Global clinical trial landscape of microbiome modulator therapy in sepsis: gut microbiota interventions and challenges

Introduction Sepsis, a life-threatening condition characterized by a dysregulated host response to infection, remains a significant global health burden[1]. Despite advances in critical care and antimicrobial therapy, sepsis continues to be associated with high morbidity and mortality rates, particularly in vulnerable populations such as the elderly and immunocompromised individuals. Current therapeutic strategies, including antibiotics, fluid resuscitation, and vasopressors, often fail to address the underlying pathophysiology of sepsis, leaving an unmet clinical need for innovative treatments[2]. The human microbiome, particularly the gut microbiota, has emerged as a critical player in modulating immune responses and maintaining homeostasis. Dysbiosis, or the imbalance of microbial communities, has been implicated in the pathogenesis of sepsis, contributing to systemic inflammation, immune dysfunction, and organ failure. Microbiome modulator therapy, which aims to restore microbial balance and enhance host immunity, represents a promising therapeutic avenue[3]. This approach includes interventions such as probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), and targeted microbial metabolites. Despite the growing interest in microbiome-based therapies for sepsis, a comprehensive analysis of the clinical trial landscape in this field is lacking. This research letter aims to provide an in-depth analysis of ongoing and completed clinical trials evaluating microbiome modulator therapy for sepsis, highlighting trends, challenges, and future directions. By doing so, we hope to inform researchers, clinicians, and policymakers about the potential of this novel therapeutic strategy to address the unmet needs in sepsis management. Methods A total of 112 eligible Sepsis and Microbiome modulator clinical trials were retrieved from the Trialtrove database as of June 14, 2025 (https://citeline.informa.com). Key metrics analyzed included treatment category (Microbiome modulator), trial Phase, trial status, and geographic distribution. The extracted dataset was cross-validated by at least two independent reviewers to ensure accuracy. This study was conducted without the use of AI tools in any phase, including design, data analysis, and conclusion formulation. In accordance with the TITAN guidelines[4], which provide a framework for transparent AI research reporting, we ensured clarity and accountability throughout the study. Result Global trial volume, developmental stages, and trial status Our analysis identified a total of 112 clinical trials for septic shock registered up to 2025, demonstrating a steady growth trajectory with a notable peak in 2018 (Fig. 1A). This surge is likely attributable to heightened research interest and robust policy support. Phase III and IV trials continue to dominate the landscape, underscoring the sustained emphasis on validating therapeutic efficacy and safety profiles. Concurrently, there has been a marked increase in early-stage (Phase I–II) trials, indicative of a burgeoning focus on therapeutic innovation and the exploration of novel molecular targets (Fig. 1A). In terms of trial status, 73% have successfully reached completion, while 4.5% are currently in the planning phase (Fig. 1B). A significant proportion of these trials are centered on modulating the gut microbiome to enhance clinical outcomes, a strategy that underscores the field’s considerable potential and its advanced readiness for clinical translation. This focus on microbiome modulation reflects a broader trend toward leveraging host-microbe interactions to develop innovative therapeutic interventions for septic shock. Figure1.: Overview of the clinical trial landscape. (A) Phase distribution of clinical trials over different periods; (B) Status distribution of clinical trials; (C) Classification of clinical trials by continents. (D) Classification of clinical trials by countries. Geographical distribution Geographically, North America and Europe continue to dominate clinical trials in septic shock research, accounting for 23 (21%) and 37 (33%) trials, respectively, with Western Europe contributing 34 trials and Eastern Europe 3 trials. This predominance reflects their advanced healthcare infrastructure and substantial research investments. Notably, the Asia-Pacific region is emerging as a rapidly growing research hub, with 34 trials (30%) conducted, primarily driven by significant contributions from China and India. This trend indicates a global shift toward a more equitable distribution of research resources. Additionally, other regions are increasingly engaging in septic shock research, highlighting an expanding global research footprint. Africa has conducted 4 trials (3.6%), South America 2 trials (1.8%), Australia/Oceania 3 trials (2.7%), and West Asia/Middle East 9 trials (8%). This broadening participation underscores the global commitment to addressing septic shock and the diversification of research efforts across different geographical regions (Fig. 1C,D). Microbiome modulators in sepsis treatment We have compiled a comprehensive list of major microbiome modulators under investigation for sepsis treatment. Among these interventions, probiotic supplementation and FMT have emerged as the most extensively studied and clinically promising modalities, accounting for 61% and 12% of the therapeutic approaches, respectively, with a combined representation of 73% (Table 1). This distribution highlights the prevailing emphasis on microbial modulation as a novel therapeutic approach in contemporary sepsis research. Table 1 - The distribution of primary tested drug.. Primary tested drug Number Probiotic therapy 68 Fecal bacteriotherapy 13 Lactic acid