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. 2025 Oct;48(10):2229-2248.
doi: 10.1007/s40618-025-02615-3. Epub 2025 Jun 17.

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

Xiaoqing You #  1 , Wei Yang #  2 , Xiuyun Li  3 , Xiaoli Li  3 , Ying Huang  4 , Congfu Huang  5
Affiliations

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

Xiaoqing You et al. J Endocrinol Invest. 2025 Oct.

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.

Keywords: Gut microbiota; Gut-brain axis; Hypothalamic maturation; Puberty timing; Short-chain fatty acids.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Flowchart of literature screening
Fig. 2
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
Fig. 3
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
Fig. 4
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
See this image and copyright information in PMC

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