Dietary modulation of pubertal timing: gut microbiota-derived SCFAs and neurotransmitters orchestrate hypothalamic maturation via the gut–brain axis

Abstract

Background

The global rise in early pubertal activation is closely linked to dietary patterns and gut microbiota (GM) dysbiosis. This review synthesizes evidence on how GM-derived metabolites modulate hypothalamic maturation and pubertal timing through the gut-brain axis.

Methods

Following PRISMA guidelines, we conducted a systematic review of human and animal studies (PubMed, Medline, CNKI, Wanfang) up to October 2024, focusing on dietary impacts (high-fat/high-sugar) on GM composition and puberty onset. Inclusion criteria prioritized studies linking GM metabolites to HPGA activation.

Results

High-fat/high-sugar diets reduce GM diversity and short-chain fatty acid (SCFA) production (e.g., butyrate, acetate), impair gut barrier integrity, and promote systemic inflammation. Dysbiosis in SCFA-producing taxa (Roseburia, Faecalibacterium) and neurotransmitter-modulating genera (Bifidobacterium, Lactobacillus) disrupts leptin/insulin signaling and kisspeptin-GnRH interactions, accelerating HPGA activation. Animal studies demonstrate SCFA supplementation delays puberty by reducing hypothalamic inflammation, while human data reveal ethnic and dietary variability in GM profiles. Western diets heighten altered pubertal timing risk via GM-mediated HPGA dysregulation, whereas fiber-rich Mediterranean diets exhibit protective effects.

Conclusion

GM dysbiosis and SCFA depletion are pivotal in diet-driven alterations of pubertal timing. Culturally adapted interventions targeting microbiota-metabolite interactions may mitigate risks of early puberty onset.

Introduction

Altered pubertal timing, encompassing both precocious and delayed puberty, is increasingly recognized as a spectrum influenced by complex interactions between genetic predisposition, environmental factors, and dietary patterns [1]. While precocious puberty (defined clinically as secondary sexual characteristics before age 8 in girls and 9 in boys) represents a pathological extreme, subtle shifts in pubertal timing—even within normative ranges—have profound implications for long-term metabolic and psychological health. This review synthesizes evidence on how diet-induced gut microbiota dysbiosis modulates hypothalamic-pituitary–gonadal axis (HPGA) maturation, bridging physiological adaptations and pathological outcomes.

Epidemiological studies reveal marked geographical disparities, with prevalence rates of precocious puberty ranging from 1:5,000–10,000 in the United States to 1:500 in Denmark, whereas urban regions in China report rates as high as 4–7% compared with 2–5% in rural areas [2, 3]. This condition is broadly categorized into central (gonadotropin-releasing hormone [GnRH]-dependent) and peripheral (non-GnRH-dependent) forms, both of which are associated with psychosocial distress, compromised final adult height, and increased risks of metabolic disorders, polycystic ovary syndrome (PCOS), and hormone-sensitive cancers in adulthood [4–7].

Emerging evidence underscores the critical impact of environmental factors, particularly dietary patterns, on the development of altered pubertal timing. This interplay between environmental influences and endocrine disruption mechanisms significantly alters the trajectory of pubertal development. High-fat and high-sugar diets, which are prevalent in urbanized populations, have been implicated in disrupting metabolic homeostasis and accelerating pubertal timing via hypothalamic inflammation and microglial activation [8–14]. Concurrently, the gut microbiota (GM), a dynamic ecosystem of bacteria, fungi, and viruses, has emerged as a critical mediator of host metabolism and endocrine signaling. Dysbiosis in GM composition, characterized by shifts in short-chain fatty acid (SCFA)-producing taxa (e.g., Roseburia, Faecalibacterium) and neurotransmitter-modulating genera (e.g., Bifidobacterium, Lactobacillus), has been observed in children with altered pubertal timing [15, 16]. These microbial metabolites interact with the gut‒brain axis, influencing GnRH pulsatility, kisspeptin signaling, and downstream gonadotropin secretion [17–19].

The analysis of GM composition commonly relies on 16S ribosomal RNA (rRNA) gene sequencing, a technique that identifies bacterial taxa by amplifying hypervariable regions of the bacterial genome. While 16S sequencing provides taxonomic resolution at the genus level, it lacks functional insights compared to metagenomic approaches [20]. Despite growing interest, critical knowledge gaps persist. First, most mechanistic insights derive from animal models, where high-fat diets induce altered pubertal timing through GM-mediated leptin resistance and insulin dysregulation [14]. Human studies, however, remain limited and heterogeneous, often conflating dietary patterns (e.g., Western vs. Asian diets) and failing to account for ethnic or lifestyle variability [21]. Second, while 16S rRNA sequencing has identified taxonomic shifts in the GM, advanced metagenomic or metabolomic analyses to elucidate functional pathways (e.g., SCFA biosynthesis and neurotransmitter metabolism) are scarce [22]. Furthermore, the bidirectional relationship between diet-specific GM alterations and sex hormone metabolism—particularly in the context of obesity-driven hyperandrogenism—remains underexplored [23, 24]. Our review bridges critical gaps by integrating preclinical and clinical data to propose a unified model of GM-HPGA interactions, emphasizing the translational potential of dietary and microbial interventions.

Methods

This systematic review was conducted following the PRISMA guidelines (Moher et al., 2009) to ensure methodological rigor. A comprehensive literature search was performed across three major databases, PubMed, Medline, CNKI, and Wanfang, spanning from their respective inceptions to October 31, 2024. The search strategy employed a combination of Medical Subject Headings (MeSH) terms and free-text keywords, including"gut microbiota,""high-fat diet,""high sugar diet,""puberty,""precocious puberty,""central precocious puberty,""peripheral precocious puberty,""short-chain fatty acids,""butyrate,""hormones,""hypothalamic‒pituitary‒gonadal axis (HPGA),""metabolites,""neurotransmitters,"and"kisspeptin."Boolean operators (AND, OR) were used to construct search queries, such as ("central precocious puberty"AND"gut microbiota") OR ("gut microbiota"AND"metabolites").

The inclusion criteria were as follows: (1) original research articles, meta-analyses, systematic reviews, or animal studies published in peer-reviewed journals; (2) investigations examining the relationship between diet (specifically high-fat/high-sugar diets) and altered pubertal timing; and (3) analyses focused on the mechanisms linking the gut microbiota composition/microbial metabolites to puberty onset through HPGA, neurotransmitter modulation, or hormonal pathways. The exclusion criteria were as follows: (1) non-English-language publications without English translations; (2) studies lacking a clear experimental design or outcome measures; and (3) reviews that did not present original data synthesis.

Data extraction was performed independently by two reviewers via a standardized form, which captured the study design, sample size, dietary interventions, microbiota analysis methods (e.g., 16S rRNA sequencing, metabolomics), and key outcome measures (e.g., age at puberty onset, hormone levels). Discrepancies were resolved through consensus or consultation with a third reviewer.

A PRISMA-compliant flowchart (Fig. 1) summarizes the literature selection process, detailing the initial identification of 1,234 studies, exclusion of 1,100 due to irrelevance or design limitations, and final inclusion of 134 studies (98 animal, 36 human). As illustrated in Fig. 1, the screening process adhered to PRISMA guidelines.

Fig. 1.

Flowchart of literature screening

Altered pubertal timing and potential mechanisms

In children with altered pubertal timing, early activation of the hypothalamic–pituitary–gonadal axis is a pivotal mechanism that initiates and regulates reproductive development. The hypothalamic secretion of GnRH is central to this process. GnRH neurons express the kisspeptin receptor GPR54 [25], and the kisspeptin–GPR54 (also known as KISS1R) signaling system is a crucial modulator of GnRH/luteinizing hormone (LH) secretion [26–28]. GnRH is a peptide hormone secreted by hypothalamic arcuate nucleus neurons; it binds to the GnRH receptor (GnRHR) on the surface of the pituitary gland, stimulating the secretion of LH and FSH by the pituitary gland [29]. GnRH pulse secretion stimulates the pituitary gland to secrete LH and FSH, thereby promoting the secretion of sex hormones and gamete production in the gonads, resulting in hypothalamic‒pituitary‒gonadal axis feedback and a negative feedback system [30]. The KISS1R system, which includes kisspeptin and its receptor KISS1R, has a significant effect on reproductive function [31]. Kisspeptin can directly act on GnRH neurons in the hypothalamus to stimulate GnRH secretion; this effect leads to depolarization and an increased firing rate of GnRH neurons, the upregulation of GnRH mRNA expression, and an increase in GnRH levels in the cerebrospinal fluid, which increases LH and FSH levels in the serum. Kisspeptin also regulates LH release through GnRH, and kisspeptin is upstream of GnRH, indicating that kisspeptin signaling can regulate gene expression in the pituitary gland, thereby regulating reproductive functions. Kisspeptin can also directly act on pituitary cells and thereby regulate the gene expression and secretion of gonadotropins. Therefore, kisspeptin enhances FSH secretion stimulated by GnRH, suggesting that kisspeptin plays an important role in regulating GnRH and pituitary hormone release.

Elevated LH levels directly stimulate thecal cells, enhancing the activity of the intracellular enzyme 3-beta-hydroxysteroid dehydrogenase. This increased activity in turn prompts the early synthesis and overactivity of androgens by ovarian follicle cells, resulting in an excess of androgens originating from the ovaries. Some studies have suggested that mutations in this enzyme may lead to altered pubertal timing [32]. Previous studies have revealed that functionally acquired mutations in KISS1R and KISS1, as well as functional loss mutations in MKRN3, LIN28, and DLK1, can lead to an earlier onset of puberty. However, according to recent research, epigenetic modifications, such as DNA methylation and histone acetylation, dynamically regulate GnRH neuronal activity. For example, hypermethylation of the KISS1 promoter has been linked to delayed puberty, whereas hypomethylation correlates with precocious activation of the HPGA [33–35]. The synergistic effect of multiple mutated genes in the gene network can thus influence the initiation of puberty development [33].

LH stimulates the synthesis of the insulin-like growth factor-1 receptor in the ovaries and increases its binding capacity, thereby encouraging the proliferation of thecal cells. This process further promotes the production and release of androgens [36], contributing to hyperandrogenism. Elevated androgen levels can lead to gut mucosal damage [37], allowing the release of lipopolysaccharides and other inflammatory mediators. These mediators, when activated by toll-like receptor 4, trigger the production of various inflammatory factors. This activation occurs by signaling pathways such as nuclear factor-kappa B, which can increase the phosphorylation of insulin receptor substrate-1 within the insulin signaling cascade, resulting in decreased insulin sensitivity and increased insulin resistance [38]. Conversely, insulin resistance can amplify the regulatory effect of LH on ovarian function and intensify the adrenal glands'androgen synthesis capabilities. Furthermore, it suppresses the production of sex hormone-binding globulin by the liver, which reduces the binding of androgens to sex hormone-binding globulin in the serum. This increases the levels of free testosterone and aggravates hyperandrogenism [39]. Multiple studies [40–43] have confirmed the presence of insulin resistance and hyperandrogenism in children with altered pubertal timing. These conditions have been proven to be the main causes of polycystic ovary syndrome [44, 45], and some children with altered pubertal timing may develop polycystic ovary syndrome in adulthood [46–48].

In addition, neurotransmitters and peripheral feedback signals in children with altered pubertal timing act on the anterior pituitary gland and/or regulate growth hormone (GH) secretion by modulating the release of GH-releasing hormone or somatostatin in the hypothalamus [49]. GH promotes the expression of insulin-like growth factor 1 (IGF-1) in the liver via the GH receptor, thereby promoting the synthesis and release of IGF-1, which in turn inhibits the release of pituitary GH via feedback. The two regulate each other, constituting a GH/IGF-1 axis [50]. Excessive levels of IGF-1 and GH may be linked to altered pubertal timing [51], as the biological function of GH is to act directly on tissue cells throughout the body via growth regulators. GH promotes the division and proliferation of bone, cartilage, muscle, and other tissue cells, thereby stimulating growth and development [52]. IGF-1, a hormone produced in the liver under GH stimulation, also plays a pertinent role in children’s growth and development [50, 51].

Current evidence predominantly supports the role of diet and microbiota in modulating the tempo of pubertal development rather than directly inducing pathological precocity. For instance, animal models demonstrate that high-fat diets accelerate hypothalamic maturation via SCFA depletion, but such effects may reflect a physiological adaptation to energy surplus rather than a dysregulated pathway. Conversely, clinical altered pubertal timing (e.g., central precocious puberty driven by KISS1 mutations) involves distinct genetic and epigenetic mechanisms. Future studies should delineate thresholds where dietary perturbations transition from physiological modulation to pathological disruption.

The gut microbiota and the growth endocrine system

The gut microbiota (GM) is a large collection of microorganisms that reside in the host’s gut and include bacteria, fungi, viruses, and protozoa. These organisms have a symbiotic relationship with the host and significantly affect the health and development of the host. The GM and growth endocrine hormones interact with each other; for example, the GM can affect estrogen levels, which in turn may be influenced by the composition and diversity of the GM [53]. Current research [54] suggests that the GM acts as an endocrine organ that influences host growth and development as well as the growth of the endocrine system via several mechanisms.

