Research progress and controversies in the treatment of functional constipation-related depression with probiotics and prebiotics: a narrative review

This manuscript is structured as a narrative review to provide a broad perspective on the emerging concept of “dual efficacy” targeting the gut–brain axis. The primary strength of this approach is its flexibility, allowing for the inclusion of diverse study designs (including pilot studies and mechanistic animal trials) that are essential for exploring complex biological mechanisms but might be excluded from rigorous systematic reviews. To mitigate selection bias, we incorporated systematic search elements (e.g., specific search strings and a PRISMA flow diagram) to ensure reproducible literature retrieval.

However, this approach has limitations. Unlike a standard systematic review, we did not perform a quantitative meta-analysis or a de novo risk of bias assessment. This decision was made because the included studies exhibited significant heterogeneity in probiotic strains, dosing regimens, and intervention durations, which would render a quantitative synthesis statistically invalid. Therefore, the findings presented here should be interpreted as a qualitative synthesis, and any certainty of evidence ratings (e.g., GRADE) are cited directly from existing high-quality meta-analyses rather than representing an independent evaluation. Although the database search was restricted to human English-language studies, preclinical mechanistic evidence was identified via targeted hand-searching and citation chasing to contextualize MGBA pathways; these preclinical sources were not counted in the PRISMA study selection totals.

To ensure a comprehensive and reproducible review, we conducted a systematic search of PubMed, Scopus, Web of Science, and the Cochrane Library for articles published from January 2015 to October 2025. Search filters were applied to restrict results to human studies and publications in the English language. Selected seminal studies published prior to this window were included where relevant. The search strategy employed Medical Subject Headings (MeSH) terms and free-text keywords connected by Boolean operators (“Probiotics” OR “Prebiotics” OR “Synbiotics” OR “Psychobiotics” OR “Lactobacillus” OR “Bifidobacterium”) AND (“Functional Constipation” OR “Chronic Constipation” OR “Rome III” OR “Rome IV”) AND (“Depression” OR “Depressive Symptoms” OR “Anxiety” OR “Mood Disorders” OR “Gut-Brain Axis”).

Inclusion and Exclusion Criteria: We included randomized controlled trials (RCTs), non-randomized controlled trials, and systematic reviews involving adults, elderly individuals, or children diagnosed with functional constipation (FC) according to standard criteria (e.g., Rome III/IV). The evaluation of clinical efficacy prioritized human studies; however, preclinical (animal) models were also reviewed to elucidate the biological mechanisms underlying the microbiota–gut–brain axis interactions. Eligibility required reporting of primary gastrointestinal outcomes (e.g., SBM, BSFS) and/or psychological outcomes (e.g., HAMD, BDI), with priority given to studies assessing both domains.

We excluded duplicate publications, conference abstracts, studies primarily focusing on constipation-predominant Irritable Bowel Syndrome (IBS-C) to maintain phenotypic homogeneity, and cases of constipation secondary to organic diseases, medications, or neurological disorders. The screening process followed PRISMA principles adapted for a narrative review, as illustrated in the flow diagram in Figure 1. Finally, regarding the certainty of evidence presented in the summary tables, ratings (e.g., high, moderate, low) were adopted directly from the included systematic reviews and meta-analyses (which utilized frameworks such as GRADE or CINeMA). These ratings reflect the assessments of the original authors and do not represent a new independent formal quality assessment by the reviewers of this manuscript.

In distinct contrast to adult data, high-quality evidence regarding the efficacy of probiotics and prebiotics in pediatric FC remains largely negative or inconclusive. As summarized in recent systematic reviews, these interventions generally failed to demonstrate significant improvements in key outcomes such as weekly spontaneous bowel movements, stool consistency, or abdominal pain (Wallace et al., 2022; Dong et al., 2023; Liu X. et al., 2023; Zhang Y. et al., 2023; Tomsa et al., 2025). Similarly, regarding psychological outcomes, recent trials indicate that while synbiotics may aid concomitant symptom relief, their standalone efficacy in improving depressive symptoms in children is limited (Chen et al., 2024; Yang et al., 2024). Consequently, current evidence does not support the routine use of PP/S in pediatric populations. Given that the pediatric microbiome and gut–brain axis are in a state of rapid maturation, extrapolating efficacy data from adult studies to children is scientifically invalid and ethically imprudent. Clinical application in children should therefore remain restrictive and distinct from adult protocols.

