We have thoroughly reviewed and understood the requirements of the 2025 TITAN Guidelines. During the research and writing of this paper, we did not utilize any AI tools[1].
Gut microbes open new avenues for kidney disease treatment through the “gut-kidney axis’[2]. Among these biomarkers, Gemmiger was associated with multiple metabolic pathways and showed a negative correlation with the urinary protein-to-creatinine ratio (uPCR) and the urinary albumin-to-creatinine ratio (uACR), suggesting a possible renoprotective role[3]. A study involving 480 patients with stage 1-5 chronic kidney disease (CKD) identified a strong positive correlation between the abundance of Lactobacillus johnsonii and renal function, as determined through macrogenomic analysis. Animal experiments partially confirmed that targeted probiotics (e.g., Lactobacillus rhamnosus) could restore intestinal homeostasis and improve renal histopathology in a chronic renal failure model[4]. Although clinical evidence supports the importance of gut microbes in kidney disease, the long-term safety of probiotics or fecal microbiota transplantation, as well as the optimal dosage and timing for modulating flora, still needs to be validated in large-scale clinical trials[5]. Furthermore, it is critical to balance the synergistic effects of gut microbes” modulation with existing therapies (e.g., RAS inhibitors, SGLT2 inhibitors)[6].
To facilitate the translation of these promising preclinical results into clinical practice, it is essential to assess the status of clinical trials investigating the efficacy and safety of modulating gut microbes. We systematically collected high-quality information on the progress of clinical trials on intestinal flora by consulting the Trialtrove database (https://citeline.informa.com/trials/results) using the keywords’ Mechanism of Action: Microbiome Modulator’ and ‘Disease: Renal Disease.’ The search was conducted up to 17 February 2025, and a total of 46 clinical trials related to renal disease were included in the analysis after excluding trials with unknown trial stages, diseases treated, and incompatible therapeutic agents. The data obtained included drug names, types, proportions, clinical trial phases, clinical indications, and other relevant clinical information and trends. These data were used to assess the global trend of clinical trials in the field of intestinal flora in renal disease.
HIGHLIGHTS
A global analysis of 46 clinical trials reveals the research landscape and trends in gut microbiota-based therapies for nephropathy.
In 2024, the initiation of trials in this field peaked, accounting for 18.6%, with China leading globally at 30%, reflecting regional research focus differences.
Probiotic therapy is the mainstay, with multi-strain probiotic trials mostly in phase Ⅳ. Emerging approaches like precision microbiota transplantation and synbiotics are in early-stage trials.
Some completed trials show promise; for instance, a phase Ⅳ trial indicates a probiotic combination improves multiple indicators and quality of life in patients with stage 3–4 chronic kidney disease. However, challenges like unclear mechanisms and a lack of large-scale, long-term RCTs remain.
The analysis of the 46 clinical trials revealed several important insights. Clinical trials in the field of gut microbes for renal diseases began in 2011, with the highest number (18.6%) initiated in 2024. Geographically, China accounted for 30% of the global clinical trials (Fig. 1), highlighting the regional prioritization of microbiome renal protection strategies. Probiotic therapies were the primary agents tested in 71.7% of trials, followed by fecal bacterial therapies (15.2%). The majority of trials testing predominantly multi-strain probiotic combinations (67.4%) were in Phase IV. In contrast, emerging therapies, such as precision flora transplantation and synbiotics, were in the early stages of clinical trials (Phases I, I/II, and II) in 19.6% of the trials. Regarding trial status, 45.7% of trials have been completed, and 23.9% are in the planning stage. The studies involved patient stratification, with a current focus on advanced CKD stage 3-4 (19.6%), diabetic nephropathy (10.9%), and type 2 diabetic nephropathy (10.9%) (Table 1). In terms of trial results, 38.5% of completed trials reported positive results, indicating early efficacy signals (Table 2).
Figure 1.
A. map of the world distribution of participating countries. b. clinical trial status of gut microbiota; c. primary tested drug counts by patient segment.
Table 1.
