Hydrogen peroxide pathway in ulcerative colitis: Promises and challenges in translating novel pathogenesis to clinical practice

Abstract

This letter addresses Pravda's innovative review, which proposes hydrogen peroxide as the primary pathogenic factor in ulcerative colitis (UC). Although the author presents intriguing mechanistic insights and reports encouraging clinical outcomes with reducing agents, several methodological and clinical considerations require discussion. We examine three key aspects: The selective evidence synthesis approach; the need for rigorous clinical validation of proposed therapies; and the integration of this novel hypothesis with established inflammatory bowel disease pathogenesis. Given the complexity of UC, future therapeutic advances may require collaborative approaches that integrate redox-based mechanisms into existing evidence-based frameworks rather than replacing current paradigms.

Key Words: Ulcerative colitis; Hydrogen peroxide; Pathogenesis; Reducing agents; Therapeutic targets

Core Tip: Pravda's hydrogen peroxide (H₂O₂) hypothesis provides mechanistic insights for ulcerative colitis but faces several clinical translation challenges. These include difficulties in H₂O₂ measurement, limited safety data for reducing agents, and the risk of patients abandoning proven therapies. We recommend conducting phase 2 trials, comprehensive safety assessments, and research approaches that integrate redox mechanisms with established frameworks. Collaborative strategies that balance scientific exploration with patient safety may ensure appropriate validation before clinical adoption.

TO THE EDITOR

Pravda's recent review[1] entitled "Ulcerative colitis: Timeline to a cure" presents a provocative perspective on ulcerative colitis (UC) pathogenesis by positioning colonocyte hydrogen peroxide (H₂O₂) as the primary etiological driver of this challenging inflammatory bowel disease. We find the systematic compilation of historical evidence intriguing and appreciate the author's effort to construct a novel therapeutic paradigm. However, several aspects of this hypothesis require closer examination.

Theoretical integration and clinical context

The H₂O₂-centric model requires integration with our current understanding of UC as a complex, multifactorial disease. The characterization of immune dysregulation as lacking evidence may overlook substantial research demonstrating specific immunological abnormalities in UC patients. These abnormalities include defective regulatory T-cell function, aberrant cytokine profiles, and compromised immune tolerance to commensal bacteria[2-4]. Modern approaches to UC pathogenesis recognize intricate interactions between genetic susceptibility[5], environmental triggers[6], microbiome composition[7], epithelial barrier function, and immune responses[8]. A singular focus on H₂O₂, while mechanistically appealing, may not fully account for this complexity. To provide a clearer comparison between the H₂O₂ hypothesis and current mainstream understanding of UC pathogenesis and treatment, we have summarized the key contrasts in Table 1.

Table 1 Comparison of pathological mechanisms and treatment methods between the new hypothesis and traditional theories of ulcerative colitis.

Mechanism	H2O2 hypothesis	Traditional treatment
Root cause	Excessive H2O2 production and accumulation in colonic epithelial cells	Abnormal activation or dysregulation of the immune system[17]
Initial event	Mitochondrial H2O2 generation increased - intracellular accumulation - transmembrane diffusion	Aberrant T-cell activation - cytokine release[18]
Neutrophil recruitment	Direct chemotactic effect of H2O2	IL-8, CXCL1, and other chemokine-mediated recruitment[19]
Inflammatory cascade	H2O2 - neutrophil infiltration - tissue damage - additional H2O2 release	Th1/Th17 activation - TNF-α/IL-17 increased - inflammatory amplification[20]
Tissue damage mechanism	H2O2-mediated disruption of tight junction proteins - epithelial barrier dysfunction	Cytotoxic T cells and NK cell-mediated epithelial cell killing[21]
Primary drugs	STS, R-DHLA	Mesalazine, biologics, immunosuppressants, JAK inhibitors[22]
Drug action	H2O2 neutralization (extracellular and intracellular)	Anti-inflammatory, immunosuppression

CXCL1: Chemokine CXC ligand 1; H₂O₂: Hydrogen peroxide; IL: Interleukin; JAK: Janus kinase; LPS: Lipopolysaccharide; NK: Natural killer; R-DHLA: R-Dihydrolipoic acid; STS: Sodium thiosulfate; TNF: Tumor necrosis factor.