The GM regulates the growth, development, and growth of the endocrine system via various mechanisms (Table 1). The first is direct hormone regulation. There are many endocrine cells in the gut, including K cells, I cells, L cells, and intestinal chromaffin cells, which secrete different hormones and signaling molecules, including cholecystokinin, motilin, secretin, leptin, adrenocorticotropic hormone, and corticotropin-releasing factor. The GM and its metabolites (such as short-chain fatty acids) can affect the activity of these endocrine cells, regulating their ability to secrete hormones such as adrenocorticotropic hormone, cortisol, and corticotropin-releasing factor [55–58]. In addition, the GM can indirectly act on endocrine organs such as the liver, pancreas, and adipose tissue, affecting the secretion of hormones such as insulin, glucagon, and leptin, which are indispensable regulatory factors in growth and development [59, 60]. Second, it involves the regulation of hormone secretion by short-chain fatty acids. These hormones, such as sex steroids and vitamin D, can regulate the production of hormones closely related to bone health [61, 62]. Third, hormone secretion is influenced by the gut–brain axis. The GM can transmit signals via this axis, regulating the secretion of GH-releasing peptides, somatostatin, and leptin [63–67]. These hormones play crucial roles in modulating GH secretion, appetite, and skeletal development via the GH/IGF-1 axis [61–63]. Fourth, the GM exerts regulatory effects on androgens. Estrogens notably influence the GM, and owing to the specific genetic ability of these microbes to metabolize estrogens, they are collectively referred to as the “estrobolome” [68]. Diverse microorganisms that form a part of the GM possess the enzymatic machinery for androgen metabolism, facilitating the synthesis and transformation of these hormones. The microbial degradation of testosterone is a documented phenomenon in various environments. Specifically, Actinobacteria and Proteobacteria are known to metabolize androgens [69]. Furthermore, Clostridium scindens, a human gut microbe, is known for its ability to convert glucocorticoids to androgens because of the presence of 20 α-hydroxysteroid dehydrogenases in its genome [70]. Fifth, the interaction between the GM and host endocrine hormones is marked by a bidirectional regulatory mechanism [63, 71]. For example, GM metabolites act as paracrine or endocrine factors to regulate host metabolism, whereas the GM regulates bioactive lipids and specific neurotransmitters (such as γ-aminobutyric acid, 5-hydroxytryptamine, and nitric oxide), which are related to the endogenous cannabinoid system [63]. Acetate and butyrate can stimulate the release of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) [72]. Certain gut-specific bacterial components, such as casein protease B (ClpB) and Amuc1100, can act as endocrine factors to regulate host metabolism [71]. In addition to the influence of the GM on the host endocrine hormones mentioned above, hormones such as GH and IGF-1 reciprocally influence the constitution and population of the GM [73].

Table 1.

Summary of the relevant GM genera and their corresponding hormone relationships:

GM genus	Related hormones	Mechanism of action	References
Actinobacteria	Androgens (such as testosterone)	Participate in androgen metabolism and promote the degradation of testosterone	[69]
Proteobacteria	Androgens (such as testosterone)	Metabolism of androgens through enzymatic reactions, affecting sex hormone levels	[69]
Clostridium scindens	Androgens, glucocorticoids	Conversion of glucocorticoids to androgens by 20 α—hydroxysteroid dehydrogenase	[70]
Unnamed genus of bacteria	GLP-1、PYY	Short-chain fatty acids (acetate, butyrate) stimulate intestinal L cells to secrete GLP-1 and PYY, regulating appetite and metabolism	[72]
Estrobolome microbiota	Estrogen	Metabolizing estrogen, regulating the enterohepatic circulation of estrogen through β-glucuronidase, and affecting estrogen levels	[68]
Unnamed genus of bacteria	GH、IGF-1	By regulating the secretion of GH releasing peptides and somatostatin through the gut brain axis, it affects the GH/IGF-1 axis and regulates bone development and growth	[63, 66]
Unnamed genus of bacteria	Leptin	Indirectly regulating the secretion of leptin by adipose tissue, affecting energy metabolism and puberty initiation	[56, 64]
Unnamed genus of bacteria	Adrenal cortex hormones (such as cortisol)	Regulating the hypothalamic pituitary adrenal axis (HPA axis) through short-chain fatty acids, affecting stress response and glucocorticoid secretion	[57, 59]

Estrobolome refers to a collection of bacteria with estrogen metabolism ability. The specific genus is not explicitly listed in the article but includes some strains with β-glucuronidase activity. Unnamed microbiota refers to a group of bacteria whose specific genera are not explicitly mentioned in the text, but their functional roles are inferred through mechanism descriptions. Abbreviations: GM: gut microbiota; GLP-1: glucagon-like peptide-1; PYY: peptide YY; GH: growth hormone; IGF-1: insulin-like growth factor 1; HPA: hypothalamic‒pituitary‒adrenal.

Abnormal dietary patterns induce or exacerbate altered pubertal timing through modulation of the gm and interaction with the hypothalamic pituitary gonadal axis (HPGA)

High-fat/high-sugar diets induce gm dysbiosis and trigger metabolic and inflammatory signals

High-fat and high-sugar diets significantly reduce gut microbiota diversity and inhibit the synthesis of short-chain fatty acids (SCFAs, such as butyrate and propionate). SCFAs have anti-inflammatory properties and maintain the integrity of the gut barrier; their reduction can lead to increased gut permeability and promote the translocation of endotoxins (e.g., lipopolysaccharides (LPS)) into the bloodstream [8, 9, 74–76]. LPS and proinflammatory cytokines (e.g., TNF-α and IL-6) reach the hypothalamus via the circulatory system, activate microglia, and induce local hypothalamic inflammation [77, 78]. Chronic inflammation results in insulin resistance and leptin resistance, further disrupting the balance of energy metabolism and reproductive hormones [79–82].

GM dysbiosis directly regulates hpga function via the gut–brain axis

The regulation of kisspeptin/GnRH signaling by SCFAs involves the following mechanisms: (1) SCFAs can cross the blood‒brain barrier and directly act on hypothalamic neurons. Animal experiments have shown that SCFA deficiency can suppress the expression of the Kiss1 gene, reduce the synthesis of kisspeptin, and consequently weaken the pulsatile release of GnRH [17, 83, 84]. (2) A high-fat diet combined with bisphenol A exposure further exacerbates the inhibition of kisspeptin expression, leading to transgenerational reproductive system damage [85]. Additionally, interactions between GM metabolites and hormones include the following: (1) Secondary bile acids and indole derivatives produced by the GM may affect GnRH secretion by modulating HPGA-related receptors (e.g., GPR54) [83, 86]; (2) artificial sweeteners (e.g., aspartame) alter the GM composition, reduce SCFA levels, and indirectly inhibit HPGA activity [86–88].

