Altered nitric oxide induced by gut microbiota reveals the connection between central precocious puberty and obesity

Abstract

Altered nitric oxide induced by gut microbiota reveals the connection between central precocious puberty and obesity Dear Editor, Central precocious puberty (CPP) is a neuroendocrine disease characterized by the rapid development of geni-talia and the presence of secondary sexual characteristics before age 8 in girls and 9 in boys. With the early activation of the hypothalamus-pituitary-gonadal axis (HPGA), CPP limits the adult height in patients and associates with higher risks of breast cancer. 1 Although the previous report has illustrated the pathogenesis of CPP from the perspective of host genetic (e.g., KISS1 and KISS1R) and peripheral factors (e.g., leptin and insulin), 2 these factors appear to account for few CPP cases. In addition, the adi-pose tissue in obese children would secret leptin, which stimulates the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH), also participating the earlier onset of puberty. Since gut microbiota (GM) associated with the hormone secretion and obesity, 3 it inspires us to detect the mechanism of GM in triggering CPP, and explore their roles for the co-occurrence of obesity and CPP. We enrolled 73 girls according to the criteria (Support-ing Information), including 27 CPP girls (CPP group), 24 over-weighted girls (OW group), and 22 healthy controls (HC group, Tables 1 and 2). To investigate the GM characteristics in CPP and OW patients, we carried out 16S rRNA sequencing on fecal samples from the participants, and obtained 877 representative amplicon sequence variants (ASVs, Table S3). Permutational multivariate analysis of variance (PERMANOVA) indicated that health status (R 2 = 0.161, p < 0.001) and weight (R 2 = 0.035, p = 0.041) contributed significantly to GM differences (Figure 1A). Based on the GM compositions at genus level, principal coordinate analysis (PCoA) with Bray-Curtis dissimilar-ity revealed separation of the three groups (Figure 1B), and the CPP patients showed the highest α-diversity value (Fig-ure 1C), which in agreement with the previous report. 4 The increased GM diversity in CPP patients attributes to the overall increased bacterial richness, suggesting the higher This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. maturity of GM. Consistent with PCoA, we discovered significant GM differences between the three groups, and the CPP group showed greater GM dissimilarity with OW than it compared with HC (p < 0.001, Figure 1D). With taxonomical annotation, the ASVs from all samples fell into 80 bacterial genera, and the top 10 abundant genera, such as Bacteroides, Prevotella, and Parabac-teroides, made up about 86.3% of the total microbiome (Figure 1E, Table S4). As compared with the HC and OW groups, the CPP group harbored distinct GM compositions (Figure 1F). Among the differentially enriched bacteria , the CPP patients exhibited overrepresented Alistipes, Klebsiella, and Sutterella (p < 0.05), which normally abundant in patients with neural diseases 5 (Figure 1G). Through secreting neurotransmission-related metabolites, such as serotonin and dopamine, the bacteria could trigger the earlier onset of puberty by activating HPGA. In addition, the OW girls shared enriched Prevotella with the CPP girls (Figure 1F). By producing branched-chain amino acid, 6 Prevotella promotes insulin resistance in host, which provides clues about the high occurrence of obesity in CPP patients. To depicted the bacterial co-occurrence relationships, we constructed bacterial networks in the three cohorts (Figure 2). Overall, the CPP patients (Figure 2C) harbored boosted bacterial correlations as compared with the HC (Figure 2A) and OW (Figure 2B) subjects (Spearman correlation coefficient ← 0.6 or >0.6, adjusted p < 0.05), and the genera from phylum Firmicutes formed complex positive relationships, indicating a positive feedback loop of the altered bacterial community on CPP progression. Notably, the CPP-enriched Gamma-aminobutyric acid-producer Bifidobacterium 6 showed negative association with the HC-enriched Bacteroides (Figure 2C), while the correlation was experimentally examined 7 and the neurotransmission-related Sutterella 5 formed positive correlation with Parabacteroides in CPP patients. These results demonstrated that the specific GM networks would Clin. Transl. Med. 2021;11:e299. wileyonlinelibrary.com/journal/ctm2 1 of 5 https://doi.