Quantification of Effect: Regarding stool frequency, a recent network meta-analysis by Deng et al. (2024) synthesized data from 37 RCTs involving 3,903 patients, with 24 RCTs specifically contributing to the stool frequency outcome. The analysis confirmed significant improvements, with synbiotics demonstrating a Mean Difference (MD) of up to 4.58 bowel movements per week compared to placebo. This magnitude exceeds the ≥1 bowel movement/week clinical anchor. However, given the inconsistent reporting of CSBM across trials, strict MCID applicability remains limited and results should be interpreted with caution. In the elderly population, Recharla et al. (2023) pooled data from 5 RCTs, reporting a moderate Standardized Mean Difference (SMD) of 0.27 (95% CI: 0.05–0.50) for defecation frequency (Mitelmao et al., 2021; Sola et al., 2022; Recharla et al., 2023; Deng et al., 2024; Garzon Mora and Jaramillo, 2024). While statistically significant, this modest effect size warrants caution, as it may not consistently translate to clinically perceptible relief for all patients.

Regarding depressive symptoms, reductions in HAMD scores across various trials typically ranged from 2 to 3.5 points. Crucially, many of these reductions hover around or fall below the MCID threshold for depression (≥3 points). This suggests that while statistical significance is frequently achieved, the clinical meaningfulness of these changes often remains borderline. Furthermore, few studies explicitly reported MCID-based responder rates, which limits the interpretation of clinical relevance. Therefore, statistically significant differences should not be assumed to represent clinically meaningful benefits when MCID thresholds are not met. Nevertheless, some evidence suggests that PP/S may offer a safer long-term alternative or adjunct to traditional laxatives, particularly for maintenance therapy (Nikolova et al., 2021; Mitelmao et al., 2022; Harris et al., 2025).

Comparative Efficacy of Formulations: Evidence regarding the superiority of complex formulations is nuanced. Synbiotics exhibit robust evidence for enhanced efficacy; for instance, a specific synbiotic mixture (“Mix7”) ranked first in the network meta-analysis with a SUCRA (surface under the cumulative ranking curve) probability of 94.8%. However, the advantage of multi-strain probiotics over single strains is less definitive and appears population-dependent. In elderly subjects, single-strain interventions actually demonstrated a significant effect size (SMD = 0.49) compared to non-significant results for multi-strain formulations (SMD = 0.48), suggesting that strain specificity may outweigh strain diversity in certain cohorts (Sola et al., 2022; Recharla et al., 2023; Deng et al., 2024). This aligns with mechanistic data indicating that therapeutic effects—particularly for mood regulation—are highly dependent on specific bacterial metabolites and neuroactive compounds (Jach et al., 2023; Li et al., 2023; Rahmannia et al., 2024).

Multi-strain versus single-strain: In adult populations, multi-strain or synbiotic PP/S formulations generally confer greater benefits in improving stool frequency and consistency (Sola et al., 2022; Deng et al., 2024).

Intervention duration: A period of ≥4–8 weeks produces more consistent effects in adult cohorts. Elderly individuals tend to respond more slowly to interventions and may require careful adjustment of both dosage and duration to achieve beneficial outcomes (Mitelmao et al., 2021; Sola et al., 2022; Deng et al., 2024).

Expanding on the significance of intervention duration, research heterogeneity further influenced results. Studies differed in baseline severity of constipation, varying lengths of follow-up, inconsistent methods for outcome measurement, and differences in blinding practices. Due to these factors, overall effects were uncertain, especially in pediatric studies (Wallace et al., 2022; Dong et al., 2023; Liu X. et al., 2023; Zhang Y. et al., 2023; Garzon Mora and Jaramillo, 2024).