Metabolic hormones mediate the Interaction between the GM and HPGA

Two important growth-related hormones are leptin and ghrelin. The associations between leptin and the kisspeptin axis include the following: (1) GM dysbiosis leads to obesity-related hyperleptinemia, but leptin receptor sensitivity is decreased (leptin resistance). Leptin should promote GnRH release by activating hypothalamic kisspeptin neurons, but leptin resistance may disrupt this process [79–82]. (2) High-fat diet-induced GM changes may exacerbate the disruption of the leptin/kisspeptin axis by reducing adiponectin levels [89, 90]. Additionally, high-fat diets increase ghrelin secretion, which directly inhibits the release of pituitary gonadotropins (LH/FSH) and further suppresses gonadal function [81].

Current evidence suggesting regional dietary patterns modulate altered pubertal timing risk

Common dietary patterns include Western, Asian, and Mediterranean diets. A Western diet, characterized by high fat and high sugar contents, significantly increases the risk of altered pubertal timing in children. The GM dysbiosis caused by this dietary pattern is closely related to the activation of the HPGA (e.g., premature GnRH release) [10–13, 91]. An Asian diet, characterized by high carbohydrate intake, may promote altered pubertal timing through GM-mediated increases in LH/FSH, although clinical evidence is limited [12]. The Mediterranean diet, which is rich in dietary fiber, may protect HPGA function by maintaining GM diversity and SCFA levels, but further research is needed to confirm this [13, 14].

Mechanisms in children with or without obesity

In children with obesity, GM dysbiosis and adipose tissue inflammation act synergistically to accelerate puberty onset through the leptin/Kisspeptin axis and HPGA inflammatory pathways [18, 82, 84]. In high-fat diet-induced obesity models, hypothalamic Kiss1 expression is significantly downregulated, and GnRH secretion is disrupted [83, 92]. Additionally, in children without obesity, even those with a normal body weight, high-fat/high-sugar diets can still activate hypothalamic inflammation and induce HPGA dysfunction through GM-SCFA depletion and gut barrier damage [10, 77].

Intervention strategies and existing issues

On the basis of the above research results (Table 2,Fig. 2), we believe that the following intervention measures can be considered for altered pubertal timing. First, dietary adjustments should be made, such as reducing saturated fat and refined sugar intake and increasing dietary fiber to restore GM diversity and SCFA levels [14]. Second, physical exercise is beneficial for improving metabolism. Studies have shown that exercise can partially reverse the inhibitory effects of a high-fat diet on the HPGA by reducing inflammation and oxidative stress [84]. Finally, targeted interventions, such as the administration of probiotics, SCFA supplements, or kisspeptin agonists, may represent new directions for the strategies to normalize pubertal timing [17, 83, 87]. While preclinical studies suggest that probiotics may delay puberty via SCFA restoration, clinical evidence remains limited and primarily hypothesis-driven [87]. However, the literature highlights issues such as insufficient sample sizes. Therefore, more human studies are needed to validate the direct interaction mechanisms between the GM and HPGA, especially clinical data from different dietary cultural backgrounds (e.g., Mediterranean/Asian diets), and to explore sex-specific responses [13, 17, 92].Of course, individual differences in probiotics (such as the risk of intestinal colonization failure) and the potential exacerbation of gastrointestinal discomfort caused by excessive dietary fiber also need to be considered [87].

Table 2.

Summary of studies on diet, the GM‒HPGA axis, and altered pubertal timing:

Year	Research subjects (type/age)	Dietary patterns	Changes in GM	Mechanism of Action	Refere -nces
2012	C57BL/6 mice (adult)	High fat diet (60% fat for energy supply)	↓Bacteroidetes ↑Firmicutes	High fat diet activates the hypothalamic pituitary adrenal axis, indirectly interfering with HPGA hormone secretion	[80]
2014	Female pigs (from weaning to puberty)	High fat diet (15% fat for energy supply)	No detection	Upregulation of Kiss1 gene expression in the hypothalamus promotes the secretion of GnRH and initiates early puberty	[81]
2016	Male rats (juvenile stage)	High fat diet (45% fat for energy)	No detection	A high-fat diet increases ghrelin levels, stimulates pituitary gonadotropin secretion, and promotes testicular development	[82]
2017	Female SD rats (prepubertal)	High fat and high sugar diet (60% fat + 30% sugar)	↑Proteobacteria ↓ Lactobacillus	Inducing polycystic ovary syndrome and disrupting HPGA hormone homeostasis through inflammation and oxidative stress	[74]
2020	Female mice (lactating mother and offspring)	High fat diet for female mice (60% fat supply)	↓Bacteroidetes ↓ Akkermansia	Maternal high-fat diet is transmitted through the microbiota metabolite axis, upregulating the Kisspeptin signaling pathway and accelerating puberty	[14]
2021	Male C57BL/6 mice (juvenile stage)	High fat diet (60% fat for energy supply)	Imbalance in the ratio of Firmicutes/Bacteroidetes	High fat diet induces hypothalamic inflammation, promotes Phoenixin neuropeptide release, and activates GnRH neurons	[77]
2022	Female SD rats (juvenile stage)	High fat diet (45% fat for energy)	No detection	Inhibit the Kiss1-GPR54 signaling pathway in the hypothalamus, but indirectly activate HPGA through leptin secretion from adipose tissue	[84]
2023	Male rat offspring (father's high-fat diet)	Father's high-fat diet (45% fat supply)	↑ Enterobacteri -aceae ↓ Lactobacillus	The father's high-fat diet regulates the offspring's HPGA related genes (such as Kiss1) through epigenetic regulation, leading to altered pubertal timing	[87, 90]
2024	Child (female, 6–12 years old)	High sugar diet (excessive intake of added sugar)	↓Bifidobacteriu-m ↑Escherichia-coli	A high sugar diet activates systemic inflammation and interferes with HPGA hormone secretion through microbial metabolites such as lipopolysaccharides	[91]
2024	Female SD rats (juvenile stage)	High fat and high sugar diet (60% fat + 30% sugar)	↓Prevotella ↑ Ruminococcus	Dysbiosis of GM leads to abnormal bile acid metabolism, affecting the levels of hepatic hormone binding globulin	[17]
2024	Female mice (pre pubertal)	High fat diet (60% fat for energy supply)	↓Lactic acid bacteria ↑Desulfovibrio	Reduction of short-chain fatty acids derived from microbiota, inhibition of intestinal barrier function, promotion of endotoxemia and HPGA activation	[11]

Fig. 2.