Research Table on the Application of Registered Gut Microbiota in Renal Diseases
| Characteristic | N = 461 |
|---|---|
| Trial Phase | |
| I | 1 (2.2%) |
| I/II | 3 (6.5%) |
| II | 5 (10.9%) |
| II/III | 3 (6.5%) |
| III | 2 (4.3%) |
| III/IV | 1 (2.2%) |
| IV | 31 (67.4%) |
| Trial Status | |
| Planned | 11 (23.9%) |
| Open | 9 (19.6%) |
| Completed | 21 (45.7%) |
| Temporarily Closed | 2 (4.3%) |
| Closed | 3 (6.5%) |
| Patient Segment | |
| CKD (Unavailable stage) | 3 (6.5%) |
| CKD stage 1-3 | 2 (4.3%) |
| CKD stage 2-3 | 2 (4.3%) |
| CKD stage 3-4 | 9 (19.6%) |
| CKD stage 3-5 | 2 (4.3%) |
| CKD stage 4 | 4 (8.7%) |
| End-Stage Renal Disease | 1 (2.2%) |
| Non-dialysis CKD | 1 (2.2%) |
| Hemodialysis Patients | 4 (8.7%) |
| automated peritoneal dialysis | 2 (4.3%) |
| Diabetic Nephropathy | 5 (10.9%) |
| type 2 diabetic nephropathy | 5 (10.9%) |
| CKD Patients With Peripheral Arterial Disease | 1 (2.2%) |
| Autosomal dominant (ADPKD) | 1 (2.2%) |
| IgA Nephropathy | 2 (4.3%) |
| Diabetic Nephropathy or Hypertensive Nephropathy | 1 (2.2%) |
| sepsis-induced AKI | 1 (2.2%) |
| Primary Tested Drug | |
| probiotic therapy | 33 (71.7%) |
| fecal bacteriotherapy | 7 (15.2%) |
| Lactobacillus rhamnosus GG | 1 (2.2%) |
| BM-306 | 1 (2.2%) |
| KT-301 | 2 (4.3%) |
| Lobun forte | 1 (2.2%) |
| synbiotics | 1 (2.2%) |
| Start Date | |
| 2011 | 1 (2.3%) |
| 2013 | 1 (2.3%) |
| 2015 | 1 (2.3%) |
| 2017 | 6 (14.0%) |
| 2018 | 4 (9.3%) |
| 2019 | 3 (7.0%) |
| 2020 | 3 (7.0%) |
| 2021 | 5 (11.6%) |
| 2022 | 6 (14.0%) |
| 2023 | 5 (11.6%) |
| 2024 | 8 (18.6%) |
| Countries | |
| Mexico | 4 (8.0%) |
| China | 15 (30.0%) |
| Taiwan | 7 (14.0%) |
| Thailand | 1 (2.0%) |
| India | 4 (8.0%) |
| Japan | 2 (4.0%) |
| Iraq | 1 (2.0%) |
| Argentina | 2 (4.0%) |
| Germany | 1 (2.0%) |
| Iran | 3 (6.0%) |
| Canada | 1 (2.0%) |
| Australia | 2 (4.0%) |
| Italy | 1 (2.0%) |
| United States | 3 (6.0%) |
| Brazil | 2 (4.0%) |
| Sweden | 1 (2.0%) |
| Trial Outcomes | |
| Positive outcome | 5 (38.5%) |
| Early positive outcome | 1 (7.7%) |
| Negative outcome | 2 (15.4%) |
| Outcome indeterminate | 1 (7.7%) |
| Outcome unknown | 4 (30.8%) |
| 1n (%) | |
Table 2.
Results of Positive Experiments Obtained
| Trial ID | Trial Phase | Trial Status | Patient Segment | Primary Tested Drug | Start Date | Countries |
|---|---|---|---|---|---|---|
| TrialTroveID-540 993 | II | Completed | CKD stage 3-5 | Lactobacillus rhamnosus GG | 2022 | Thailand |
| TrialTroveID-372 881 | IV | Completed | Diabetic Nephropathy or Hypertensive Nephropathy | fecal bacteriotherapy | 2018 | Mexico |
| TrialTroveID-363 774 | IV | Completed | CKD stage 4 | probiotic therapy | 2017 | Italy |
| TrialTroveID-359 216 | IV | Completed | CKD stage 3-4 | Lobun forte | 2019 | India |
| TrialTroveID-311 543 | I/II | Completed | Hemodialysis Patients | synbiotics | 2017 | Iran |
One Phase IV trial (TrialTroveID-359216) demonstrated that the probiotic combinations LobunForte and Renadyl effectively modulated uremic toxins, renal parameters, inflammatory biomarkers, oxidative biomarkers, and eGFR, thereby improving the quality of life in patients with stage 3-4 CKD[7]. Additionally, CKD patients experienced less disease progression after receiving fecal microbial transplantation[8]. Considering the current state of clinical research, intestinal flora modulation, while showing potential in the treatment of renal disease, still faces numerous challenges. Firstly, the elucidation of mechanisms is insufficient, and most trials lack integrated metabolomic and immunohistochemical analyses, making it difficult to establish a clear causal relationship between flora modulation and therapeutic efficacy. Moreover, most current clinical trials are small-scale and short-term, and there is a lack of large-scale, long-term randomized controlled trials to verify their effectiveness and safety.