bacteria, VSL 6 Prebiotic therapy 4 Lactobacillus rhamnosus GG 4 Undisclosed – antibiotic 2 Probiotic therapy Zinc 1 Probiotic therapy Prebiotic therapy Vancomycin 1 SER-155 Undisclosed – antibiotic 1 Fecal bacteriotherapy Probiotic therapy 1 Prebiotic therapy Probiotic therapy 1 Natural product Probiotic therapy 1 Fecal bacteriotherapy Probiotic therapy 1 Azithromycin (oral), unspecified Prebiotic therapy Nutritional supplement 1 Probiotic therapy Cefotaxime sodium Polymyxin E/gentamicin/amfotericin B paste Nutritional supplement 1 Probiotic therapy Nutritional supplement 1 Prebiotic therapy Methylene blue + phototherapy 1 MaaT-013 1 Lactobacillus rhamnosus GG 1 bifidobacterium infantis, Procter & Gamble Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis, Sigma-Tau 1 fecal microbiota, live-jslm 1 Discussion According to our data analysis, the number of clinical trials for microbiome modulation therapies in sepsis has been steadily increasing worldwide, with a primary focus on North America, Europe, and the Asia-Pacific region. Among these trials, Phase III and Phase IV studies dominate, reflecting the ongoing validation of the efficacy and safety of these therapies. Our research further indicates that probiotics and FMT are the most extensively studied interventions, demonstrating significant potential for immune modulation and clinical improvement. Microbiota modulation therapies, including probiotics and FMT, represent a promising frontier in the treatment of sepsis by regulating the gut microbiota and enhancing immune responses. Probiotics exert their therapeutic effects through multiple mechanisms: they promote the colonization and diversity of beneficial bacterial strains, strengthen intestinal barrier function, and modulate immune regulation[5,6]. In early-stage sepsis patients receiving multi-strain probiotic interventions, although no significant changes in intestinal permeability were observed, levels of endotoxins, endotoxin-binding proteins, and peptidoglycans were markedly elevated, suggesting that probiotics may enhance intestinal immune responses[7]. Furthermore, pediatric patients with severe sepsis demonstrated improved outcomes following probiotic supplementation, including reduced pro-inflammatory cytokine levels, increased anti-inflammatory cytokine levels, and significant improvements in Sequential Organ Failure Assessment (SOFA) scores, highlighting their potential to mitigate inflammation and organ dysfunction[8]. FMT, on the other hand, reshapes the gut microbiota structure, corrects dysbiosis, and activates the cholinergic anti-inflammatory pathway, thereby ameliorating sepsis-associated brain dysfunction and systemic inflammatory responses. In lethal sepsis models, FMT restored host immune function through an interferon regulatory factor 3 (IRF3)-dependent mechanism, enhancing pathogen clearance and reversing disease progression[9]. Furthermore, a pivotal Phase II clinical trial (TrialTroveID-571786) has provided compelling evidence that FMT may exploit bacterial strain competition dynamics to facilitate the decolonization of multidrug-resistant organisms, presenting a novel therapeutic paradigm for sepsis management through modulation of the gut microbiota and subsequent improvement in clinical outcomes[10]. Looking ahead, microbiota modulation therapies represent a transformative frontier in sepsis treatment, offering multifaceted opportunities for innovation and clinical advancement. A deeper understanding of the intricate interplay between gut microbiota and the immune system will not only clarify therapeutic targets but also pave the way for precision medicine. Emerging technologies, such as postbiotics, engineered microbes, and microbiome editing, are poised to revolutionize personalized therapy. For instance, gene-edited probiotics or strain-specific postbiotic formulations could optimize therapeutic efficacy while minimizing adverse effects. Concurrently, the integration of artificial intelligence and big data analytics will enable the identification of optimal microbial combinations and the refinement of treatment protocols, further enhancing therapeutic precision. In the realm of clinical research, future efforts must prioritize large-scale, multicenter, randomized controlled trials to rigorously evaluate the safety and efficacy of probiotics and FMT across diverse sepsis patient populations. Establishing standardized treatment protocols and robust quality control systems will be critical to ensuring the reproducibility and reliability of these interventions. Global collaboration and resource integration will accelerate the clinical translation of these approaches, fostering widespread adoption in sepsis management. Moreover, the potential of microbiota modulation therapies extends beyond standalone applications. Integrating these therapies with complementary modalities, such as immunomodulators or nutritional support, holds promise for synergistic effects that could significantly enhance therapeutic outcomes. While current research predominantly focuses on isolated microbiota interventions, future studies should prioritize combinatorial approaches to maximize clinical efficacy. Additionally, the development of tailored microbiota-based strategies for specific patient subgroups will enable more precise and personalized care, addressing the heterogeneity inherent in sepsis pathology. In summary, microbiota modulation therapies open new horizons for sepsis treatment, offering not only the potential to improve patient outcomes but also the possibility of fundamentally transforming sepsis management. Through continued advancements in basic research, technological innovation, and clinical practice, these therapies are poised to become a cornerstone of sepsis treatment, providing renewed hope and opportunities for patients.