A high-fat/high-sugar diet affects HPGA mainly through the following mechanisms: 1) inducing hypothalamic inflammation and oxidative stress; 2) regulating the kisspeptin/GPR54 signaling pathway; 3) changing the levels of metabolic hormones such as leptin and ghrelin; and 4) disrupting hormone homeostasis through microbial metabolites such as short-chain fatty acids and lipopolysaccharides. Abbreviations: GnRH: gonadotropin-releasing hormone; HPGA: hypothalamic pituitary gonadal axis; SCFA: short-chain fatty acid; TNF: tumor necrosis factor; GABA: aminobutyric acid; GPR: G protein-coupled receptor

Age of animal research subjects: Animal experiments often focus on the juvenile or prepubertal stage to simulate the window period of human altered pubertal timing. Abbreviations: GM: gut microbiota; GnRH: gonadotropin-releasing hormone; HPGA: hypothalamic pituitary gonadal axis.

Mechanisms of action of short-chain fatty acids in altered pubertal timing

Short-chain fatty acids are key mediators of microbial crosstalk in the host

Short-chain fatty acids are predominantly generated via the fermentation of dietary carbohydrates by gut bacteria and are composed of organic, low-molecular-weight compounds. The primary short-chain fatty acids include butyrate, acetate, and propionate, with isobutyrate, valerate, and isovalerate being produced in lesser amounts. These short-chain fatty acids are synthesized primarily by colonic bacteria such as Bifidobacterium, Lactobacillus, members of the Lachnospiraceae family, Blautia, Coprococcus, Roseburia, and Faecalibacterium. These fatty acids serve as energy sources for colonic epithelial cells[93]. Short-chain fatty acids affect the mechanism of altered pubertal timing. On the one hand, they interact with the gut–brain axis by binding to receptors expressed in cells (including neurons, intestinal endocrine cells [EECs], and immune cells) and altering host gene expression. On the other hand, the expression of genes that encode cAMP response element binding proteins is modulated, which influences the production of catecholamine neurotransmitters, including dopamine [94, 95]. This regulation enhances the activity of tyrosine hydroxylase, which catalyzes the initial step in dopamine synthesis and concurrently decreases the expression of dopamine-β-hydroxylase, the enzyme that converts dopamine to norepinephrine [96, 97]. In addition, short-chain fatty acids can modulate the neuronal signaling of neurotransmitters, such as serotonin, γ-aminobutyric acid, and dopamine [98, 99].

Two studies [12, 13] conducted in Shenzhen, China, reported that children with altered pubertal timing exhibit significant dysbiosis in their GM. Among them, Dong et al.[15] reported that the intestines of children with idiopathic central precocious puberty are rich in obesity-related bacterial species, such as Ruminococcus gnavus, Ruminococcus callidus, Ruminococcus broni, Roseburia inulivorans, Coprococcus euactus, Clostridium leptum, and Clostridium lactiferans, which mainly produce butyrate. Huang et al. [16] compared the GM of children with idiopathic central and peripheral precocious puberty with that of healthy children and reported that the abundance of butyrate-producing bacteria (such as Lachnospiraceae incertae sedis, Roseburia, and Ruminococcus) and carbohydrate-degrading bacteria (such as Prevotella) decreased gradually. In contrast, the abundance of these bacteria was significantly greater in children with idiopathic central and peripheral precocious puberty than in healthy children. Another study [23] conducted in Shandong, China, revealed that the abundance of short-chain fatty acid-producing bacteria, including Tyzzerella, Butyricicoccus, Ruminococcus, and Erysipelatocostridium ramosum, was increased in the gut of girls with central and peripheral precocious puberty. These changes in microbiome-mediated functional potential indicate that fatty acid biosynthesis is associated with altered pubertal timing. The above studies were conducted in mainland China, and the results revealed a significant increase in the abundance of short-chain fatty acid-producing bacteria in the intestines of children with altered pubertal timing. However, no reports have been published from Western countries, and there are considerable differences in dietary structure, race, and lifestyle between Western countries and mainland China. Additionally, current human studies suffer from inadequate ecological analysis (85% relying on stool samples rather than duodenal/ileal microbiota), short durations (< 6 months), and failure to control for excessive exposure (e.g., phthalates) that independently alter microbial β-glucuronidase activity. Therefore, this issue warrants further investigation.

Research in China suggests that the enrichment of SCFA bacteria in the gut of children with altered pubertal timing may affect puberty initiation through the"microbiota metabolite endocrine axis", but the aforementioned confounding factors (diet, medication, genetics, and methodological differences) may weaken the reliability of the conclusion. Environmental pollutants, such as phthalates and bisphenol A, may independently alter GM composition and β-glucuronidase activity, potentially confounding the association between SCFAs and altered pubertal timing [100, 101]. To enhance causal inference, it is necessary to design a multicenter, cross-racial prospective cohort and strictly control for confounding variables; verify the direct effect of SCFAs on altered pubertal timing by combining animal models (such as fecal microbiota transplantation experiments); and explore the dynamic association mechanism between SCFAs and sex hormones such as luteinizing hormone and estradiol.

However, current animal experiments have reported contradictory results. A study by Wang et al. [17] noted a substantial decrease in the levels of acetic acid, propionic acid, and hexanoic acid within the intestinal tract in rats with early puberty induced by a high-fat diet. The administration of acetate, propionate, butyrate, or a combination of these short-chain fatty acids significantly counteracted the development of altered pubertal timing. This intervention alleviated the secretion of GnRH in the hypothalamus and delayed the maturation of the gonadal axis, which suggests the involvement of the Kiss1-GPR54-PKC-ERK1/2 signaling pathway in this process. The authors believe that interventions with acetate, propionate, and other drugs can be considered for obesity-induced altered pubertal timing in rats. Yuan et al. [102] reported that an excess of 95% daidzein during puberty can lead to a decrease in the abundance of the Oscillospira and Sutterella genera in the gut of female mice as well as a decrease in the concentration of short-chain fatty acids, such as butyric acid, isovaleric acid, and hexanoic acid, resulting in early puberty. Treatment with lactobacilli and bifidobacteria can normalize the onset of puberty.

Emerging evidence highlights a notable inconsistency between diet-induced altered pubertal timing models in rodents and clinical observations in children, particularly regarding gut microbiota-derived short-chain fatty acids (SCFAs). Our analysis identified four primary factors contributing to these interspecies divergences (summarized in Table 3). To reconcile these interspecies discrepancies, we propose the following multidisciplinary approaches: (1) advanced animal model development: (a) generation of humanized microbiota mice through fecal microbial transplantation from altered pubertal timing cohorts coupled with region-specific diet simulations (e.g., highly refined carbohydrates/low fiber mimicking Chinese dietary patterns); (b) engineering of transgenic rodent models expressing humanized GPR41 or puberty-related genetic variants (e.g., the ESR1 PvuII polymorphism) via CRISPR–Cas9 technology. 2) Precision Human Cohort Investigations: (a) Implement targeted metabolomics to quantify systemic and fecal SCFA levels, circumventing inference biases from 16S rRNA-based functional predictions; (b) conduct stratified analyses adjusting for dietary components (via validated food frequency questionnaires), antibiotic exposure, and genetic risk profiles. 3) Cross-species mechanistic validation: (a) intestinal organoid models derived from human and murine tissues were employed to compare SCFA dose‒response effects on GnRH neuronal activity; (b) single-cell transcriptomics was integrated with spatial metabolomics to identify threshold-dependent molecular switches governing SCFA‒endocrine interactions.

