Our present study identified a typical alteration of gut microbial pattern in women with PCOS, characterized by a high abundance of Lachnoclostridium and Veillonella in the genus level and a higher abundance of Bacteroides Coprocola, Bifidobacterium pseudocatenulatum, Sutterella Wassworthensis, Megasphaera Micronuciformis, Clostridium butyicum and Paraprevotella Xylaniphila in the species level. Particularly, the abundance of Bacteroides Coprocola was detected predominantly in the PCOS patients. These results extend previous understanding of the differential gut microbiota composition in the PCOS which reported colibacterium, Kandleriagenera [16] and Bacteroides vulgatus [17] were significantly increased in patients with PCOS. Our study is also partly consistent with Liu et al [18] who reported Bacteroides, Escherichia Coli/shigella, streptomcoccus, Akkermansia were changed in the faeces of PCOS patients.
Bacteroides Coprocola [19, 20], Lachnospiraceae and Bifidobacterium pseudocatenulatum play critical roles in maintaining normal endocrine function of the intestinal tract and microbial balance, which is of great significance to the metabolic health. Women with PCOS were verified with a higher incidence of metabolic syndrome, which mostly shown as abnormal glucose level and changes of lipid metabolic parameters. Our study showed significant imbalance of these gut microbiota that implicated those differences in the microbiota structures may underlie the pathogenesis of the hyperinsulinemia and hypertension in the PCOS. Considering the important role of Bacteroides and Bifidobacterium pseudocatenulatum in chronic inflammation, colitis [21], obesity, and type 2 diabetes [22], the altered Bacteroides and Bifidobacterium pseudocatenulatum may affect endocrine disorder through chronic inflammatory mechanism. These results are similar with Ling Zhou et al [23] who reported that the abundance of Lachnoclostridium was markedly higher in the obese PCOS patients.
Veillonella species, known as the early colonizer of oral biofilm, is associated with the occurrence and development of periodontal diseases by providing adhesion sites and boosting immune responses [24]. Abundance of Veillonella was significantly increases in gestational diabetes mellitus with hyperlipidemia patients [25]. Megasphaera micronuciformis is gram-negative, anaerobic bacteria [26] associated with periodontal disease in infants [27] and changes in salivary microflora after bariatric surgery in obese patients [28]. Clostridium butyricum modulates intestinal immune homeostasis by inducing colonic regulatory T cells [29] and has been confirmed a correlation with Type 2 diabetes [30]. Paraprevotella xylaniphila belongs to the genus paraprevotella. Lin Wan et al’s study revealed that the abundance of Paraprevotella xylaniphila is higher in the attention deficit hyperactivity disorder children, which probably affected neurotransmitter levels and changed the fuction of brain-gut axis [31]. Based on previous studies, those bacteria were linked to endocrine disorders including obesity, diabetes, hypertension and hyperlipidemia that tightly coupled with the PCOS through manipulating chronic inflammation, neurotransmitters balancing and affecting the functional brain-gut axis. The mechanisms underlying the altered abundance of these bacteria in the PCOS needs further verification.
The α diversity reflects the number of bacterium in microbial communities, while β diversity generally measures the diversity of different microbial communities. Multiple studies had reported differences in gut microflora between PCOS and healthy women. There was a study pointed out that no bacterial diversity indices differences in the PCOS patients, either in shannon diversity index or PCoA based on unweighted UniFrac distance [32]. The analysis of α and β diversity in the PCOS studies is controversial in recent years [33, 34, 35]. The α and β diversities of gut microflora might depends upon different geographical environment and diagnostic criteria. However, our current study supported that the PD whole tree index and sobs index of PCOS patients were significantly lower than that of the controls but there was no difference in β diversity.
