ABSTRACT
Aim
The primary aim of this scoping review is to synthesize fragmented evidence on gut microbiota‐targeted interventions for frailty. As a complementary objective, we conducted a bibliometric analysis to map the evolving knowledge landscape of this interdisciplinary field, thereby informing the development of future personalized therapeutic strategies and research priorities.
Methods
We searched nine databases (PubMed, Embase, Web of Science, Scopus, Cochrane Library, CNKI, Wanfang, SinoMed, and VIP) from inception to July 2025 for the scoping review. A dedicated search of the Web of Science Core Collection (up to September 2025) was conducted for the bibliometric analysis to ensure data consistency. Two reviewers independently screened and extracted data. Bibliometric analyses (collaboration networks, keyword co‐occurrence, and research trends) and visualizations were performed using CiteSpace (v6.3.R1).
Results
The scoping review screened 3216 records and included 10 studies. Interventions—probiotics, prebiotics, synbiotics, and fecal microbiota transplantation—lasted 4 weeks to 6 months. Frailty was mainly assessed using Fried's phenotype, with outcomes covering frailty severity, physical function, gut microbiota composition, and inflammatory/metabolic markers. Bibliometric analysis identified 358 publications, revealing a sharp rise after 2016. China produced the most studies, and the University of Parma was the top institution. Key themes included gut microbiota, frailty, aging, inflammation, and sarcopenia.
Conclusions
Given the rapidly growing interest, gut microbiota‐targeted interventions represent a promising strategy to slow frailty progression. Future efforts should therefore focus on establishing standardized, multidisciplinary assessment frameworks and elucidating the underlying mechanisms to advance precision nutrition for healthy aging.
Keywords: fecal microbiota transplantation, frailty, gut microbiome, probiotics
Targeted interventions that modulate the gut microbiota hold promise for delaying the progression of frailty; a bibliometric analysis indicates both a rapidly expanding research landscape and emerging frontiers in this domain.
1. Introduction
Frailty syndrome is defined as a state of heightened vulnerability and impaired stress resistance arising from diminished physiological reserves or multisystem dysfunction, and represents a key research focus in geriatrics [1]. With the intensification of aging in our country, the health problems of older adults have become an increasingly concerning issue [2]. Nutritional and pharmacological interventions improve clinical outcomes and quality of life in older adults [3]. The gut microbiome regulates the risk of various age‐related chronic diseases and syndromes. Studies have shown that obesity syndrome, sarcopenia, and cognitive decline are associated with reduced fecal microbiota biodiversity, decreased abundance of bacteria capable of synthesizing short‐chain fatty acids (SCFAs), and lower fecal butyrate levels [4]. Thus, targeted microbiota intervention is closely tied to improvements in frailty [5].
Although global research on gut microbiota interventions for frailty in older adults has advanced, evidence for probiotics, prebiotics, and fecal microbiota transplantation remains limited [6]. Therefore, we conducted a scoping review [7] to synthesize current evidence on gut microbiota interventions for frailty in older adults. By analyzing domestic and international literature, this review evaluates the effects of such interventions on both frailty syndrome and gut microbial composition.
Bibliometric analysis has been widely used to quantitatively assess research status and map scientific trends [8]. Recognizing the limitations of purely quantitative approaches, an increasing number of researchers are incorporating qualitative data. Accordingly, this study integrates scoping review methodology with bibliometric analysis to comprehensively examine the current applications and research frontiers of gut microbiota interventions for frailty syndrome.
2. Materials and Methods
For the development of this study, two methodologies were employed to facilitate its progression and enhance understanding [9, 10, 11], which are described below.
The methodology employed for the scoping review in this study was adapted from Arksey and O′Malley's approach [12]. The five key steps of Arksey and O′Malley's approach are summarized in Table 1. Consistent with the scoping review framework, we did not perform formal risk‐of‐bias assessment or evidence certainty grading, as the primary aim was to map the available evidence rather than to pool effect estimates or generate clinical recommendations [7]. A bibliometric analysis to quantitatively examine the publication patterns, research hotspots, and knowledge structures within the literature. In developing this analytical framework, the following dimensions were considered: the most prolific authors, frequently used keywords, countries of origin of the research, and the scientific journals in which the studies were published [13]. In addition, Microsoft Excel, VOSviewer (v1.6.20), CiteSpace, and the “bibliometrix” package in RStudio were employed for bibliometric analysis. The descriptions of how these two approaches were carried out are provided below. For a detailed description of the bibliometric analysis procedures, see the Bibliometric Analysis and Data Extraction section.