Table 3.

Key factors contributing to rodent-human discrepancies in SCFA-related altered pubertal timing research

Determinant	Rodent models (SCFA reduction)	Human studies (SCFA-producer enrichment)
Dietary composition	High-fat chow suppresses SCFA producers	Processed carbohydrates may selectively enrich butyrogenic taxa
SCFA exposure	Pharmacological doses inhibit steroidogenesis	Physiological levels activate GPR41-leptin axis
Genetic landscape	Inbred strains lack human puberty SNPs	ESR1/GPR41 polymorphisms modulate host response
Microbial functionality	Cellulose-driven acetate dominance	Human-specific Ruminococcus strains enhance butyrate synthesis

However, both human and animal studies have shown that short-chain fatty acids play important roles in the occurrence and development of altered pubertal timing (Table 4). Hence, we speculate that in altered pubertal timing, short-chain fatty acids are key mediators of microbial crosstalk in the host.

Table 4.

Summary of research on the relationships between altered pubertal timing and changes in the GM and SCFAs:

Year	Research subjects (type/age)	Research design	Sampl-e size	Changes in GM	Possible mechanisms of action	References
2020	ICPP in girls (6–12 years old)	Case control study	N = 48	↑Bacteroidetes ↓Firmicutes	SCFAs reduce endotoxemia by improving intestinal barrier function and inhibit abnormal activation of HPGA by inflammatory factors	[15]
2022	Children with ICPP and PPP(5–14 years old)	Cohort study	N = 68	ICPP: ↓Bifi -dobacteria ↑Escherichia coli; PPP: ↓Lactobacillus	M Microbial dysbiosis interferes with hormone binding globulin levels through metabolic products (possibly containing SCFAs)	[16]
2022	Female SD rats (obesity induced altered pubertal timing, juvenile stage)	Experimental study	N = 24	↑Akmansia ↓Ruminococcus	SCFAs activate intestinal L cells to secrete GLP-1, inhibit hypothalamic Kisspeptin expression, and delay puberty initiation	[23]
2024	Children with precocious puberty and healthy control group (female, 6–12 years old)	cross-sectiona-l study	N = 114	↓Prevotella ↑ Desulfovibrio	A high-fat diet leads to dysbiosis of the microbiota and a decrease in SCFAs. After the intestinal barrier is disrupted, lipopolysaccharide enters the bloodstream and activates HPGA	[17]
2023	Female mice (soy isoflavone induced altered pubertal timing, juvenile stage)	intervention study	N = 50	↑ lactobacilli ↓ enterococci	Probiotics inhibit excessive activation of estrogen receptors and alleviate altered pubertal timing phenotype by regulating SCFAs such as butyric acid	[102]

Some studies did not specify the specific types of SCFAs and inferred them on the basis of the metabolic characteristics of the microbiota (such as the dominance of butyrate production by Bacteroidetes) or mechanism descriptions. Research subjects: Clinical studies have focused on children, and animal experiments often use juvenile rodents to simulate the window of altered pubertal timing in humans. Abbreviations: ICPP: idiopathic central precocious puberty; PPP: peripheral precocious puberty; SCFAs: short-chain fatty acids; HPGA: hypothalamic pituitary gonadal axis; GM: gut microbiota

The mechanism by which butyrate regulates altered pubertal timing

Butyrate is the anionic part of free butyrate and its salts and plays a role in various host physiological functions, such as energy balance, obesity, immune system regulation, cancer, and even brain function[103]. The two most important bacteria that produce butyrate are Faecalibacterium praussnitzii in Clostridium cluster IV and Roseburia in Clostridium cluster XIVa [104]. In addition to these groups, bacteria that produce butyrate are widely distributed in several clusters, including Clostridium clusters IX, XV, XVI, and XVII[105]. Changes in bacteria that produce butyrate promote the occurrence and development of altered pubertal timing via the following pathways (Fig. 3). First, butyrate preferentially binds to GPR41, thereby increasing the expression of human leptin. The latter plays an important role in the development of adolescent girls by regulating kisspeptin neurons and promoting the pulse release of GnRH [106–108]. Second, butyrate induces increased insulin secretion via GLP-1[109, 110]. Insulin augments the transcription of GnRH genes by stimulating the mitogen-activated protein kinase pathway, leading to increased secretion of GnRH in the hypothalamus [111]. Third, butyrate can also increase the proportion of cholinergic intestinal neurons via epigenetic mechanisms, affecting the release of acetylcholine[112]. Fourth, when there is a considerable increase in butyrate concentration, it causes an increase in nitric oxide synthesis [113]. Butyrate, via transmembrane transport, binds to GPR41 expressed by noradrenergic sympathetic neurons in the brain, which can either increase or inhibit the release of NE[114]. The above studies imply that butyrate affects neurotransmitter release. Fifth, butyrate directly affects the release of serotonin and gastrointestinal hormones in the intestinal nervous system, thereby stimulating the vagus nerve and triggering endocrine signals, both of which influence brain function.

Fig. 3.

Short-chain fatty acids (especially butyrate) affect hormones such as leptin and insulin, as well as neurotransmitters such as acetylcholine and nitric oxide, through different mechanisms of action. They regulate kispeptin neurons and promote the pulse release of GnRH, leading to early GnRH activation. Abbreviations: GPR41: G protein-coupled receptor 41; GLP-1: glucagon-like peptide-1; HPGA: Hypothalamic pituitary gonadal axis

The mechanism by which acetate regulates altered pubertal timing

Acetate produced by intestinal microorganisms in the colon crosses the blood–brain barrier and becomes concentrated in the hypothalamus, thereby causing the brain to produce γ-aminobutyric acid[102]. Furthermore, acetate can stimulate the secretion of auxin-releasing peptides [115], higher levels of which are linked to increased levels of dopamine [116].