The original review's characterization of current immunosuppressive therapies as representing primarily commercial interests rather than evidence-based medicine risks undermining patient confidence in treatments that have demonstrated clinical efficacy through rigorous randomized controlled trials. When alternative hypotheses are accompanied by sweeping dismissals of established therapies, patients may discontinue or refuse proven treatments based on incomplete evidence. Current immunosuppressive therapies, while not curative, have documented benefits in inducing and maintaining remission, improving quality of life, and reducing surgical interventions in many UC patients. Scientific progress benefits from challenging existing paradigms, but this must be balanced with responsibility toward patients who rely on current treatments. Novel therapeutic approaches should be evaluated using the same rigorous standards applied to existing therapies, rather than being promoted as alternatives to evidence-based care before adequate validation.

Systematic evaluation of evidence quality and clinical validation

The author's selective focus on < 12 studies across seven decades provides a historical perspective but raises concerns regarding the comprehensiveness of the evidence base. Although focused analyses can elucidate specific mechanisms, they may unintentionally omit contradictory findings or alternative explanations from decades of inflammatory bowel disease research. The emphasis on historical case reports, particularly H₂O₂ enema studies from the mid-20th century, provides mechanistic insights but limits extrapolation to spontaneous UC. Chemical-induced colitis models are useful for understanding acute inflammatory responses but often fail to replicate the chronic, relapsing-remitting pattern characteristic of human UC[9]. This discrepancy between experimental models and clinical reality warrants acknowledgment. The author's confidence in reducing agents as curative therapy, despite encouraging preliminary data demonstrating histological remission in 36 patients with refractory UC, requires more rigorous evaluation. Most importantly, randomized controlled trials comparing reducing agents to established therapies are needed before drawing definitive conclusions regarding curative potential. Dismissing current evidence-based therapies as merely immunosuppressive undervalues their sophisticated mechanisms of action and established clinical efficacy, as demonstrated in numerous well-designed clinical trials.

Methodological and implementation challenges

Although the H₂O₂ hypothesis provides plausible mechanistic insight into UC pathogenesis, its clinical translation is fundamentally constrained by the biochemical properties of H₂O₂. As a short-lived signaling molecule with a tissue half-life < 1 min, H₂O₂ exhibits rapid fluctuations influenced by dietary factors, microbiota composition, mucosal oxygenation, and sampling location[10,11]. These variables contribute to substantial heterogeneity in baseline H₂O₂ levels across studies, thereby precluding the establishment of consistent reference ranges - a prerequisite for diagnostic applications and therapeutic monitoring.

This measurement paradox directly undermines the proposed therapeutic approach using reducing agents such as sodium thiosulfate (STS) and R-dihydrolipoic acid (R-DHLA). Without reliable H₂O₂ quantification, confirming H₂O₂-mediated disease through therapeutic response lacks both validation and standardization. The long-term safety profiles of these agents in UC populations remain largely unknown. This knowledge gap is particularly concerning given the chronic nature of the disease, which necessitates prolonged treatment. Current safety data for these reducing agents are primarily derived from other clinical applications, such as STS use in calcific uremic arteriolopathy[12]. These applications differ significantly from potential UC protocols in patient populations, dosing regimens, and treatment duration. Available evidence indicates that STS may cause gastrointestinal symptoms (nausea and vomiting), electrolyte disturbances, and occasional hypersensitivity reactions. However, serious adverse events appear uncommon at therapeutic doses[13,14]. Although R-DHLA demonstrates theoretical biocompatibility as a lipophilic antioxidant, comprehensive safety evaluation in inflammatory bowel disease populations remains lacking[15]. Critical questions remain regarding the long-term effects on hepatic and renal function, potential drug-drug interactions with standard UC therapies, and the risk of withdrawal reactions in vulnerable populations.

Future directions and ethical implementation framework

Despite these concerns, the H₂O₂ hypothesis warrants rigorous scientific investigation. We recommend the following research priorities. First, well-designed mechanistic studies should quantify colonic H₂O₂ concentrations across different UC phenotypes and disease severities using standardized methodologies. Second, proof-of-concept randomized controlled trials should evaluate reducing agents in treatment-naïve UC patients, with predefined primary and secondary endpoints. Third, comprehensive safety studies must evaluate the long-term effects of candidate reducing agents in inflammatory bowel disease populations. Based on existing preliminary clinical evidence and current understanding of UC pathophysiology, we recommend conducting a multicenter, randomized, double-blind, placebo-controlled phase 2 clinical trial. The specific trial design protocol is detailed in Table 2.