TABLE 1.
Five‐step scoping review framework.
| Step | Description |
|---|---|
| 1. Identification of research questions and related studies | To accomplish the purpose of this study, the following research questions were identified. |
| What are the primary methods used in clinical practice to target gut microbiota for interventions in older frail patients? How effective are these interventions in improving frailty status? What impacts do these interventions have on microbial diversity, abundance, and structural composition? What limitations currently exist? | |
| 2. Identification of related studies | A preliminary review of relevant studies was conducted to identify the keywords and terms used in the article selection. |
| 3. Study selection | Original studies published in peer‐reviewed journals, written in English or Chinese, were eligible for inclusion. Studies that evaluated the effects of intestinal flora interventions on frailty in older adults met the selection criteria for this review. |
| 4. Charting the data | Data were systematically collated from each paper utilizing a structured Microsoft Excel data‐extraction sheet. Subsequently, formal data extraction was meticulously conducted by two researchers (see Table S1). |
| 5. Collating, summarizing, and reporting the results | We performed qualitative analyses of the results of the scoping review in order to enhance the quality and applicability of the literature review. The qualitative analysis, for its part, consisted of using content analysis to categorize the study objectives and to group them by category. |
2.1. Literature Search Strategy
A comprehensive literature search was conducted using databases including Web of Science, PubMed, Embase, Scopus, the Cochrane Library, CNKI, WanFang Database, CBM, and VIP Chinese Scientific Journals Database. Subject headings and free‐text terms were combined to search from database inception through July 15, 2025. Search strategies used structured Boolean logic based on the Population–Intervention framework. Terms for frailty (“frailty,” “frailty syndrome,” “debility”) were combined with terms for gut microbiota–targeted interventions (“probiotics,” “prebiotics,” “inulin,” “fructooligosaccharides,” “fecal microbiota transplantation,” “FMT”) using AND. Synonymous terms within each category were linked with OR. Full search strings for each database are in Supporting Information S1.
2.2. Inclusion and Exclusion Criteria
2.2.1. Inclusion Criteria Were Determined Based on the PCC Principle
Participants—Adults diagnosed as frail using any validated frailty assessment tool (e.g., Fried Frailty Phenotype or FRAIL scale) [14]. Concept—Studies evaluating targeted microbiome interventions (e.g., single‐strain probiotics, prebiotics, synbiotics, or FMT) and their effects on frailty status, gut microbiome features, or physical function. Context—Trials conducted in hospitals, community health centers, long‐term care facilities, or home‐based settings, without restrictions on intervention parameters or comparator type. Exclusion criteria were as follows: (1) studies in which the primary intervention was antibiotic‐based or involved combined interventions that precluded isolation of microbiome‐specific effects; (2) review articles, conference abstracts, case reports, editorials, and opinion pieces; (3) studies not published in English or Chinese; (4) studies with incomplete outcome data that hindered meaningful data extraction; (5) duplicate publications or studies for which the full text was unavailable.
2.3. Data Collection and Analysis
After importing records into EndNote 20, duplicates were removed via automated detection, followed by manual verification by two reviewers (JYZ and LLY); disagreements were resolved by consensus or by a third reviewer (HC). For data extraction, a standardized, pilot‐tested form was used. Two reviewers independently extracted key details—including first author, publication year, country, study design, sample size, intervention characteristics, frailty assessment tools, outcomes, and other relevant parameters—and resolved discrepancies through discussion; unresolved disagreements were adjudicated by HC. Final data were synthesized and tabulated for analysis.