Neurotransmitters regulate altered pubertal timing via GnRH neurons and kisspeptin neurons

GM and neurotransmitters

The interconnection between the gut microbiota and the central nervous system involves the following five important pathways[117]: 1) The immune pathway involves a close interaction between the gut microbiota and the gut immune system, and microbial components such as metabolites (e.g., short-chain fatty acids [SCFAs]) and membrane components (e.g., polysaccharide A) can affect immune homeostasis, resulting in proinflammatory or anti-inflammatory local immune responses. 2) Endocrine/systemic pathways: Microbial components and metabolites, such as secondary bile acids, indole derivatives, and SCFAs, can signal through EECs and enterochromaffin cells (ECCs) to regulate the secretion of neuropeptides, such as appetite-regulating GLP1 and neuromodulators (such as hormones and the neurotransmitter serotonin). 3) Neuropathways: Certain microbial components, microbial regulatory hormones, and microbiota-dependent immune mediators can directly interact with the enteric nervous system and its innervated vagus and spinal afferent nerves. 4) Vagus nerve: The vagus nerve is a key neural pathway that connects the central nervous system and the gut microbiota. It not only transmits information from the gut to the brain but also participates in regulating the balance of the gut microbiota, thereby exerting several positive effects on the gut microbiota and probiotics. 5) Blood‒brain barrier: The blood‒brain barrier serves as a selective barrier between the brain and the circulatory system, allowing compounds with specific characteristics (such as low-molecular weight, being uncharged, being lipophilic) to freely pass through the intestine and regulate brain physiology.

Neurotransmitters can be categorized into several groups, such as amino acid-based neurotransmitters (e.g., glutamate, aspartate, D-serine, GABA, and glycine), monoamines (such as dopamine, adrenaline, noradrenaline, histamine, and serotonin), trace amines (phenylethylamine, N-methylphenylethylamine, tyramine, 3-iodothyronine, octopamine, and tryptamine), peptide neurotransmitters (oxytocin, somatostatin, substance P, and endorphins), gasotransmitters (nitric oxide, carbon monoxide, and hydrogen sulfide), purines (ATP and adenosine), and other small molecules, including acetylcholine and anandamide. Glutamate, GABA, glycine, dopamine, norepinephrine, serotonin, and histamine play particularly significant roles in neurotransmission [118].

The GM is an important source of neurotransmitters and neurotransmitter activity in the body. For instance, Bifidobacterium and Lactobacillus produce acetylcholine and γ-aminobutyric acid, whereas Escherichia coli, Streptococcus, and Enterococcus produce serotonin, dopamine, and norepinephrine[119, 120]. Therefore, alterations in the composition of the GM may interfere with the communication of the gut–brain axis [121]. Conversely, the activity of the central nervous system directly regulates the activity of the GM. For example, microbiota expressing γ-aminobutyric acid, norepinephrine, and serotonin receptors can extract neurotransmitters from motor or efferent signals emitted by the brain [122, 123]. In addition, neurotransmitters can interact with each other. For example, endogenous nitric oxide has a significant effect on dopamine-, norepinephrine-, and neurotransmitter-promoting abilities and is beneficial for the release of norepinephrine in the hippocampus of children with altered pubertal timing [124]. Moreover, a reduction in γ-aminobutyric acid can promote nitric oxide production [125]. Therefore, the composition of the GM and changes in its composition are crucial for the normal neurotransmitter turnover rate of the central nervous system. The microbiota directly interacts with brain neurons via the release of neurotransmitters in the gut and affects the hypothalamic–pituitary–gonadal axis via the gut–brain axis.

GM dysfunction in children with altered pubertal timing leads to abnormal production of neurotransmitters

Children with altered pubertal timing also have abnormal neurotransmitter secretion (Table 5). Li et al. [18] compared the GM of children with central precocious puberty, those with obesity, and healthy children. These findings indicated that the gut of children with central precocious puberty was enriched in neurotransmitter-producing bacterial genera, such as Alistipes, Klebsiella, and Sutterella. Furthermore, the researcher used the gut–brain module database and combined it with software for functional prediction. The results revealed that the proportion of neuroendocrine-related gut–brain modules, including dopamine and nitric oxide synthesis, was significantly greater in children with central precocious puberty. Moreover, Huang et al. [19] conducted 16S rRNA sequencing and untargeted metabolomics analysis on 91 patients with central precocious puberty and 59 healthy controls and constructed a classifier based on microorganisms and metabolites for functional and pathway enrichment analysis. The observations revealed that the gut of children with central precocious puberty was enriched in Bifidobacterium, Blautia, Streptococcus, NO synthesis, and other gut–brain module-related pathways, which demonstrated increased activity in the central precocious puberty group. The above results indicate alterations in neurotransmitters, such as NO, in children with altered pubertal timing. However, these results were obtained via Spearman correlation analysis, and metabolomic studies and relevant animal experimental reports supporting these findings are lacking.

Table 5.

Summary of research on neurotransmitters produced by the altered pubertal timing and GM

Research subjects (type/age)	Changes in gut microbiota	Neurotransmitter types	Possible mechanisms of action	Refere -nces
CPP combined with obesity in children (female, 6–12 years old)	↓Bacteroidetes ↑Proteobacteria	No	Dysbiosis of obesity related microbiota leads to abnormal NO metabolism, activating GnRH neurons in HPGA	[18]
CPP children (female, 5–14 years old)	↓Bifidobacteri -um ↑Enterococcus	5-HT, GABA	Microbial metabolites regulate the levels of 5-HT and GABA in the hypothalamus through GBA, affecting the Kisspeptin signaling pathway	[19]

Reference [20] does not specify the direct association between specific bacterial genera and neurotransmitters, but it is inferred through metabolomics analysis that microbial metabolites (such as tryptophan metabolites) may affect 5-HT synthesis. Abbreviations: GM: gut microbiota; CPP: central precocious puberty; NO: nitric oxide; GnRH: gonadotropin-releasing hormone; GBA: gut–brain axis; 5-HT: 5-hydroxytryptamine; HPGA: hypothalamic–pituitary–gonadal axis

Neurotransmitters affect the regulatory effects of GnRH on neurons during altered pubertal timing

The mechanism by which neurotransmitters affect GnRH neurons is illustrated in Fig. 4. First, neurotransmitters affect the hypothalamic–pituitary–gonadal axis. Common neurotransmitters produced by intestinal bacteria include dopamine, norepinephrine, serotonin, γ-aminobutyric acid, and acetylcholine[118, 126]. A rat model confirmed that these neurotransmitters bind to neurotransmitter receptors in the brain and act on the pituitary gland, regulating ovarian and reproductive functions [127, 128]. Research on mice has revealed that increased carbohydrate intake can increase the entry of neurotransmitters into the hypothalamus via the gut–brain axis[129]. For example, alterations in gut tryptophan metabolism (glutamate and the metabolite γ-aminobutyric acid) can affect the availability of peripheral and central tryptophan levels, leading to changes in central serotonin metabolism[130]. Furthermore, gut serotonin neurons, such as dopaminergic and γ-aminobutyric acid, can affect the development/survival of neurons born in the late stage of piglets [131]. Second, neurotransmitters are involved in the activity and secretory regulation of GnRH neurons [132]. The stimulating effect of NE on LH release is mediated by β-adrenergic receptors, whereas α-adrenergic receptors inhibit LH release in a rat polycystic ovarian syndrome model[133]. Dopamine primarily suppresses the release of GnRH, whereas serotonin exerts a dual effect on GnRH neurons. While γ-aminobutyric acid inhibits the release of LH triggered by GnRH, glutamate serves as the principal excitatory neurotransmitter during its release. Research in mice has shown that acetylcholine may increase the frequency of GnRH and LH pulses [134] and that nitric oxide influences the activity of GnRH neurons in the preoptic area. It is also involved in the regulation of GnRH release at the median eminence, affects the ability of the pituitary gland to secrete LH, and inhibits testosterone production in male rats [135].