Heterogeneity in product types (multi-strain vs. single-strain), dosing regimens, study designs, and outcome assessment standards remains the principal barrier. This diversity makes it difficult to establish consistent evidence-based recommendations for probiotic interventions (Sola et al., 2022; Liu X. et al., 2023; Deng et al., 2024; Garzon Mora and Jaramillo, 2024).

Prebiotics are non-digestible substances that help beneficial bacteria grow and offer health benefits. Main types include Fructo-Oligosaccharides (FOS), inulin, Galacto-Oligosaccharides (GOS), and resistant starch (Erhardt et al., 2023; He et al., 2025). Building on this, these substrates are fermented by colonic microbiota (e.g., Bifidobacterium, Lactobacillus) to produce SCFAs, which lower colonic pH, promote intestinal motility and barrier function, and may improve constipation-related symptoms via the enteric neuroendocrine pathway (Deng et al., 2024; Erhardt et al., 2024).

A summary of key evidence regarding prebiotic interventions, including specific findings on inulin and fructo-oligosaccharides (FOS) from recent randomized controlled trials and meta-analyses, is presented in Table 2. Specifically, a double-blind randomized controlled trial in adults with chronic constipation demonstrated that inulin supplementation increased weekly bowel movement frequency and improved clinical symptoms (Terren Lora et al., 2024). In addition to the RCT findings, a network meta-analysis indicated that prebiotics overall outperformed placebo, though effect sizes showed heterogeneity, with no significant differences between types (GOS/FOS/inulin) (Deng et al., 2024). Specific data on galacto-oligosaccharides (GOS) also confirm their safety and bifidogenic potential in managing constipation-related symptoms (Lee et al., 2024). Regarding safety, the profile is favorable: adverse reactions primarily include mild bloating, borborygmi, and abdominal pain, with no serious adverse events reported (Terren Lora et al., 2024).

However, age-related differences in response kinetics are notable. While adults often respond within 4 weeks, elderly individuals typically require a longer intervention duration of at least 4–8 weeks to achieve statistically significant improvements. Regarding formulation, emerging evidence suggests that multi-strain probiotics or synbiotics (combinations of probiotics and prebiotics) may exhibit enhanced efficacy compared to single-strain preparations, likely due to synergistic effects on the gut microbiota, although head-to-head comparisons remain limited.

The therapeutic potential of probiotics and prebiotics is largely attributed to their modulation of the microbiota-gut-brain axis (MGBA). Preclinical studies have elucidated several key pathways. First, the serotonergic pathway plays a critical role; probiotics may enhance the intestinal availability of serotonin (5-HT), a neurotransmitter essential for mood regulation, thereby improving signaling along the gut-brain axis (Rajanala et al., 2021; Suda and Matsuda, 2022; Radford-Smith and Anthony, 2023).

Second, interventions have been observed to upregulate neurotrophic factors, specifically Brain-Derived Neurotrophic Factor (BDNF) and Gamma-Aminobutyric Acid (GABA). These changes support neuroplasticity and help suppress the neuroinflammation often associated with depressive behaviors in animal models (Rajanala et al., 2021; Radford-Smith and Anthony, 2023; Patel et al., 2025).

Additionally, the fermentation of prebiotics by colonic microbiota produces Short-Chain Fatty Acids (SCFAs), such as acetate, propionate, and butyrate. SCFAs serve to lower colonic pH and enhance intestinal barrier integrity (Liu et al., 2021; Zhang S. et al., 2021; Zou et al., 2024).

This barrier restoration is crucial for preventing the translocation of bacterial toxins, thereby reducing systemic inflammation markers (e.g., IL-6, TNF-α) (Yang et al., 2022; Mohan et al., 2023; Radford-Smith and Anthony, 2023), that can negatively impact the central nervous system (Zhang X. et al., 2021; Jankiewicz et al., 2023; Zhang Q. et al., 2023; Zou et al., 2024). A schematic overview of the proposed microbiota–gut–brain mechanisms is provided in Figure 2.

Translating mechanistic findings to human subjects has yielded consistent but variable signals. In patients with functional constipation and comorbid depression, baseline assessments frequently reveal gut dysbiosis characterized by reduced diversity and lower levels of fecal SCFAs (Liu et al., 2021; Zhang S. et al., 2021; Zou et al., 2024).

Following biotic interventions, clinical studies have reported increases in SCFA levels and improvements in microbial diversity, which correlate with symptom relief. Furthermore, reductions in pro-inflammatory cytokines (IL-1β, IL-6, CRP) (Yang et al., 2022; Mohan et al., 2023; Zou et al., 2024), and increases in serum BDNF levels have been documented (Zhang Q. et al., 2023; Zou et al., 2024), supporting the hypothesis that these interventions exert anti-inflammatory and neuroprotective effects in humans (Rajanala et al., 2021; Suda and Matsuda, 2022; Radford-Smith and Anthony, 2023). However, the linear correlation between these biomarker changes and clinical symptom improvement remains complex and non-linear (Liu et al., 2021; Zhang S. et al., 2021; Zou et al., 2024).

Regarding psychological outcomes, results remain heterogeneous. While pooled data from randomized controlled trials and systematic reviews generally suggest that probiotics and prebiotics may help alleviate depressive symptoms, demonstrating statistically significant improvements with small-to-moderate effect sizes (SMD) rather than uniform point reductions across different scales (El Dib et al., 2021; Gawlik-Kotelnicka et al., 2023; Zhang Q. et al., 2023; Asad et al., 2025). However, individual high-quality RCTs specifically targeting FC-related depression often report mixed results, with some trials observing non-significant differences compared to placebo. These benefits appear most stable when the intervention duration ranges from 4 to 8 weeks. Nevertheless, evidence regarding the long-term sustainability of these mood improvements beyond 6 months is currently limited and requires further validation (Dong et al., 2023; Radford-Smith and Anthony, 2023; Zhang Q. et al., 2023; Zhang Y. et al., 2023; Soderberg Veiback et al., 2025).

To bridge the gap between preclinical insights and clinical realities, it is critical to distinguish established associations from speculative pathways. Currently, the strongest human-level evidence links SCFAs—particularly butyrate—to gastrointestinal endpoints; increased fecal butyrate correlates reliably with reduced colonic transit time and improved stool consistency (BSFS) via G-protein-coupled receptor activation (Jach et al., 2023; Rahmannia et al., 2024). Conversely, the translational validity of neurotrophic and inflammatory markers is less robust. While BDNF upregulation is a consistent driver of antidepressant effects in rodent models, evidence in human trials is conflicting, with serum BDNF levels often failing to mirror clinical mood recovery (Li et al., 2023). Similarly, while reductions in pro-inflammatory cytokines (e.g., IL-6, TNF-α) theoretically underpin the “psychobiotic” effect, distinct correlations between cytokine profiles and HAMD score reductions in FC patients remain inconsistent (Zhang X. et al., 2021). Thus, while metabolic modulation (SCFAs) is a proximal driver of GI relief, neuro-immune pathways (BDNF, cytokines) currently represent plausible but largely inferred mechanisms for psychological benefits in this specific comorbidity.

Overall, probiotics and prebiotics are considered safe for the general population, with the most common adverse events being mild, transient gastrointestinal symptoms such as bloating, flatulence, and abdominal distension (see Table 4). However, serious adverse events, though rare, have been documented. Case reports of bacteremia, fungemia, and sepsis have been linked to probiotic use in high-risk groups, including severely immunocompromised patients, those with central venous catheters, and critically ill individuals with impaired intestinal barrier integrity (Mayer et al., 2023; Sada et al., 2024; Xu et al., 2025). Therefore, caution is warranted when prescribing PP/S to these vulnerable populations.