Given the heterogeneity of frailty assessment tools across studies, we classified frailty into three ordinal categories—non‐frail, pre‐frail, and frail—based on each study's reported severity level. For studies using continuous scores, we applied the original authors' cut‐offs to assign categories.
2.4. Bibliometric Analysis and Data Extraction
For bibliometric analysis, we searched the Web of Science Core Collection up to September 16, 2025, using a Boolean strategy: frailty‐related terms in the title field and microbiota‐related terms in the topic field. The full search string and detailed inclusion/exclusion criteria are provided in Supporting Information S2.
After selecting the included articles, data from the Web of Science (WoS) were first exported in tab‐delimited format and then imported into Microsoft Excel 2019 for preliminary organization. A total of 421 articles were retrieved from the Web of Science Core Collection. Of these, 21—reviews, meeting abstracts, editorials, and book chapters—were excluded by document type; no duplicates were found. The remaining 400 underwent full‐text screening: 42 were excluded (32 irrelevant to the topic; 10 lacking interventions), leaving 358 for bibliometric analysis. Full bibliographic records were exported as plain text (.txt) and imported into VOSviewer and CiteSpace.
Before keyword co‐occurrence analysis, synonymous terms were harmonized to a single canonical term using a predefined synonym mapping table (Supporting Information S3). Co‐occurrence analyses of authors, institutions, and countries were conducted using VOSviewer with full counting [13, 15]. CiteSpace was employed for keyword clustering, timeline visualization, and detection of emerging research hotspots.
Bibliometric analysis objectively identifies hotspots and trends at the field level; conversely, a scoping review contextualizes these patterns through qualitative assessments of research design and clinical validation. This dual approach ensures both macro‐trend detection and micro‐evidence evaluation [11]. Full parameter settings for VOSviewer and CiteSpace are provided in Supporting Information S2.
3. Results
3.1. Description of Studies
A total of 3216 relevant articles were identified through the comprehensive literature search. After deduplication and initial screening based on titles and abstracts, followed by a full‐text review for further screening, 10 studies were ultimately included in this review. Among these, 2 articles were in Chinese and 8 were in English. The process and results of the literature selection are illustrated in Figure 1.
FIGURE 1.
Flow diagram of the systematic review process.
The Web of Science database was searched through September 16, 2025, yielding a total of 421 publications; notably, the number of publications has increased year‐on‐year since 2016. The bibliometric analysis workflow is illustrated in Figure S1.
3.2. Data Charting
In the scope review, we combined narrative synthesis with bibliometric analysis to improve the comprehensiveness and objectivity of our findings [11]. The narrative review strategy involves systematically summarizing and synthesizing selected literature to identify and describe central themes or concepts descriptively. In contrast, co‐occurrence keyword analysis adopts a quantitative approach to analyze patterns of term co‐occurrence within the same corpus, enabling the detection of latent patterns, thematic clusters, and underlying relationships that may not be easily discernible through traditional narrative synthesis.
3.3. Basic Characteristics of Included Literature
A total of 10 studies were included in the scope review, with publication dates ranging from 2013 to 2025. The countries of publication are as follows: China (n = 2), Spain (n = 3), the Netherlands (n = 1), Italy (n = 1), Ireland (n = 1), and Brazil (n = 1). The sample sizes of the included studies varied from 17 to 200 participants. The interventions encompassed fecal microbiota transplantation (FMT), synbiotics, prebiotics, probiotics, and their composite formulations, with intervention durations ranging from 4 weeks to 6 months. Assessment of frailty primarily utilized the Fried Frailty Phenotype, followed by individual components related to Fried's criteria, the Clinical Frailty Scale (CFS), the Frailty Index (FI), and the Tilburg Frailty Indicator (TFI). The basic characteristics of the included literature are presented in Table S1. Among the 421 articles retrieved from the Web of Science (WoS) database, a marked increase in publications on the association between frailty and the gut microbiota has been observed since 2016; further details regarding this trend are presented in Figure 2.
FIGURE 2.
Publication output related to frailty and gut microbiota research by year from 2010 to 2025.
