Abstract
Research on effects of synbiotics in older adults with functional constipation (FC) is limited. This randomized, double-blind, placebo-controlled trial evaluated a 4-week synbiotic (Bifidobacterium animalis subsp. lactis BL-99 and fructooligosaccharides [FOS]) intervention in 67 participants ≥60 years old meeting Rome IV FC criteria. Compared to placebo, the synbiotic group showed significant improvements in weekly spontaneous bowel movements (Least squares mean ± standard error: 4.94 ± 0.25 vs. 3.00 ± 0.26, P < 0.001) and whole gut transit time (37.13 ± 3.78 vs. 50.64 ± 4.22 h, P = 0.019), with benefits sustained 2 weeks post-intervention. It also reduced time per toilet attempt and alleviated rectal discomfort symptoms more effectively than placebo. Fecal microbiome analysis revealed increased abundance of beneficial Bifidobacterium species, correlating with symptom improvement (P < 0.05). These findings demonstrate that BL-99/FOS supplementation ameliorates FC symptoms in older adults, with effects sustained post-discontinuation, potentially mediated through gut microbiota modulation. Further mechanistic investigation is warranted.
Keywords: Synbiotics, Probiotics, Functional constipation, Older adults, Gut Microbiota
1. Introduction
Functional constipation (FC), characterized by infrequent and/or difficult defecation without organic etiology [1], disproportionately affects older adults due to age-related gut dysfunctions including neuromuscular degeneration, neurotransmitter imbalance, and microbiota alterations [2,3]. Epidemiological surveys indicate a rising FC prevalence from 3 to 11% in Chinese adults to 13–32.6% in the older population [4,5]. FC not only influences the quality of life but also exacerbates the risk of cardiovascular diseases and neurodegenerative conditions [6,7]. Current therapies (e.g., osmotic/stimulant laxatives) are limited by adverse effects and declining long-term efficacy, underscoring the demand for safer and more sustainable alternatives.
Emerging evidence highlights gut microbiota modulation as a promising therapeutic strategy. Age-related depletion of Bifidobacteria [8] and dysbiosis observed in FC patients [9] support the potential benefits of probiotic/prebiotic interventions. Probiotics can improve intestinal motility [10], while prebiotics can promote the growth of beneficial bacteria and increase the water content of stool to facilitate defecation [11]. Synbiotics, which combine both the effects of probiotics and prebiotics, may amplify these benefits [12]; however, clinical outcomes remain inconsistent. While some trials using synbiotic interventions demonstrate improved transit time [13] or symptom relief [14], others indicate no significant effects [15]. Moreover, a meta-analysis of 4 studies revealed no significant impact of synbiotic intervention on symptoms of constipation [16]. Notably, there is a critical lack of studies specifically targeting the older population.
Bifidobacterium animalis subsp. lactis BL-99, isolated from the gut of healthy infants, demonstrates preclinical efficacy in remodeling gut microbiota, increasing short-chain fatty acids [17,18], and enhance fructooligosaccharide (FOS) utilizations [19]. Mechanistically, BL-99/FOS alleviates constipation by upregulating 5-hydroxytryptamine and exerting anti-inflammatory effects [20]. This randomized controlled trial evaluates the efficacy and sustainability of a 4-week BL-99/FOS intervention in generally healthy older adults (≥60 years) meeting Rome IV FC criteria.
2. Materials and methods
2.1. Study design
This study is a randomized, double-blind, placebo-controlled clinical trial. The study was approved by the Ethics Committee of the Chinese People's Liberation Army (PLA) General Hospital (approval number: S2023-101-01) and was performed according to the Declaration of Helsinki from November 17, 2023 to January 31, 2024. All participants provided written informed consent. The study was registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn/) with the registration number ChiCTR2300077723.
Eligible participants underwent a 2-week washout period prohibiting probiotic/prebiotic-containing products. At the end of the washout period (V0), participants were randomly assigned to either the synbiotic or the placebo group and received the intervention for 4 weeks. Upon completion of the 4-week intervention (V1), participants stopped consuming the synbiotics or placebo. Two weeks later (V2), a follow-up assessment was conducted to evaluate whether the effects of synbiotics persisted. The frequency of bowel movements, constipation symptoms, and the whole gut transit time (WGTT) were assessed at V0, V1 and V2. Fresh fecal samples were collected at V0 and V1 for gut microbiota analysis. Participants were instructed to maintain their usual diet and exercise routines throughout the study.