Fig. 4.

The metabolic products of the gut microbiota, neurotransmitters, act on the pituitary gland through the gut‒brain axis, participate in the activity of GnRH neurons, regulate ovarian and reproductive functions, promote the secretion of hormones such as FSH and LH, and affect children's gonadal development. Abbreviations: HPGA: Hypothalamic pituitary gonadal axis; LH: Luteinizing hormone; FSH: Follicle stimulating hormone; DA: Dopamine; 5-HT: 5-hydroxytryptamine; γ-GABA: γ-aminobutyric acid; E2: Estradiol; TES: Testosterone

Altered pubertal timing is regulated via the interaction between neurotransmitters and kisspeptin neurons

The interaction between neurotransmitters and kisspeptin neurons is illustrated in Fig. 3. First, this interaction affects GnRH neurons. Kisspeptin-expressing neurons are predominantly located in the hypothalamus, and these neurons often coexpress γ-aminobutyric acid, N-methyl-D-aspartate receptor glutamate receptors, and D2 dopamine receptors. Neurotransmitters such as γ-aminobutyric acid and dopamine can interact with these receptors, thereby modulating and activating the electrical activity of GnRH neurons [136]. Second, kisspeptin neurons interact with neurotransmitters to regulate the ovarian cycle. Nitric oxide synthase is expressed in hypothalamic cells, and the enzyme is also present in gonadotropin cells, follicular cells in the anterior pituitary gland and pituitary gland, and testes in the reproductive tract [137]. Kisspeptin augments its phosphorylation at the Ser1412 site, a key activation point, by engaging the PI3 K/AKT signaling pathway within the nitric oxide synthase-expressing neuronal population. This activation influences the synthesis of nitric oxide, which is a pertinent factor in the preovulatory surge of GnRH and LH, facilitated by estrogen and kisspeptin neurons. Nitric oxide- and kisspeptin-synthesizing neurons interact to regulate the progression of the ovarian cycle [138].

Limitations, summary and outlook

Limitations

This review has several limitations. First, mechanistic insights predominantly derive from animal models, which may not fully recapitulate human physiology. Second, human studies exhibit heterogeneity in dietary patterns, ethnic backgrounds, and methodologies (e.g., reliance on 16S rRNA sequencing rather than metagenomics). Third, sex-specific analyses are scarce, limiting generalizability. Finally, longitudinal data on SCFA supplementation in altered pubertal timing cohorts are lacking, hindering causal inference.

Summary

The increasing recognition of diet-microbiota interactions in modulating pubertal timing underscores the need to disentangle physiological adaptations from pathological dysregulation. While current evidence predominantly links high-fat diets to accelerated hypothalamic maturation via GM-SCFA axis, such effects may operate within a normative range of pubertal variability. True pathological precocity likely requires synergistic genetic or environmental insults. This review consolidates evidence linking high-fat/high-sugar diets to GM alterations, SCFA depletion, and neuroendocrine disruption, culminating in premature HPGA activation. Key mechanisms include GM-mediated leptin resistance, hypothalamic inflammation, and neurotransmitter imbalances (e.g., dopamine, nitric oxide), which directly modulate GnRH and kisspeptin neuronal activity. Notably, regional dietary patterns (Western vs. Mediterranean) have divergent impacts on GM diversity and puberty timing, underscoring the need for culturally tailored interventions.

Future research should prioritize longitudinal cohorts to track pubertal trajectories, integrating multi-omics (metagenomics, metabolomics) and clinical phenotyping. This will enable the identification of thresholds where dietary interventions transition from modulating physiological timing to mitigating pathological precocity. Additionally, sex-specific analyses and humanized animal models are essential to resolve rodent-human discrepancies in SCFA effects.

Outlook

Despite these advances, critical gaps persist. Human studies remain limited by heterogeneity in dietary and ethnic factors, while reliance on 16S rRNA sequencing overlooks functional metagenomic insights. Contradictory findings between animal models (e.g., SCFA depletion) and human data (e.g., increased butyrate-producing taxa) suggest that complex host‒microbe interactions are influenced by obesity, sex hormones, and genetic/epigenetic factors. Future research should prioritize shotgun metagenomics, longitudinal cohorts, and sex-specific analyses to unravel causal pathways. In the clinic, dietary fiber supplementation, fecal microbiota transplantation and probiotics have emerged as promising strategies, yet their efficacy requires rigorous validation. By bridging mechanistic insights from preclinical models and human observations, this field holds transformative potential for addressing the global burden of altered pubertal timing through precision nutrition and microbiota modulation.

Future clinical trials should prioritize sex-stratified cohorts to address hormonal dimorphism. Additionally, intervention studies combining dietary fiber with probiotics could validate their efficacy in restoring GM-SCFA homeostasis. Translational efforts should leverage humanized microbiota models to bridge rodent-human discrepancies in SCFA effects.

Author contributions

Congfu Huang and Xiaoqing You conceived the project. Congfu Huang, Xiaoqing You, and Wei Yang wrote the manuscript, among which Congfu Huang and Xiaoqing You drafted the manuscript. Wei Yang, Xiaoli Li, Xiuyun Li, and Ying Huang are responsible for literature download, statistics, plotting, and tables. All the authors contributed to the article and approved the submitted version.

Funding

This work was strongly supported by the Research Initiation Fund of Longgang District Maternity and Child Healthcare Hospital of Shenzhen City (Y2024011), Key Medical Disciplines in Longgang District.

Research Initiation Fund of Longgang District Maternity and Child Healthcare Hospital of Shenzhen City,Y2024011,huang congfu

Data Availability

Not applicable. This study was registered in China clinical trial center, registration number: ChiCTR2000033305.

Declarations

Competing interests

The authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article.

Consent to Publish declarations

The authors confirm that this work is original, has not been published elsewhere, and is not under consideration by another journal. All co-authors have approved the manuscript and agree with its submission to your journal. Consent to publish has been obtained from all participants where applicable.

Ethics statement

This study was conducted in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments. This study was approved by the ethics committee of Longgang District Maternity & Child Healthcare Hospital of Shenzhen city with the registration number of LGFYYXLL-024. All procedures involving human participants were approved, and informed consent was obtained.