3.4. Authors and Institutions
The results of the bibliometric analysis are summarized as follows. The top three authors by publication volume are O'Toole, Paul W. (14 publications), Ticinesi, Andrea (12 publications), and Meschi, Tiziana (10 publications), with Nouvenne, Antonio also included in this group but without significant centrality. The ranking of the top 10 authors can be found in Table S2. The five countries with the highest number of publications are China (78 articles), the United States (77 articles), Italy (69 articles), the United Kingdom (32 articles), and Japan (24 articles). Centrality analysis revealed China, the United States, and Italy as the most central nodes in the network. The countries ranked by centrality are China (0.18), the United States (0.18), and Italy (0.16). Notably, Italy's institutional network is especially integrated—four of the top five institutions are based there. The ranking of the top ten countries is available in Table S3. In terms of institutional analysis, the institutions with the highest publication volumes are Univ Parma (14 publications), Univ Bologna (13 publications), Univ Coll Cork (13 publications), and Univ Milan (11 publications). The ranking of the top 10 institutions can be found in Table S4.
3.5. Keyword Analysis
Keyword analysis was conducted using “Keyword” as the node, resulting in a visualization map, as shown in Figure 3. The top 10 keywords identified are gut microbiota, frailty, aging, inflammation, sarcopenia, older individuals, probiotics, diet, nutrition, and dysbiosis. In the keyword emergence analysis, “fecal microbiota” exhibited the longest emergence duration; among the thematic keywords, “intestinal microbiota” was identified as such, while “oxidative stress” demonstrated the highest emergence intensity. The most recently emerged keyword was “risk.” The top six keywords from the emergence analysis are presented in Figure 4. Additional visualizations are provided in the Supporting Information: keyword clustering (seven clusters, Figure S2), VOSviewer heatmap (Figure S3), timeline view (Figure S4), and thematic mapping (Figure S5).
FIGURE 3.
Overlay visualization of keywords.
FIGURE 4.
Top six keywords with strong citation bursts between 2010 and 2025.
3.6. Effects of Microbiota‐Targeted Interventions on Frailty
Several trials demonstrate that specific prebiotic or synbiotic formulations can modify frailty status. A combination of inulin and oligofructose (15 g/d) administered over 12–13 weeks significantly reduced Fried frailty scores and Frailty Index while improving grip strength and walking speed, particularly in individuals with higher baseline frailty [16, 17, 18]. These benefits were linked metagenomically to enriched microbial pathways for fatty acid and butanoate metabolism [18]. In contrast, interventions using galacto‐oligosaccharides or certain synbiotics showed no significant effects on frailty or functional outcomes [19, 20].
More complex, multi‐modal regimens have also been explored. In frail older adults with cognitive impairment, probiotics combined with cholinesterase inhibitors improved frailty scores, nutritional markers, and inflammatory profiles, though concomitant nutritional and exercise support complicates attribution of effects solely to probiotics [21, 22]. Similarly, a combined intervention of prebiotic‐fortified high‐protein supplements and structured exercise improved physical performance and nutritional status, with benefits accentuated in frailer participants [23]. In the cohort reported by [24], the success rate of FMT for Clostridioides difficile infection was lower among severely frail patients (CFS ≥ 7) than among less frail individuals.
3.7. The Impact of Targeted Microbiota Intervention on Gut Microbiota
Among the 10 included studies, three assessed changes in α/β diversity. One prebiotic trial found no significant change in α diversity, though β diversity differed significantly on principal coordinate analysis [18]. Another study reported that GOS slightly reduced overall α diversity, possibly due to selective promotion of Bifidobacterium [19]. A large cross‐sectional study (n = 1551) further revealed that higher Fried frailty scores were associated with lower baseline α diversity, suggesting that reduced microbial diversity may characterize frailty [25]. Both prebiotic and synbiotic interventions consistently increased the abundance of Bifidobacterium [18]. Species‐level analysis revealed that B. adolescentis was significantly enriched in the pre‐frailty group, while B. pseudocatenulatum and Escherichia coli increased in the frail group, indicating strain‐specific responses at different stages of frailty [18]. In a 26‐week prebiotic intervention trial that detected no significant change in overall microbial diversity, there was a significant increase in SCFA‐producing bacteria, including members of the family Ruminococcaceae and the genus Prevotella, accompanied by decreased serum CXCL11 levels [26]. While this association is consistent with the immunomodulatory effects of SCFAs, it should be interpreted cautiously, as multiple factors beyond microbial metabolites may contribute to the observed changes in CXCL11.
