Gut Microbiota Research in Sepsis Reveals New Therapeutic Targets and Biomarkers
A comprehensive bibliometric analysis of research on intestinal microbiota in sepsis has revealed significant growth in scientific interest and identified promising therapeutic targets and diagnostic biomarkers. The analysis, published in Frontiers in Medicine, provides a systematic overview of emerging trends and research hotspots in this rapidly evolving field.
Growing Research Interest in Gut Microbiota and Sepsis
Sepsis, defined as a dysregulated host response to infection leading to life-threatening organ dysfunction, remains a major global health concern with mortality rates of approximately 25% for sepsis and over 40% for septic shock. Despite advances in treatment protocols since the inception of the "Surviving Sepsis Campaign" in 2002, outcomes remain unsatisfactory.
The relationship between intestinal microbiota and sepsis has gained increasing attention since the 1986 hypothesis that the gastrointestinal tract is the initiating organ of multiple organ dysfunction syndrome (MODS). The bibliometric analysis revealed that both publication numbers and citation frequencies in this field have shown a consistent upward trend from 2011 to 2024, with a particularly significant increase in publications between 2019 and 2020.
"Research activity in this field is continuously increasing," the authors noted, with publications in 2023 reaching nearly nine times the number recorded in 2011. Citation frequency has also risen substantially, particularly from 2020 to 2021, demonstrating the growing influence of research in this area.
Key Research Hotspots and Therapeutic Targets
The analysis identified five major research hotspots that represent promising therapeutic targets for sepsis:
1. Lipopolysaccharides (LPS)
LPS, a large glycolipid molecule in the outer membrane of gram-negative bacteria, plays a central role in sepsis pathophysiology. Research on novel therapeutic strategies involving LPS focuses on three main directions:
- In-situ neutralization of LPS to eliminate or mitigate inflammatory responses
- Development of Toll-like receptor-4 (TLR4) and CD14 antagonists
- Investigation of caspase family inhibitors
While some synthetic compounds and natural TLR4 antagonists have failed in clinical trials, research continues on combining sepsis treatment with internal LPS receptor antagonists and neutralizing circulating LPS to enhance effectiveness.
2. Short-Chain Fatty Acids (SCFAs)
SCFAs, common microbial metabolites in the intestines, have demonstrated both anti-inflammatory and immunomodulatory effects. They reduce inflammatory responses by decreasing pro-inflammatory substances and increasing anti-inflammatory substances. Research has shown that SCFAs can:
- Facilitate the translocation of Nrf2 into the nucleus
- Protect cells and enhance angiogenesis
- Decrease inflammatory reactions via the NF-κB pathway
- Control innate immune cell activity and impact T-cell and B-cell development
SCFAs have shown particular promise in treating sepsis-related encephalopathy (SAE) by maintaining SCFA concentration after sepsis onset and as a dietary intervention.
3. Probiotics
Beneficial intestinal microorganisms perform crucial functions including immune regulation, pathogen prevention, and improvement of intestinal barrier function. Multiple randomized controlled trials have shown that probiotic treatment effectively enhances the diversity of fecal bacteria in early sepsis patients. Probiotics can:
- Regulate inflammatory pathways in epithelial and immune cells
- Influence gene expression within the immune system
- Reduce the proportion of NKT cells and inflammatory factors in septic children
- Protect lung function in sepsis patients
However, simultaneous administration of broad-spectrum antibiotics might impede the colonization and positive impacts of probiotics, highlighting the need for further research on specific probiotic strains and combinations.
4. Fecal Microbiota Transplantation (FMT)
FMT involves transferring feces from healthy donors to patients' intestines for recolonization. In critically ill patients, more than half of the commensal microbiota is lost within hours of injury, leading to overgrowth of potentially pathogenic bacteria. FMT operates by:
- Altering the expression of IRF3
- Enhancing the presence of butyrate-producing bacteria
- Altering systemic immune response to infection
The widespread use of FMT is primarily limited by the need to discontinue antibiotics, which are generally considered a key component of sepsis treatment. Future research may focus on targeted FMT therapy or delivery of specific bacterial communities.
5. Gut-Liver Axis
The gut-liver axis, or gut-liver crosstalk, focuses on the two-way connection between the gut microbiota and the liver. In sepsis, a compromised gut barrier and disruption of the gut microbiota result in the transmission of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) from the intestines to the liver and throughout the body.
New therapeutic targets focusing on the gut-liver axis include epithelial barrier-targeted therapy, targeting the gut microbiome, duodenal mucosal resurfacing, intestinal restrictive polymers, and intestinal peptides.
Ferritin Emerges as Powerful Prognostic Biomarker
A separate study published in Frontiers in Medicine has identified serum ferritin as a key prognostic biomarker for sepsis patients in medical departments. The study analyzed data from 4,375 sepsis patients admitted to four internal medicine units in Lombardy, Italy, over a 12-year period.
The research found that baseline ferritin >553 ng/mL is a strong independent predictor of in-hospital mortality (OR 18.37, 95% CI 3.095 to 188.4, p=0.0043), with high predictive power (AUC=0.866). This makes ferritin a more powerful prognostic indicator than traditional markers such as baseline lactate or procalcitonin.
"Results suggest incorporating ferritin as a routine biomarker in risk stratification for sepsis patients in medical wards, where targeted interventions could be developed for high-ferritin patients to ameliorate their outcomes," the authors concluded.
Antimicrobial Resistance Trends
The study on sepsis in internal medicine also revealed important trends in antimicrobial resistance. While there has been an overall reduction in multidrug-resistant (MDR) sepsis in recent years due to a significant drop in the resistance of Gram-negative bacteria to cephalosporins, fluoroquinolones, and aminoglycosides, septicemia caused by carbapenemase-producing and ESBL+ Gram-negative bacteria, as well as vancomycin-resistant enterococci (VRE), is on the rise.
The inappropriate use of broad-spectrum nosocomial antimicrobials during the COVID-19 pandemic likely contributed to increased resistance to specific antibiotics. The researchers emphasized the need for further implementation of antibiotic stewardship programs in internal medicine units, with less protracted and more targeted therapies.
Future Research Directions
Both studies highlight the need for continued interdisciplinary research in the field of sepsis and intestinal microbiota. The bibliometric analysis suggests that future research should focus on:
- Developing more effective LPS neutralization strategies
- Establishing qualitative and quantitative standards for SCFA species and abundance
- Identifying specific next-generation probiotic strains and combinations
- Exploring targeted FMT therapy or delivery of specific bacterial communities
- Further investigating the gut-liver axis in sepsis pathophysiology
Meanwhile, the study on sepsis in internal medicine calls for prospective, multicenter studies to validate the role of ferritin and other biomarkers in predicting outcomes and guiding treatment.
As research in this field continues to evolve, these findings offer valuable insights for clinicians and researchers working to improve sepsis outcomes and develop more effective therapeutic strategies.