2.2. Inclusion and exclusion criteria
This study focused on a population of generally healthy older individuals aged 60 years or older who meet the Roman IV diagnostic criteria for FC, have no significant comorbidities or other factors that could influence the trial, and voluntarily consent to participate by signing the informed consent form. Detailed inclusion, exclusion, and withdrawal criteria are provided in the supplementary methods section of the supplementary materials.
2.3. Randomization and blinding
A dedicated statistician assigned participants to either the synbiotic or the placebo group using the dynamic randomization method of minimization. Stratification factors included gender, age, and the frequency of spontaneous bowel movements per week (SBM). The role of the statistician was limited to randomization, and the statistician did not participate in other processes of the study. Both the researchers and participants were blinded to treatment assignment throughout the study. The synbiotic and placebo sachets were identical in appearance, color, smell, and taste.
2.4. Intervention
Both the synbiotics and placebo were manufactured by Beijing Heyiyuan Biotechnology Co., Ltd. (Beijing, China). The synbiotic formula contained BL-99 powder (2 × 1010 CFU per sachet, 1010 CFU represents the number of viable bacteria of BL-99 strain) and FOS powder (0.8 g per sachet). The placebo was maltodextrin (2.0 g per sachet). Participants were instructed to consume one sachet daily, dissolved in warm water, within 1 h after dinner during the intervention period. Both the synbiotic and placebo sachets were stored in a refrigerator at 2–8 °C.
2.5. Constipation symptom assessment
Constipation symptoms were assessed using an online questionnaire completed by participants within a specified timeframe.
The primary endpoint was the frequency of SBM reported by the participants.
Stool consistency was quantified using the Bristol Stool Form Scale (BSS): types 1 and 2 were designated as hard; types 3, 4, and 5 as normal; and types 6 and 7 as loose.
The constipation symptoms were also assessed using the the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire and the Constipation Scoring System (CSS). The PAC-SYM consists of 12 items in three dimensions (Stool, Rectal, and Abdominal symptoms). Each item was scored using a 5-point Likert scale, with increasing severity from 0 (no symptoms) to 4 (very severe symptoms). The CSS includes seven items. The item “Assistance: type of assistance” is scored on a 3-point scale (0–2 points), while the remaining items are scored on a 5-point Likert scale, with increasing severity from 0 (no symptoms) to 4 (very severe symptoms).
2.6. Whole gut transit time measurement
Participants were recruited to voluntarily undergo the assessment of WGTT using the blue dye method [21]. Specifically, participants consumed cakes containing a blue dye, and the time of consumption and the time of the first appearance of blue stool were recorded. The time interval between these two events was considered as the WGTT. A total of 45 participants (20 in the placebo group and 25 in the synbiotic group) completed the WGTT measurement.
2.7. Fecal sample collection and 16S amplicon sequencing
Fresh fecal samples were collected in sterile bottles, immediately placed on ice, transported to the laboratory within 1 h, and stored at −80 °C for later analysis. The sequencing method of the 16S amplicon is detailed in the supplementary methods section of the supplementary materials.
2.8. Statistical analysis
The primary endpoint was the frequency of SBMs. Based on Ojetti et al. [22], the sample size was calculated assuming a Type I error rate (α) of 0.05 and a statistical power (1 − β) of 0.80. This resulted in 29 participants per group, increased to 34 per group to account for a 20% dropout rate. A total of 67 participants were recruited, with 34 and 33 participants in the synbiotic and placebo groups, respectively. Although the placebo group had one fewer participant than planned, no dropouts occurred, maintaining statistical significance.
In the baseline characteristics, quantitative data with normal or near-normal distributions were described using mean ± standard deviation, while non-normal data were described using the median (interquartile range). Categorical data were presented as frequencies (percentages). Efficacy indicators (SBM, WGTT, and symptom scores) were analyzed using linear mixed-effects models (LMEM), which calculated least squares means (LSM) with standard errors (SE) or 95% confidence intervals (CI) for repeated measurements and compared between-group differences. The models included fixed effects of group, time, and their interaction (group × time), with individual subjects as random effects. A significant interaction term indicated a significant intervention effect. The chi-square test was used for intergroup comparison of categorical variables.
For gut microbiota analysis, we examined α diversity (including Sobs, ACE, Shannon, and Simpson indices) and β diversity (by Principal coordinate analysis, PCoA). Linear discriminant analysis Effect Size (LEfSe) was employed to identify bacterial groups with differential abundances in the placebo group and the synbiotic group before and after the intervention (LDA score ≥2.0 and P < 0.05). Spearman correlation analysis was conducted to evaluate the correlation between constipation phenotypic indicators and gut microbiota. More detailed methods of gut microbiota analysis are present in the supplementary materials.
Statistical analyses were conducted using SPSS 20.0, SAS 9.4 and GraphPad Prism 9. All statistical tests were two-sided, and P < 0.05 was considered statistically significant.
3. Results
3.1. Characteristics of participants
From 101 initial applicants, 27 were excluded based on inclusion criteria. Of the remaining 74 participants, 7 were excluded (2 with blood phobia, 3 declining consent, and 2 with scheduling conflicts), leaving 67 eligible adults with FC (placebo:33, synbiotic:34). All completed the 4-week intervention without dropouts (Figure S1). Baseline characteristics (Table S1) showed no significant intergroup differences in age, gender, BMI, SBM frequency, WGTT, Rome IV symptom profiles, or constipation medication use.
3.2. Effects of synbiotic intervention on constipation symptoms
3.2.1. Spontaneous bowel movements and whole gut transit time
The LMEMs revealed significant group × time interactions for both SBM (Fig. 1A) and WGTT (Fig. 1B), which implies that synbionic intervention had a significant effect on both of these indicators. After 4-week intervention, the synbiotic group showed increased SBM frequency (LSM ± SE: 4.94 ± 0.25 vs. 3.00 ± 0.26 times/week, P1< 0.001) and reduced WGTT (LSM ± SE: 37.13 ± 3.78 vs. 50.64 ± 4.22 hours, P1 = 0.019) compared to placebo, with no significant changes observed in the placebo group. Two weeks post-intervention, synbiotic effects persisted with sustained SBM elevation (LSM ± SE: 4.18 ± 0.25 vs. 3.03 ± 0.26 times/week, P2 = 0.002) and WGTT reduction ((LSM ± SE: 39.71 ± 3.78 vs. 51.46 ± 4.22 hours, P2 = 0.041) compared to placebo, despite partially rebounding compared with that at the 4-week intervention.
Fig. 1.
Effect of synbiotic intervention on SBMs and WGTT.
The data are the least squares means and 95% confidence intervals of the predicted values calculated using the linear mixed effects model. The Pinteraction value represents the interaction effect of group × time. P1 represents the differences between groups after 4 weeks of intervention; P2 expressed the differences between groups 2 weeks post-intervention. SBM, spontaneous bowel movements per week; WGTT, whole gut transit time.
3.2.2. Constipation symptoms assessed by BSS, PAC-SYM and CSS
The results of stool consistency, as measured by the BSS, are presented in Table S2. It suggest that synbiotics intervention does not significantly influence the stool consistency.
The LSMs and SEs of PAC-SYM and CSS symptom scores estimated by the LMEMs are shown in Tables S3 and S4. In the PAC-SYM score, items 7 (“Feeling like you had to pass a bowel movement but you could not”, P = 0.040), 8 (“Rectal bleeding or tearing during or after bowel movement”, P = 0.029), and 9 (“Rectal burning during or after a bowel movement”, P = 0.007) showed significant intergroup differences 2 weeks post-intervention, with significantly lower scores in the synbiotics group compared with placebo group. In the CSS scores, the fifth item (“Time: minutes in lavatory per attempt”) was significant lower in the synbiotic group compared to the placebo group both at 4-week intervention (P = 0.021) and 2 weeks post-intervention (P = 0.014). The remaining scores showed no significant inter-group differences after the intervention or post-intervention.