4. Discussion
This review synthesizes evidence from 10 interventional studies and integrates bibliometric analysis of 358 publications to evaluate the role of gut microbiota modulation in frailty. Collectively, the findings indicate that interventions such as probiotics, prebiotics, and synbiotics can significantly improve key physical frailty components [18], although the evidence is strongest for multi‐strain probiotics, prebiotic effects have been more variable and largely observed in populations with higher baseline frailty. The observed associations appeared more pronounced in individuals with higher baseline frailty or in early stages, underscoring the importance of intervention timing [19, 26]. Synergistic improvements in cognition and inflammation with probiotic‐cholinesterase inhibitor co‐administration provide clinical support for the gut‐brain‐muscle axis [21, 22]. However, the host's physiological reserve may limit efficacy, as seen with reduced benefits of fecal microbiota transplantation (FMT) in severe frailty (CFS ≥ 7) [24].
Mechanistically, interventions are linked to selective increases in beneficial taxa (e.g., Bifidobacterium spp.) and short‐chain fatty acid production [27], yet their impact on overall microbial diversity and systemic inflammation remains limited [19, 26]. This suggests that singular microbial modulation is insufficient for this multifactorial syndrome. Therefore, it is essential to consider the roles of multiple microbial communities and conduct further research to explore the complex regulatory effects of prebiotics and probiotics on the immune system [28].
Bibliometric clustering also identifies fecal microbiota transplantation as a therapeutic theme, suggesting ongoing efforts to intervene in frailty by modulating the gut microbiota. Personalized microbiome modulation strategies may be more effective than singular prebiotic interventions; thus, when designing intervention programs for frail older adults, considering individual differences alongside other intervention measures could enhance effectiveness [29, 30]. Substantial heterogeneity in intervention protocols, frailty assessment tools, and study populations [31], often with small sample sizes and inadequate control for confounders [32, 33]—hinders comparability. This highlights the critical need to employ standardized and psychometrically validated instruments to ensure the reliability and reproducibility of findings across diverse populations and settings [34]. Safety data for supplements are generally reassuring but short‐term; long‐term safety of FMT in frail, multimorbid older adults requires further evaluation [23, 35].
Bibliometric analysis reveals an evolving field, shifting from descriptive correlation to integrated mechanistic and translational research. This shift is likely associated with advances in high‐throughput sequencing and wider availability of multi‐omics tools. The sustained burst of “fecal microbiota” and the high‐intensity burst of “oxidative stress” indicate that gut microbial ecology and redox biology have remained central to frailty research over an extended period—likely owing to their mechanistic links to inflammaging and mitochondrial dysfunction. In contrast, the recent emergence of “risk” as a keyword reflects a growing emphasis on clinical translation and preventive strategies. The collaboration network shows a multipolar structure, with China, the United States, and Italy as the main hubs. Their high centrality scores reflect both strong publication output and a bridging role between research communities. Italy's concentration of top institutions suggests a well‐connected domestic network that supports coordinated research and resource sharing. Key themes include the metabolism‐inflammation axis, direct interventions like FMT, and risk prediction models. Despite these promising findings, infection risks and benefit durability require validation in well‐designed, long‐term, controlled trials before FMT can be established as a definitive frailty intervention [36]. Future work should prioritize standardized assessments, integrated multi‐omics to decode patient‐specific dysbiosis [37, 38], and stratified management—from prevention in pre‐frail adults to combined nutrition‐exercise‐microbiome interventions in overt frailty [39]. Ultimately, long‐term RCTs in diverse populations are essential to translate these insights into clinical practice [40].