Table 2 Phase 2 randomized controlled trial design for mild to moderate active ulcerative colitis.

Design requirements	Specific protocol	Key considerations
Study design	Multicenter, randomized, double-blind, placebo-controlled phase 2 trial	Compliance with ICH-GCP standards
Target population	Patients with mild to moderate active UC (PRO2 score 2-5 points)	Balance baseline risk; standardize severity assessment
Inclusion criteria	Age 18-65 yr; MES score 1-2 points; discontinue biologics ≥ 8 wk	Exclude severe UC and active infectious diseases
Sample size	180 subjects (90 per group)	80% statistical power; anticipated 15% dropout rate[23]
Randomization design	1:1 randomized allocation by disease severity stratification	Ensure balanced baseline characteristics and reduce bias
Treatment groups	Group A: 5-ASA + STS (extracellular H2O2 scavenger); Group B: 5-ASA + placebo	Specific dosing regimens determined through phase 1 dose-escalation studies
Biomarker assessments	Weeks 0, 4, 8, 12: CRP, fecal calprotectin, neutrophil count, serum 8-isoprostane F2α, malondialdehyde, GPx activity	Based on STRIDE-II criteria[24]; combined oxidative stress biomarkers
Primary endpoint	Clinical response rate at week 12 (PRO2 score reduction ≥ 50%)	Meets STRIDE-II recommended patient-reported outcome measures
Key secondary endpoints	Clinical remission, endoscopic response, histological improvement, oxidative stress biomarker changes at week 12	Endoscopic response: MES ≤ 1 point; Histological improvement: Geboes score < 2.0
Safety assessment	Liver and kidney function tests at Weeks 0, 4, 8, 12; document and evaluate adverse events at each visit	Balance safety monitoring requirements with patient convenience
Follow-up plan	Treatment period: 12 wk + long-term follow-up to 52 wk	Evaluate long-term efficacy maintenance and safety

UC: Ulcerative colitis; ICH-GCP: International Council for Harmonisation-Good Clinical Practice; MES: Mayo Endoscopic Score; PRO2: Patient-Reported Outcome 2; 5-ASA: 5-aminosalicylic acid; GPx: Glutathione peroxidase; STRIDE-II: Selecting Therapeutic Targets in Inflammatory Bowel Disease Initiative update; CRP: C-reactive protein.

Although reducing agents demonstrate acceptable safety profiles as monotherapies in other indications, their combination use in UC lacks adequate nonclinical toxicological support. Existing safety data cannot be extrapolated to UC populations. This necessitates exceptionally cautious first-in-human studies. Once preliminary efficacy data emerge, investigators may face pressure for compassionate use from patients with refractory UC. This creates an ethical dilemma between denying potentially beneficial treatment to those with the greatest clinical need and exposing patients to unknown risks in the absence of sufficient evidence[16]. The complexity is amplified by the impact of UC on younger populations with extended life expectancies. This magnifies long-term treatment consequences and necessitates risk-benefit assessments that consider decades of safety data rather than short-term efficacy alone. If reducing agent therapy demonstrates curative potential, the benefits may justify certain risks; however, such assessments require exceptionally rigorous and comprehensive evidence. Systematic approaches are also required to address informed consent challenges, medical equity considerations, regulatory ethics, and research integrity oversight. H₂O₂-targeted therapy can advance only within an ethically sound framework that comprehensively addresses these considerations. Such thorough ethical deliberation is essential for translating theoretical innovations into clinical practice.

CONCLUSION

Pravda's[1] H₂O₂ hypothesis offers a valuable novel perspective on UC pathogenesis research. Its compilation of historical evidence and mechanistic analysis warrant serious consideration. However, translating this theory into clinical practice faces significant challenges. The short half-life of H₂O₂ limits its practicality as a diagnostic and monitoring biomarker. The long-term safety profile of reducing agents lacks adequate validation. Additionally, a single mechanism cannot fully explain the multifactorial complexity of UC. Given the heterogeneous nature of UC, future therapeutic advances may require several key strategies. These include integrating novel mechanistic insights such as the H₂O₂ pathway with established evidence-based treatments, validating reducing agent efficacy through rigorous randomized controlled trials, and exploring personalized treatment approaches while ensuring patient safety. Genuine progress in this field will depend on collaboration between investigators exploring novel hypotheses and those working within established frameworks. This approach should challenge existing paradigms while maintaining rigorous scientific standards, ultimately providing more effective therapeutic options for UC patients.