Letter to the Editor: Adolescent mental health in transition - bridging neurobiological insights and modifiable risk factors for anxiety and depression

Abstract

Adolescence represents a neurobiologically dynamic phase, during which vulnerability to anxiety and depression markedly increases. Recent large-scale epidemiological data from Chinese adolescents reveal alarming rates of depressive (16%) and anxiety (24%) symptoms, with comorbidity in over 13%. Beyond established psychosocial determinants; such as gender, family conflict, and socioeconomic stressors, emerging evidence implicates functional constipation as a marker of brain-gut axis dysregulation, highlighting the interplay between neurobiology and lifestyle. Integrating current neuropsychiatric perspectives, inflammation, neurotransmitter imbalance, and aberrant neuroplasticity appear central to disease onset. The challenges lie in early identification, limited mental health literacy, and underdiagnosis in low-resource settings. Future perspectives demand precision prevention through integrative, school-based, and gut-brain-targeted interventions. A multidisciplinary framework combining neuroscientific insight, behavioral health strategies, and digital engagement is pivotal to reshape adolescent mental health outcomes globally.

Key Words: Adolescents; Functional constipation; Anxiety; Depression; Brain-gut axis; Neuropsychiatry; Neuroinflammation; Neuroplasticity

Core Tip: Yang et al’s large adolescent cohort suggests that functional constipation reflects gut-brain axis disruption associated with increased anxiety and depression risk. This letter integrates emerging evidence indicating that gut dysbiosis, altered microbial metabolites, systemic inflammation, microglial activation, and reduced brain-derived neurotrophic factor-mediated neuroplasticity converge on mood regulation. It further underscores the need for longitudinal, biomarker-informed studies and scalable school-based interventions targeting diet, lifestyle, and microbiome-modulating strategies to enable precision prevention in youth mental health.

TO THE EDITOR

Yang et al’s large-scale study[1] of 22925 Chinese adolescents documents a substantial burden of affective symptoms with 16.0% screened positive for depressive symptoms, 24.1% for anxiety, and 13.1% had both, while also detecting meaningful, independent associations between mental symptoms and commonly modifiable conditions. Notably, functional constipation (FC) (diagnosed by Rome IV) emerged as an independent risk correlate for both depression and anxiety, supporting a clinically relevant gut-brain axis link in adolescents. The study advances the field by combining population-scale prevalence estimates with identification of actionable targets: Physical activity, smoking, screen time, and social support, suggesting avenues for screening and multi-level prevention.

STUDY DESIGN AND ANALYTICS

Yang et al[1] performed a stratified, school-based, cross-sectional online survey (Wenjuanxing) across eight secondary schools (grades 7-12) from September 2023 to November 2023, yielding 22925 complete responses after standard exclusions. Mental symptoms were measured with validated scales: Patient Health Questionnaire (cutoff ≥ 10), Generalized Anxiety Disorder-7 (cutoff ≥ 7), FC by Rome IV criteria, and perceived social support by the physical activity, smoking, screen time, and social support. Analyses used descriptive statistics, univariate testing (t-tests, χ²), and multivariable binary logistic regression to identify independent risk factors; sample-size and effect-size planning used G*Power. Results report adjusted odds ratios and 95% confidence intervals for key predictors, enabling assessment of clinical and public-health significance. This study is strengthened by its large, a priori powered sample, validated measures, and multivariable adjustment. However, the cross-sectional design precludes causal inference, and self-reported data may introduce reporting bias. Residual confounding by factors such as diet or laxative use cannot be excluded, and online school-based recruitment from a single Chinese region may limit generalizability. These limitations support the need for longitudinal, mechanism-driven studies.

FROM GUT DYSBIOSIS TO NEUROINFLAMMATION: A MECHANISTIC CONTINUUM

Yang et al’s population data[1] linking FC with adolescent-anxiety and depression provides a valuable epidemiologic anchor for emerging mechanistic models of gut-brain communication. Recent pediatric and adolescent-focused work strengthens and contextualizes Yang et al’s population finding[1] by documenting that childhood and adolescent constipation are consistently associated with substantial psychosocial burden, including elevated emotional and behavioral symptoms and impaired quality of life for both children and their families[2]. Systematic syntheses focused on youth now report that gut microbial composition and metabolite profiles correlate with core depressive and anxiety symptoms in adolescents and highlight the potential - yet currently heterogeneous - benefit of microbiome-informed behavioral and nutritional interventions[3]. Foundational reviews further characterize adolescence as a developmentally sensitive window in which the microbiota-gut-brain axis undergoes rapid change and can therefore influence the emergence of psychiatric vulnerability, supporting the rationale for age-stratified, mechanism-driven prevention trials[4]. Experimental and clinical studies support a coherent biological sequence in which disturbances of the gut microbiota - marked by loss of short-chain fatty acid (SCFA) producers, shifts in microbial metabolite pathways, and increased intestinal permeability - alter the repertoire of circulating microbial products and neuroactive precursors[5]. Recently characterized gut-vascular barrier acts as a critical checkpoint regulating bacterial dissemination, and its disruption permits microbial translocation into the bloodstream and peripheral organs[6]. Once microbial products or inflammatory mediators enter circulation, they can activate innate immune pathways, elevating cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha and engaging inflammasome signaling, which in turn interact with or traverse the blood-brain barrier to influence microglial state[7]. Microglial activation, together with cytokine-induced alterations in glutamatergic and gamma-aminobutyric acid balance, reduces neurotrophic signaling, particularly within the brain-derived neurotrophic factor-tropomyosin receptor kinase B axis, and weakens activity-dependent plasticity across prefrontal, hippocampal, and amygdala circuits central to emotional regulation[8]. These converging neuroimmune and neuroplasticity findings provide a biologically plausible framework that contextualizes Yang et al’s observations[1] and underscores the need for longitudinal and mechanistic intervention studies to determine whether modifying gut microbial or inflammatory pathways can enhance neurodevelopmental resilience and mitigate adolescent mood vulnerability, while recognizing that much of the mechanistic evidence currently derives from adult or preclinical models and that direct human adolescent data remain limited[4].

