Clinical landscape of gut microbiota modulators in cardiovascular disease therapy: Current status and future perspectives

Dear Editor,

Cardiovascular disease (CVD) remains a leading cause of global morbidity and mortality, with persistent residual risk despite therapeutic advances. The gut microbiota influences host metabolism, immunity, and vascular function via metabolites such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs) playing a key role in CVD pathogenesis [1]. Interventions like probiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation (FMT), and microbiota-targeting agents show promise but require rigorous clinical evaluation. This article systematically analyzes the clinical trial landscape of gut microbiota modulators in CVD therapy, covering geographic distribution, trends, trial phases, intervention types, and therapeutic targets.

Data were sourced from the Trialtrove database, which integrates major clinical trial registries including ClinicalTrials.gov, the EU Clinical Trials Register, and selected national registries, providing structured trial metadata. The search cutoff date was March 15, 2026, combining gut microbiota-related terms (e.g., “probiotics", “FMT") with the therapeutic area “Cardiovascular". Interventional trials (any CVD subtype) were included; observational studies and those missing key information were excluded. Two independent investigators extracted and cross-checked data, standardizing unstructured information. Analysis indicators included geographical location, trial phase, recruitment status, sponsor type, intervention, CVD subtype, primary endpoint, and participant demographics. Multi-field cross-validation mitigated registry limitations (e.g., underreporting of negative results, heterogeneity in endpoint definitions), ensuring reliability of trend conclusions.

A total of 90 interventional trials were included. Global distribution: China ranked first (n = 30), followed by Canada, Iran, and Brazil (n = 5 each), with fewer trials in South Korea, the United States, and others (Fig. 1A and B). Temporal trends: gradual increase from 2008, peaking during 2018–2022. Most trials were early-phase (Phase I/II), with fewer Phase III/IV trials (Fig. 1C). The chord diagram showed that completed trials were predominantly late-phase, whereas ongoing and planned trials were mostly early-phase (Fig. 1D). Sponsor types: academic institutions accounted for 76.3%, government 11.3%, industry 6.2%, and others in descending order (Fig. 1E). Intervention diversity: probiotics were most common (27 trials), followed by inulin, nutritional supplements, FMT, and combination interventions (Fig. 1F–Supplementary Table 1). CVD subtypes: hyperlipidemia (n = 55) and hypertension (n = 21) were most frequently studied, with fewer trials on coronary artery disease, heart failure, etc. (Fig. 1G). Primary endpoints: serum lipids (n = 34), LDL-C (n = 24), triglycerides (n = 17), total cholesterol (n = 15), HDL (n = 14), gut microbiota composition (n = 13), CRP (n = 12), and composite lipid indices (n = 12) (Fig. 1H). Demographic characteristics indicated that trials predominantly enrolled adults and older adults (n = 82), with limited pediatric enrollment (n = 3) and 5 mixed-age studies; most trials included both sexes, with a few single-sex studies (Table 1). Outcome reporting: 16 trials met primary endpoints, 15 completed but results unknown, 3 did not achieve primary endpoints, 7 planned but not initiated, and 48 had not disclosed results (Supplementary Table 2).

Fig. 1.

Overview of clinical trials on gut microbiota modulators for cardiovascular disease (CVD). (A, B) Global geographic distribution; (C) Distribution of trial phases; (D) Relationship between trial phase and recruitment status; (E) Composition of sponsor types; (F) Diversity of intervention types; (G) Number of studies by CVD subtype; (H) Distribution of primary endpoint types.

Table 1.

Sex and age distribution of participants across included clinical trials.

	Adults	Adults; Older Adults	Children	Children; Adults	Children; Adults; Older Adults	Older Adults	Unspecified	Total
Both	34	43	3	1	1	1	0	82
Male	1	1	0	0	0	0	0	2
Female	0	1	0	0	0	0	0	1
N/A	1	1	0	0	1	0	1	5
Total	36	46	3	1	2	1	1	90

The clinical trial landscape of gut microbiota modulators in CVD illustrates both promise and ongoing translational challenges. The dominance of Chinese academic centers underscores strong research interest, while the limited number of late-phase trials reflects the early developmental stage of this field. Notably, the predominance of early-phase trials and biomarker-based endpoints aligns with our results, indicating a logical progression from safety and mechanistic exploration toward potential efficacy evaluation. This continuity between results and discussion underscores a coherent translational trajectory.

Mechanistically, preliminary outcomes suggest modulation of lipid profiles and inflammatory biomarkers, consistent with preclinical evidence indicating TMAO reduction, SCFA-mediated anti-inflammatory effects, and improved endothelial function [2]. However, heterogeneity in intervention type, dosing, delivery route, and endpoint selection complicates cross-trial comparison and regulatory assessment. While FDA, EMA, and NMPA guidance exists for live biotherapeutic products, disease-specific frameworks for CVD remain limited [3].

Patient heterogeneity further complicates translation, as individual microbiota composition may significantly influence therapeutic response. Precision approaches incorporating AI-driven stratification, multi-omics profiling, and predictive biomarkers could enhance trial efficiency and optimize patient selection. Practical considerations, including formulation stability, microbial viability, and delivery efficiency, remain critical; emerging solutions involve encapsulation, nanocarrier systems, and genetically engineered probiotics [4].

Recent preclinical studies support innovative strategies such as synbiotic cocktails, metabolite-targeted inhibitors, and engineered probiotic strains designed to optimize metabolite production and host response. These approaches provide a conceptual bridge between the early mechanistic findings reported in our results and the potential for clinically meaningful outcomes. Future trials should prioritize multicenter randomized designs with standardized interventions, rigorous endpoint definitions, and long-term follow-up. Cross-disciplinary collaboration across cardiology, microbiology, pharmacology, bioengineering, and computational modeling will be essential to overcome translational barriers and accelerate regulatory approval pathways [5].

In conclusion, CVD trials of gut microbiota modulators are predominantly academic, targeting hyperlipidemia/hypertension with probiotics/prebiotics. While biomarker benefits are suggested, clinical efficacy remains unproven. Large-scale, standardized, multicenter RCTs with precision and multi-omics approaches are required for translation.

Authors' statement

The work has not been published previously and it is not under consideration for publication elsewhere.

Data availability

This study is based on publicly available databases and therefore does not require any ethics statement.

Funding

None.

CRediT authorship contribution statement

Rengyun Xiang: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Yaqun Tang: Data curation, Visualization, Writing – review & editing. Bin Cao: Conceptualization, Project administration, Writing – review & editing.

Declaration of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

Appendix A. Supplementary data

The following is the Supplementary data to this article: