceae_R-7_group, UBA1819, Family_XIII_AD3011_group, and unclassified_o__Bacteroidales were the top four significantly decreased genera in OB + high-cIMT children compared with normal groups. Our findings were supported by previous studies of related metabolic outcomes that increased relative abundance of Christensenellaceae_R-7_group had a protective effect on BP both in adults and mice (43, 44). Overrepresented UBA1819 could improve the body weight in high-fat-fed mice and rats by reducing adipose tissue inflammation and glucolipid metabolism disorder (45, 46). Although Shi et al. found the abundance of Family_XIII_AD3011_group was increased in high-fat-fed rats (46), a study reported by Lüll et al. among polycystic ovary syndrome women in Finland that Family_XIII_AD3011_group was decreased in females with obesity (47), and our findings among children were consistent with the latter. As reported by metagenomic sequencing on type 2 diabetes mice, the increased abundance of unclassified_o__Bacteroidales was associated with improved glycolipid metabolism (48). Interestingly, we firstly found that genus Christensenellaceae_R-7_group, UBA1819, unclassified_o__Bacteroidales, and Family_XIII_AD3011_group had moderate ability in identifying OB + non-cIMT from normal groups and high ability in identifying OB + high-cIMT from normal groups. Our findings suggest that a decreased abundance of genus Christensenellaceae_R-7_group, UBA1819, Family_XIII_AD3011_group, and unclassified_o__Bacteroidales play a vital role in the development of obesity and damage of carotid intima-media. Interventions targeting these biomarkers may be used as one of the non-invasive diagnoses of obese children with or without damage of carotid intima-media.
Moreover, we found that thiamine metabolism and methane metabolism were significantly lower in OB + high-cIMT group vs. OB + non-cIMT group. In addition, hydrolysis of compounds and substrates pathways contributed to differentiate OB + high-cIMT group from normal group. Thiamine was a cofactor for enzymes regulating glucose metabolism (49), and its concentrations were decreased in patients with type 1 and type 2 diabetes mellitus through the reinforcement of hyperglycemic damage (50). Several studies showed that the use of multivitamins that contained thiamine was inversely associated with myocardial infarction and may reduce the risk of CVD in adults (51, 52). Methane can be produced by Methanomassiliicoccales, which involves the progress of adult CVD (53), and plays a protective effect through anti-inflammation, anti-oxidation, and anti-apoptosis (54, 55). In addition, the imbalanced hydrolysis of compounds and substrates could affect intestinal permeability and microbiota density, which could lead to chronic inflammation (56–61). Our findings suggest that the development and progress of obesity might be mediated by gut microbiota through these pathways.
To the best of our knowledge, this is the first study to explore the association between gut microbiota and obesity with high cIMT in children, and we have found several biomarkers that have moderate to high ability in identifying OB + high-cIMT children and OB + non-cIMT children from normal children. However, several limitations should be noted. First, 16S rRNA sequencing generally does not provide a level of species resolution, and more comprehensive technologies, such as in vivo experiments in mice and metagenomic sequencing, are needed to analyze the underlying mechanisms of the gut microbiota in depth. Second, our case-control study cannot be used for causal inference. Third, our sample size is small compared with studies in adults which need to be further verified in large cohort studies. However, substantial changes in microbiota can be easily measured (62). The flattened rarefaction curves indicate that the sample size is sufficient and reasonable, and more samples will only produce a few new features. Fourth, our study is based on a single center, which needs to be validated in multiple centers and other ethnic groups.
In conclusion, we found that dysbiosis of gut microbiota is associated with obesity with or without carotid intima-media damage in children, and Christensenellaceae_R-7_group, UBA1819, Family_XIII_AD3011_group, and unclassified_o_Bacteroidales had the ability identifying obesity and its progress from normal status. Our study provides effective and targeted guidance for the interventions for children with obesity and target organ damage.