TRANSLATING EVIDENCE INTO PRECISION PREVENTION

To move from mechanistic insight to prevention, it is crucial to identify modifiable upstream factors and stratification tools that allow risk-tailored interventions. Instead of revisiting neuroimmune pathways, this section centres on translating them into actionable strategies. Emerging evidence shows that dietary patterns profoundly influence microbial composition, metabolic function, and inflammatory tone, positioning diet-mediated microbiome modulation as a practical and scalable entry point for precision prevention. Schneider et al[9] demonstrate that specific dietary components, particularly fermentable fibers, polyphenol-rich foods, and unsaturated fats, can selectively enrich microbial taxa that generate neuroactive metabolites, including SCFAs, indoles, and amino acid derivatives, which collectively support mucosal integrity, attenuate peripheral inflammation, and influence neural plasticity pathways relevant to mood regulation. Integrating these insights with population signals such as FC suggests that simple clinical markers, combined with microbial or metabolic profiling, may help identify adolescents who are most likely to benefit from microbiome-modifying interventions.

Within this precision framework, the goal is not merely to apply generic probiotics or anti-inflammatory strategies, but rather to tailor interventions to an individual’s microbial capacity, dietary habits, inflammatory burden, and neurodevelopmental stage. Adolescents with reduced SCFA-producing taxa or heightened inflammatory markers, for example, may benefit from personalized dietary modulation or synbiotics chosen to restore specific metabolic pathways, while those exhibiting disrupted sleep, reduced physical activity, or psychosocial stress may require multimodal approaches that pair microbiome-directed strategies with established neuroplasticity-enhancing interventions[10,11]. Early trials of probiotics, synbiotics, and nutritionally anchored interventions show promise but variable effect sizes, underscoring the importance of mechanistically anchored, age-stratified randomised controlled trials that incorporate microbial, metabolic, and inflammatory biomarkers as endpoints[12]. As illustrated in Figure 1, integrating population epidemiology with mechanistic markers and targeted interventions offers a translational roadmap toward precision prevention approaches that strengthen neurobiological resilience in adolescents at risk for anxiety and depression.

Figure 1 Hypothetical conceptual model illustrating how functional constipation and gut dysbiosis may contribute to adolescent anxiety and depression through systemic inflammation, microglial activation, and impaired neuroplasticity in mood-regulating circuits. Integrating epidemiologic insights with neurobiological mechanisms supports gut-brain-targeted, school-based, and precision prevention strategies to strengthen adolescent mental health. This figure was created by BioRender (Supplementary material).

FUTURE PERSPECTIVE

Yang et al’s cross-sectional design[1] cannot establish causality or the temporal sequence between gut perturbations, systemic inflammation and emerging mood symptoms, so longitudinal, age-stratified cohorts with repeated microbiome, inflammatory and neuroplasticity measures are essential[13]. Current microbiome-directed randomized controlled trials show modest, heterogeneous effects and frequently lack mechanistic biomarkers, indicating an urgent need for larger, mechanistically informed trials that pre-specify mediator/end-point panels (e.g., SCFAs, tryptophan-kynurenine, IL-6/IL-1β, brain-derived neurotrophic factor, synaptic-density markers)[10,14]. Pragmatic and ethical challenges such as standardizing interventions, ensuring school-based delivery feasibility in low-resource settings, and harmonizing biomarker assays and data-sharing/privacy safeguards, will determine whether epidemiologic associations can be translated into scalable, precision prevention[15,16]. Given the cross-sectional design, FC should be interpreted as associated with, rather than causal of, altered gut-brain signaling. FC may reflect broader gut-brain perturbations and may also represent a somatic expression of psychological distress in youth, consistent with a bidirectional, biopsychosocial framework.

CONCLUSION

Yang et al’s large-scale findings[1] implicate gut-brain perturbations in adolescent anxiety and depression, highlighting modifiable upstream targets. Translating this insight requires longitudinal, mechanistic trials, biomarker-stratified prevention, and scalable school-based programs that combine gut-directed, anti-inflammatory and neuroplasticity-promoting strategies. Integrated, multidisciplinary efforts could shift care from symptom management toward precision prevention for youth mental health.