5. Limitation
A limitation is the absence of formal quality appraisal; our findings are descriptive and do not constitute a definitive assessment of efficacy. Another limitation is the heterogeneity of frailty assessment tools and intervention protocols across studies. Although we harmonized frailty status into a three‐tier framework, comparability across studies may still be limited [31]; we therefore did not pool results across intervention categories. These caveats highlight the critical need for standardized assessment tools and rigorous, formal evidence appraisal in future research [34]. A distinct methodological limitation pertains to the bibliometric analysis: the use of a single database may have introduced coverage bias, as relevant publications indexed only in Scopus, Dimensions, or other regional databases could have been missed. In addition, the absence of ORCID‐based author disambiguation may have introduced bias stemming from unresolved name ambiguity.
6. Conclusion
The interplay between gut microbiota and frailty represents a promising frontier in geriatric and metabolic research. Current evidence indicates associations between microbiota‐targeted interventions—including prebiotics, probiotics, and fecal microbiota transplantation—and improvements in physical function, nutritional status, and cognitive performance among frail older adults [16, 21]. However, mechanisms differ markedly by intervention type: Prebiotics act mainly by enriching SCFA‐producing bacteria and their immunomodulatory effects [41]; probiotics exert their primary effects through direct host–microbe interactions and enhancement of intestinal barrier function [42]; FMT mediates its therapeutic benefits predominantly via broad‐scale restructuring of the gut microbial community and restoration of colonization resistance [43]. Nevertheless, the underlying biological mechanisms remain incompletely characterized for all three interventions. Definitive conclusions are constrained by heterogeneity in study designs, small sample sizes, and the absence of standardized assessment protocols. Future research must prioritize large‐scale, mechanism‐guided, prospective clinical trials to establish optimal strategies and ensure long‐term safety. Integrating multi‐omics technologies within interdisciplinary frameworks will be essential to developing precise, effective interventions aimed at mitigating frailty and supporting healthy aging.
Author Contributions
Yuanzhuo Jiao: conceptualization, methodology, data curation, formal analysis, writing – original draft, writing – review and editing. Lingyun Li: writing – review and editing, validation. Xinxin Ji: data curation, formal analysis. Hui Cheng: supervision, project administration.
Funding
This work was supported by the National Natural Science Foundation of China (Youth Science Fund Project, Grant No. 82301786).
Ethics Statement
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Data S1: Supporting Information 1.
Data S2: Supporting Information 2.
Data S3: Supporting Information 3.
Data S4: Supporting Information 4.
Data S1: Supporting Information.
S1 Figure. Flowchart of study selection for bibliometric analysis.
S2 Figure. Cluster analysis of co‐occurring keywords generated by CiteSpace.
S3 Figure. Density visualization of keywords.
S4 Figure. Timeline visualization of co‐citation cluster evolution.
S5 Figure. Bibliometric analysis of thematic maps relating to frailty and gut microbiota.
S1 Table. Characteristics of included reviews.
S2 Table. The ranking of the top ten authors.
S3 Table. The ranking of the top ten countries.
S4 Table. The ranking of the top ten institutions.
S5 Table. The ranking of the top ten keywords.
S6 Table. The ranking of the top ten journals.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Youth Science Fund Project, Grant No. 82301786).
Data Availability Statement
The data that supports the findings of this study are available in the Supporting Information of this article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1: Supporting Information 1.
Data S2: Supporting Information 2.
Data S3: Supporting Information 3.
Data S4: Supporting Information 4.
Data S1: Supporting Information.
S1 Figure. Flowchart of study selection for bibliometric analysis.
S2 Figure. Cluster analysis of co‐occurring keywords generated by CiteSpace.
S3 Figure. Density visualization of keywords.
S4 Figure. Timeline visualization of co‐citation cluster evolution.
S5 Figure. Bibliometric analysis of thematic maps relating to frailty and gut microbiota.
S1 Table. Characteristics of included reviews.
S2 Table. The ranking of the top ten authors.
S3 Table. The ranking of the top ten countries.
S4 Table. The ranking of the top ten institutions.
S5 Table. The ranking of the top ten keywords.
S6 Table. The ranking of the top ten journals.
Data Availability Statement
The data that supports the findings of this study are available in the Supporting Information of this article.