3.3. Effects of synbiotic intervention on gut microbiota
16S rRNA sequencing revealed significant microbial changes after intervention. The synbiotic group showed increased α-diversity richness (Ace and Chao indices, P < 0.001) versus placebo, with elevated Shannon (P = 0.016) and reduced Simpson indices (P = 0.034) post-intervention (Fig. S2a-h). PCoA demonstrated significant group separation after intervention(P = 0.016) (Fig. S2i-j).
The results on the composition of gut microbiota are shown in Fig. 2. At the phylum level (Fig. 2a), Bacillota, Actinomycetota, Verrucomicrobiota and Bacteroidota were dominant. At the genus level (Fig. 2b), Bifidobacterium, Akkermansia, Escherichia, Faecalibacterium, and Blautia were dominant. LEfSe analysis identified baseline Megamonas enrichment, shifting to Bifidobacterium and Segatella post-intervention in the synbiotic group(Fig. 2c). Intergroup LEfSe analysis revealed synbiotic-specific enrichment of Bifidobacterium, Akkermansia, Veillonella, Citrobacter, and Collinsella contrasted to the placebo group (Fig. 2d). In the pearson correlation analysis, Bifidobacterium abundance was positively correlated with SBMs and negatively correlated with WGTT (P < 0.05), while Lachnospira was positively correlated with WGTT (P < 0.05) (Fig. 2e).
Fig. 2.
Effects of synbiotic intervention on gut microbiota composition and their correlation with constipation phenotypic indexes.
Species composition at Phylum (a) and Genus (b) levels. Lefse LDA plots of V0_Synbiotics vs V1_Synbiotics (c) and V1_Placebo vs V1_Synbiotics (d), showing the significant species with statistically significant differences in LDA score, with the default preset value of 2.0. Pearson correlation heatmap (e) of constipation phenotypic indexes (SBMs and WGTT) with differential gut microbiota at genus level.
4. Discussion
This randomized trial demonstrates that a 4-week BL-99/FOS synbiotic intervention significantly improved FC symptoms in older adults, with sustained efficacy two weeks post-treatment. Key outcomes included increased SBMs, accelerated WGTT, reduced lavatory time per attempt, and improved rectal symptoms. The intervention concurrently enhanced gut microbiota diversity and selectively enriched Bifidobacterium, whose abundance positively correlated with clinical improvements. These findings suggest BL-99/FOS as a potential synbiotic strategy for FC in older adults.
Numerous studies have investigated the effects of microecological agents on FC, but relatively few have focused on older adults and synbiotic formulations. A randomized controlled trial using FOS/Lactobacillus/Bifidobacterium synbiotics improved bowel movement frequency and stool consistency in constipated women [23], while other trials using Lactobacillus plantarum LP01 or Bifidobacterium animalis lactis formulations showed no such benefits [24,25]. A 2022 meta-analysis including 30 probiotic and 4 synbiotic trials [16] reported that probiotics significantly increased bowel movement frequency and integrative symptom scores, while synbiotics had no significant effect. In contrast, our BL-99/FOS intervention significantly increased SBMs and reduced WGTT in older adults, with sustained effects post-intervention. These results highlight BL-99/FOS as an effective synbiotic for FC in older adults.
The PAC-SYM and CSS questionnaires are commonly used for assessing constipation-related symptoms and have been widely used in clinical trials [26,27]. This study demonstrated that a 4-week BL-99/FOS intervention significantly reduced the time spent per toilet attempt as measured by the CSS questionnaire, with this effect persisting after the intervention ended. This finding align with the observed effects on SBM and WGTT in this study, collectively underscoring the efficacy of BL-99/FOS synbiotics in promoting defecation. Additionally, among the symptoms evaluated using the PAC-SYM questionnaire, rectal-related symptoms such as bleeding, tearing, and burning sensation were notably alleviated in the synbiotic group compared to the placebo group. These results suggest that BL-99/FOS synbiotics may possess potential advantages in mitigating rectal symptoms, however, warranting further investigation for confirmation.
