Molecular Hydrogen: A Promising Therapeutic Approach for Sepsis, Gastric Protection, and Intestinal Health

Molecular hydrogen (H₂) has emerged as a fascinating therapeutic agent with significant potential for treating and preventing conditions affecting the gastrointestinal system and systemic inflammatory responses like sepsis. Recent research demonstrates that this simple molecule offers multiple protective mechanisms that could transform treatment approaches for these challenging conditions.

Molecular Hydrogen in Sepsis Management

Sepsis remains a major cause of morbidity and mortality in critically ill patients despite advances in monitoring devices, diagnostic tools, and therapeutic options. Recent studies have identified molecular hydrogen as a promising intervention for sepsis and its complications.

Research published in 2014 found that hydrogen gas can improve survival and reduce organ damage in animal models of sepsis. The mechanisms behind these benefits are associated with the regulation of oxidative stress, inflammatory response, and apoptosis, potentially through modulation of the NF-κB pathway.

More recent research has specifically examined hydrogen’s effects on sepsis-associated encephalopathy (SAE), a serious neurological complication affecting up to 70% of severely ill sepsis patients. A 2022 study demonstrated that molecular hydrogen treatment significantly improved functional outcomes of SAE and downregulated inflammatory reactions in both the brain and gut. This dual-site anti-inflammatory action highlights hydrogen’s systemic benefits in sepsis management.

Importantly, the study found that hydrogen treatment—whether administered as 2% hydrogen gas inhalation or hydrogen-rich water—improved gut microbiota dysbiosis and partially amended metabolic disorders after SAE. This suggests that hydrogen’s benefits in sepsis may be partly attributable to its ability to increase beneficial bacteria, repress harmful bacteria, and reduce metabolic disorders and inflammation.

Gastric Protection Mechanisms

Hydrogen-rich water (HRW) has demonstrated significant protective effects against gastric mucosal injury, particularly in the context of aspirin-induced damage. A 2014 study found that pretreatment with HRW obviously reduced aspirin-induced gastric damage scores from 4.04 ± 0.492 to 2.10 ± 0.437.

The protective mechanisms of hydrogen on gastric tissue operate through multiple pathways:

Antioxidant Effects

Hydrogen significantly reduces oxidative stress markers in gastric tissues. In aspirin-treated models, HRW decreased malondialdehyde (MDA) levels from 2.43 ± 0.145 to 1.79 ± 0.116 nmol/mg protein and myeloperoxidase (MPO) from 2.53 ± 0.238 to 1.40 ± 0.208 U/g tissue. Simultaneously, hydrogen increased superoxide dismutase (SOD) activity from 37.94 ± 8.44 to 59.55 ± 9.02 nmol/mg protein, enhancing the stomach’s antioxidant defenses.

Anti-inflammatory Properties

Hydrogen significantly reduces inflammatory markers in gastric tissues. Pretreatment with HRW decreased IL-06 levels from 46.65 ± 5.50 to 32.15 ± 4.83 pg/mg and TNF-α from 1305.08 ± 101.23 to 855.96 ± 93.22 pg/mg in gastric tissue. Similar reductions were observed in serum inflammatory markers, with IL-1β decreasing from 505.38 ± 32.97 to 343.37 ± 25.09 pg/mL and TNF-α from 264.53 ± 28.63 to 114.96 ± 21.79 pg/mL.

COX-2 Modulation

Hydrogen significantly decreases cyclooxygenase-2 (COX-2) expression in gastric tissues, with staining scores reduced from 8.4 ± 2.1 to 2.9 ± 1.5. This modulation of COX-2 may be a key mechanism in hydrogen’s gastric protection, particularly against NSAID-induced injury.

Histopathological examination confirmed these biochemical findings, showing that while aspirin induced severe congestion and multiple hemorrhagic erosions in stomach tissue, pretreatment with HRW considerably attenuated these changes.

Intestinal Microbiome Modulation

One of the most intriguing aspects of hydrogen therapy is its ability to modulate the gut microbiome. A 2022 study investigating the effects of long-term hydrogen consumption found that hydrogen-rich water intake induced significant changes in the structure of gut microbiota, while hydrogen inhalation showed less pronounced effects on bacterial communities.

Specifically, HRW intake was associated with significant increases in beneficial bacteria including Lactobacillus and Ruminococcus. These bacteria are known to play important roles in maintaining intestinal health, with Lactobacillus contributing to gut barrier function and immune modulation, while Ruminococcus species are important butyrate-producing bacteria that support intestinal epithelial health.

Most studies have shown that hydrogen-rich water could improve intestinal structural integrity and upregulate butyrate-producing bacteria, ameliorating clinical features of gut microbiota disturbances. This suggests hydrogen may help maintain a healthy intestinal environment by promoting beneficial bacterial populations.

Metabolic Effects

Beyond direct effects on gut microbiota, hydrogen consumption also influences metabolic pathways that may contribute to its gastrointestinal benefits. Compared with control groups, hydrogen-rich water and hydrogen inhalation were associated with different metabolic signatures.

Pathway enrichment analysis showed that HRW intake mainly affected starch and sucrose metabolism, while differential metabolites in the hydrogen inhalation group were primarily enriched in arginine biosynthesis. These metabolic effects may work synergistically with hydrogen’s direct antioxidant and anti-inflammatory properties to promote gastrointestinal health.

Conclusion

The growing body of evidence suggests that molecular hydrogen represents a promising therapeutic approach for sepsis, gastric protection, and intestinal health. Its unique properties—including selective antioxidant activity, anti-inflammatory effects, COX-2 modulation, and gut microbiome regulation—address multiple aspects of these conditions simultaneously.

From improving outcomes in sepsis and sepsis-associated encephalopathy to protecting against gastric mucosal injury and promoting beneficial gut bacteria, hydrogen therapy shows remarkable versatility in its gastrointestinal applications. As research continues to advance, molecular hydrogen may emerge as an important complementary or alternative approach in gastroenterology and critical care medicine, offering new hope for patients with these challenging conditions.

Molecular Hydrogen: A Promising Therapeutic Approach for Sepsis, Gastric Protection, and Intestinal Health

Molecular Hydrogen in Sepsis Management

Gastric Protection Mechanisms

Antioxidant Effects

Anti-inflammatory Properties

COX-2 Modulation

Intestinal Microbiome Modulation

Metabolic Effects

Conclusion

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