Our spearman correlation analysis revealed that the altered gut microbiota of PCOS was associated with the clinical characteristics, metabolic parameters and brain-gut peptides. CAG 6 and 19 were enriched in the PCOS group and show had a positive correlation with obesity, inflammation and hyperlipemia but a negative correlation with values of Ghrelin and 5-HT; CAG 6 belongs to family Lachnospiraceae, while CAG19 belonged to genera Haemophilus and Veillonella. The dominant OTUs in the decreased CAGs 18, 21, 25, 26 and 27 mostly belong to genera Anaerotruncus, Alistipes, Bacteroides, Actinomyces, and Ruminiclostridium. The relative abundance of Lachnospiraceae UCG-008 and Lachnospiraceae NK4A136 was reported increased in a PCOS-IR rat model [36]. The Veillonella was significantly increased in gestational diabetes mellitus with hyperlipidemia patients [25], possible related to glucose and lipid metabolism disorder in the PCOS. Although the Haemophilus parainfluenzae causes respiratory, soft tissue, central nervous system infections and endocarditis [37]. Whether the Haemophilus involves in the incidence of clinic phenotypes of PCOS remains unknown.
Serotonin, GLP-1 and Ghrelin, involved in appetite regulation, serum LH level and the occurrence of PCOS [11–13, 38]. Gut microbiota produced short-chain fatty acids by fermenting dietary fiber in the intestine, activates G protein coupled receptor on the surface of intestinal endocrine cells to secrete brain-gut peptides [39, 40]. Gram-negative bacteria in the gut producing Lipopolysaccharide, which could act on Toll-like receptor to activate nuclear factor on the surface of intestinal epithelial cells by κB pathway, leading to inflammatory response [41], intestinal mucosa barrier destroying and intestinal permeability increasing. As well, brain-gut peptides, neurotransmitters and inflammatory factors in the intestine could enter the circulation and transmit signals to the central nervous system through vagus nerve and body fluid circulation [42], especially the arcuate nucleus of hypothalamus. Since hypothalamic neurons that modulating feeding and metabolism are sensitive to gut hormones and play critical roles in reproductive regulation, altered gut bacteria-induced gut hormones secretion disorder possibly affects the function of hypothalamic-pituitary-ovarian axis, caused abnormal secretion of gonadotropins and promotes the occurrence of PCOS [38]. However, the relationship between the levels of serum mediators of the brain-gut axis and PCOS remains controversial in human studies.
Women with PCOS show decreases in serotonin, Ghrelin, and PYY that negatively correlated with PCOS-related parameters, including waist circumference and testosterone [18]. Micic et al [43] indicated that the Ghrelin level had significant difference between PCOS and BMI-matched controls in a Spanish study, but this orexigenic hormone showed association only with body weight in an Australian PCOS cohort [44]. While, the secretion of some brain-gut peptides was regulated by gut microbiota. For example, serotonin biosynthesisis promoted mainly by Clostridial species isolated from the human and mouse gastrointestinal tract, while species Bacteroides didn't show this function [45]. In our current study, we also found the association between Ghrelin, 5-HT and gut microbiota. For example, CAG19, which includes genera Haemophilus and Veillonella, was negatively correlated with Ghrelin and 5-HT, while CAG21 (including genera Anaerotruncus, Hungatella, Flavonifractor, Ruminiclostridium, Lachnoclostridium and Tyzzerella) and CAG27 (including genera Alistipes, Desulfovibrio, Anaerotruncus, Sellimonas and Ruminiclostridium) were positively correlated with Ghrelin. But we did not find a positive association between GLP-1 and the gut microbiota. These results indicated that targeting gut microbiota to regulate the brain-gut axis might be one of the therapeutic methodologies for treating PCOS.
This cross-sectional study suppoets the association between gut microbiota and PCOS. The dysbiosis of gut microbiota might contribute to the development of PCOS through diverse mechanisms including manipulating chronic inflammation, neurotransmitters balance and affecting the functional brain-gut axis. However, the observation of association but not causality, further studies are needed to enlarge sample size and explore the mechanisms underlying gut microbiota and PCOS. Taken together, our work suggests an altered composition of gut microbiota in PCOS, represented by the reduction of α diversity and the increase of genera Lachnoclostridium and Veillonella, species Bacteroides Coprocola, Bifidobacterium pseudocatenulatum, Sutterella Wassworthensis, Megasphaera Micronuciformis, Clostridium butyicum and Paraprevotella Xylaniphila, but there was no significant difference in β diversity in the PCOS. This study also demonstrated the association between gut microbiota and PCOS-related clinical parameters. It laid a foundation of research on the interaction between gut microbiota and its host with PCOS.