Footnotes
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Published online 5 June 2025
Ethical approval
Not applicable.
Consent
Not applicable.
Sources of funding
This work was supported by a grant from Reserve Talents Project for Young and Middle-aged Academic and Technical Leaders of Yunnan Province (Project Number: 202205AC160062), Yunnan Key Laboratory of Organ Transplantation (202449CE340016), “ChengFeng” Talent Training Project for Young and Middle-aged Academic Leaders and Reserve Talents of Kunming Medical University, and First-Class Discipline Team of Kunming Medical University (Project Number: 2024XKTDPY03).Yunnan Provincial Education Department Scientific Research Fund Project (Project Number: 2024Y229), Innovation Fund for Postgraduate Education of Kunming Medical University (Project Number: 2024S069).
Author contributions
L.S. and W.F. contributed to the design, production and editing of the manuscript. C.L. contributed to the data analysis.
Conflicts of interest disclosure
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Research registration unique identifying number (UIN)
Not applicable.
Guarantor
Wenxing Fan.
Provenance and peer review
Not commissioned, externally peer-reviewed
Data availability statement
Data is openly available in a public repository that does not issue Digital Object Identifiers (DOIs). The data that support the findings of this study are openly available in [Focusing on the gut-kidney axis: the global clinical landscape of gut microbial therapy for kidney disease] at [https://osf.io/v7kyu/?view_only=0132d85116b54f17b79a9dc68ad72d36].
References
- [1].Agha R, Mathew G, Rashid R, et al. Transparency in the reporting of artificial intelligence – the TITAN guideline. PREprints 2025;10:100082. [Google Scholar]
- [2].Cheung CK, Alexander S, Reich HN, Selvaskandan H, Zhang H, Barratt J. The pathogenesis of IgA nephropathy and implications for treatment. Nat Rev Nephrol 2025;21:9–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Wu I-W, Liao Y-C, Tsai T-H, et al. Machine-learning assisted discovery unveils novel interplay between gut microbiota and host metabolic disturbance in diabetic kidney disease. Gut Microbes 2025; 17:2473506. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Miao H, Liu F, Wang Y-n, et al. Targeting lactobacillus johnsonii to reverse chronic kidney disease. Sig Transduct Tgt Therapy 2024; 9:195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [5].Qin L, Fan B, Zhou Y, et al. Targeted gut microbiome therapy: applications and prospects of probiotics, fecal microbiota transplantation and natural products in the management of type 2 diabetes. Pharmacol Res 2025;213:107625. [DOI] [PubMed] [Google Scholar]
- [6].Blum MF, Neuen BL, Grams ME. Risk-directed management of chronic kidney disease. Nat Rev Nephrol 2025;21:287–98. [DOI] [PubMed] [Google Scholar]
- [7].Kalidindi RK, Reddy P, Kishan P, Kompella P. The efficacy and safety of probiotic combinations lobun forte® versus renadyl® in patients with chronic kidney disease: a comparative, phase iv, randomized, open-label, active-controlled, parallel study. Cureus 2024;16:e67987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].Arteaga-muller GY, Flores-treviño S, Bocanegra-ibarias P, et al. Changes in the progression of chronic kidney disease in patients undergoing fecal microbiota transplantation. Nutr 2024;16:1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data is openly available in a public repository that does not issue Digital Object Identifiers (DOIs). The data that support the findings of this study are openly available in [Focusing on the gut-kidney axis: the global clinical landscape of gut microbial therapy for kidney disease] at [https://osf.io/v7kyu/?view_only=0132d85116b54f17b79a9dc68ad72d36].