The regulatory framework for PP/S varies significantly by region. In the United States, the FDA distinguishes between dietary supplements and “Live Biotherapeutic Products” (LBPs) regulated as drugs; the European Union enforces strict health claim substantiation under EFSA; and China operates a dual-track system involving “Health Food” (SAMR) and pharmaceutical (NMPA) pathways (Cordaillat-Simmons et al., 2020). Despite these evolving frameworks, currently, in many jurisdictions, these products are still regulated as dietary supplements or foods rather than pharmaceuticals. This classification often implies less stringent pre-market approval requirements compared to drugs, potentially leading to variability in product potency and purity. Moving forward, the development of LBPs intended for specific medical indications (such as treating FC-related depression) will require adherence to stricter pharmaceutical standards regarding strain characterization, stability, and manufacturing quality (GMP) (Jin et al., 2024; Zhang et al., 2025). From a clinical risk management perspective, ensuring strain traceability and batch-to-batch consistency is paramount to guarantee reproducible therapeutic effects. Clinicians must exercise heightened vigilance, strictly assessing contraindications to avoid use in high-risk immunocompromised populations. Furthermore, future RCTs are urged to implement systematic pharmacovigilance protocols to rigorously capture and report adverse events, moving beyond the passive monitoring often seen in nutritional studies.

This review synthesizes the current evidence on the use of PP/S for managing functional constipation (FC) and its co-occurring depressive symptoms. Data suggest that PP/S interventions are generally effective in increasing stool frequency in adults, with synbiotics showing promising efficacy (Deng et al., 2024). However, evidence in pediatric populations remains inconsistent. Regarding psychological outcomes, while “psychobiotics” have demonstrated efficacy in primary depression, evidence for their specific benefit in “FC-related depression” remains preliminary and largely extrapolated. As summarized in Table 3, trials evaluating dual outcomes [e.g., (Zhang X. et al., 2021)] often observe improvements in bowel function but non-significant differences in mood scores compared to placebo, highlighting the complexity of gut-brain interactions.

Several limitations in the current literature must be acknowledged. First, substantial heterogeneity in study protocols constitutes a primary barrier. Variations in probiotic strains (single vs. multi-strain), dosages (ranging from 10⁸ to 10¹¹ CFU), and treatment durations complicate direct cross-study comparisons and the identification of a “gold standard” regimen. Furthermore, there is a distinct scarcity of “dual-targeted” RCTs; most included studies focus singly on either GI symptoms or mood outcomes, with few high-quality trials specifically recruiting patients who meet diagnostic criteria for both functional constipation and depression.

Additionally, the assessment of “dual efficacy” is confounded by the substantial placebo response characteristic of both functional gastrointestinal disorders (FGIDs) and mild-to-moderate depression. In many trials, symptom improvements in the placebo group nearly match those in the intervention group, making it difficult to isolate the specific biological effect of the probiotic. Consequently, much of the evidence supporting dual benefits remains exploratory rather than definitive (Zhang X. et al., 2021).

Crucially, a distinction must be drawn between statistical significance and clinical relevance. While several studies reported statistically significant improvements, few explicitly interpreted these findings in the context of Minimal Clinically Important Differences (MCIDs). For constipation, an increase of ≥1 CSBM/week is commonly used as a clinically meaningful threshold in regulatory guidance (U.S. Food and Drug Administration, 2012). Similarly, for depression scores (e.g., HAMD), a reduction of ≥3 points is generally required to reflect a perceptible alleviation of symptoms (Leucht et al., 2013); thus, statistically significant reductions of smaller magnitude (e.g., 1–2 points) may lack tangible clinical impact. The current scarcity of MCID-based responder rate reporting represents a critical gap, and future trials should prioritize these established thresholds to validate real-world therapeutic value.

Methodologically, as a narrative review, this study provides a qualitative synthesis but does not perform a quantitative meta-analysis. Unlike systematic reviews, this review did not involve a formal risk of bias (RoB) assessment or quantitative quality grading (e.g., GRADE) for all included studies. Consequently, potential selection bias cannot be entirely ruled out, and the strength of the synthesized evidence should be interpreted with appropriate caution.

Future research should prioritize: (1) Dual-Targeted RCTs specifically recruiting FC patients with comorbid mood disorders using Rome IV and DSM-5 criteria; (2) Mechanistic Biomarkers incorporating multi-omics to identify specific metabolites correlating with clinical gains; and (3) Standardization of PP/S formulations to enable meaningful comparisons. Furthermore, future research should compare functional constipation with constipation secondary to neurological disorders [e.g., Parkinson’s disease (Ghalandari et al., 2023)] to better isolate specific gut-brain axis pathways.