Emerging evidence suggests a link between FC and gut microbiota dysbiosis, characterized by an overgrowth of harmful bacteria that disrupts the balance of beneficial gut microbiota [28]. Our 16S rRNA gene sequencing revealed that after 4 weeks of intervention, the synbiotic group exhibited a significant enrichment in beneficial bacteria, particularly Bifidobacterium, which was associated with symptom improvement. Studies have shown that supplementation with Bifidobacterium can alleviate intestinal barrier dysfunction in mice, restore enteric nerves, and increase the levels of SCFAs and water in stools [29]. Furthermore, the combination of BL-99 and FOS has been shown to increase the abundance of Bifidobacterium and propionate levels in the intestines while reducing the relative abundance of harmful bacteria, such as Escherichia coli and Shigella, thereby reshaping the gut microbiota structure [19,20]. These results collectively indicate that BL-99/FOS synbiotics may alleviate constipation symptoms through the regulation of the microbiota; however, the precise mechanism underlying this effect requires further investigation.
To the best of our knowledge, this study represents one of the few studies that focus on the effects of synbiotics on older adults with FC, and it demonstrated the beneficial effects of BL-99/FOS synbiotics on defecation frequency and WGTT. However, this study has several limitations. First, the gender ratio was imbalanced due to the generally higher prevalence of constipation in women in the older population [30]. Second, although this study demonstrated a significant efficacy of the synbiotic intervention, it did not include dosage comparisons, making it difficult to evaluate whether alternative dosages might yield more favorable outcomes. Third, despite instructing the participants to keep their lifestyles unchanged during the trial, residual confounding factors may potentially influence the outcome interpretation. Lastly, this study only provided a descriptive analysis of the gut microbiota; further research is needed to investigate the microecological mechanisms by which synbiotics relieve FC in older adults.
In conclusion, our research demonstrates that a 4-week BL-99/FOS synbiotic intervention significantly increased SBMs, reduced WGTT, and reduced the time spent per toilet attempt in older adults with FC, and these effects persisted 2 weeks post-intervention. The intervention also modulated the gut microbiota diversity and increased the abundance of beneficial bacteria like Bifidobacterium. This study validated the efficacy of a synbiotic combination for older adults with FC and supports their potential application. However, further research is needed to explore the specific underlying mechanisms.
CRediT authorship contribution statement
J.J.H., R.W., and M.N.L designed the study. M.N.L, Q.Z., J.J.H., W.Z., J.C., Y.H.L., and L.M.Z. were responsible for patient recruitment and obtaining informed consent signatures. J.J.H. and M.N.L. were responsible for the random allocation of participants. M.N.L., Q.Z., L.R.W., Y.R.G., J.H., Q.Y.J., Z.Z.Z., X.M.G. and C.L. conducted the clinical trial and collected the data. Q.Z. and M.N.L. designed 16S rRNA analysis protocols. M.N.L., Q.Z., L.W.Z. conducted the microbiome analyses and prepared figures and tables. M.N.L., and J.J.H. drafted the manuscript. W.Z., Y.H.L., Y.Z., W.L.H., J.L. and J.J.H. revised the manuscript. All contributing authors meticulously reviewed the manuscript, unanimously approving the final version of the manuscript.
Informed consent statement
All participants provided written informed consent.
Funding
This study was supported by National Center of Technology Innovation for Dairy (No 2023-JSGG-15), National Center of Technology Innovation for Dairy (No. 2022-KYGG-6) and The 9th China Association for Science and Technology Youth Talent Promotion Project (2023-2026) (202404623140567).
Institutional review board statement
The study was approved by the Ethics Committee of the Chinese People's Liberation Army (PLA) General Hospital (approval number: S2023-101-01) and was performed according to the Declaration of Helsinki.
Declaration of Generative AI and AI-assisted technologies in the writing process
During the preparation of this manuscript, the authors utilized Youdao AIBox for assistance with grammar and spelling corrections. Following the use of this tool, the authors conducted a thorough review and made necessary edits to the content, thereby assuming full responsibility for the final version of the publication.
Data availability statement
The corresponding authors can be contacted if needed.
Declaration of competing interest
The authors declare that there are no conflicts of interest in this article.
Acknowledgments
None.
Footnotes
Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jnha.2025.100598.
Contributor Information
Wei-Lian Hung, Email: hongweilian@yili.com.
Jingjing He, Email: hejingjing89@cau.edu.cn.
Ran Wang, Email: wangran@cau.edu.cn.
Appendix A. Supplementary data
The following are Supplementary data to this article:
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