2024 · Chen — Hydrogen-rich water alleviates constipation by attenuating oxidative stress through the sirtuin1/nuclear factor-erythroid-2-related factor 2/heme oxygenase-1 signaling pathway.
Super-Abstract
In constipated rats, hydrogen-rich water (HRW) improved stool output, intestinal motility, and gut microbiota composition by reducing oxidative stress through a specific protective signalling pathway. The study also identified two metabolites (β-leucine and traumatic acid) that may mediate the benefit by activating a key antioxidant regulator. (World Journal of Gastroenterology, 2024.)
Commentary
This animal study established a loperamide-induced constipation model in Sprague-Dawley rats and allowed them to drink HRW freely. The HRW group showed improved stool weight, fecal water content, charcoal transit rate, and intestinal mucus layer thickness, as well as better preservation of intestinal neurons and expression of the c-kit receptor (important for gut motility). Gut microbiome analysis and serum metabolomics revealed that HRW modulated microbial composition and raised levels of two unusual metabolites — β-leucine (β-Leu) and traumatic acid — which in NCM460 intestinal cells were shown to upregulate SIRT1 and thereby reduce oxidative stress via the SIRT1/Nrf2/HO-1 pathway. A SIRT1 inhibitor (EX527) reversed the constipation relief, providing mechanistic support. The study is methodologically thorough, but all data are from a rat model. Human constipation is highly heterogeneous in its causes, and the metabolomic findings in rat serum may not translate to humans.
Key quotes
- „HRW alleviated constipation symptoms by improving the total amount of stool over 24 h, fecal water content, charcoal propulsion rate, thickness of the intestinal mucus layer, c-kit expression, and the number of intestinal neurons.“ — the multi-parameter improvement in constipation markers observed in rats
- „HRW could also reduce intestinal oxidative stress through the SIRT1/Nrf2/HO-1 signaling pathway.“ — the proposed anti-constipation mechanism: antioxidant signalling via SIRT1
- „β-Leu and traumatic acid are potential metabolites that upregulate SIRT1 expression and reduce oxidative stress.“ — the metabolomics discovery: two specific metabolites may be the active mediators
Our assessment
This is an animal study (rat model of constipation). The mechanistic evidence — including the SIRT1 inhibitor rescue experiment — is methodologically sound and the pathway is plausible. However, results from loperamide-induced constipation in rats cannot be directly applied to human constipation, which has diverse causes (diet, neurological, drug-related, etc.). The identified metabolites (β-leucine, traumatic acid) are interesting but their relevance in human gut physiology is unknown. No human data exist for this specific intervention. The study is a well-designed preclinical investigation that supports further research, not a clinical recommendation.
Study design
- Type: animal study (rat) · Model: loperamide-induced constipation, Sprague-Dawley rats · H₂ delivery: ad libitum hydrogen-rich water (HRW) + intravenous saline (rescue arm: SIRT1 inhibitor EX527 i.p.)
- Result: HRW improved stool output, fecal water content, intestinal motility, mucus layer, c-kit and neuron count; SIRT1/Nrf2/HO-1 pathway activation confirmed; β-Leu and traumatic acid identified as potential SIRT1-activating metabolites — rat model only
Abstract
BACKGROUND: Constipation, a highly prevalent functional gastrointestinal disorder, induces a significant burden on the quality of patients' life and is associated with substantial healthcare expenditures. Therefore, identifying efficient therapeutic modalities for constipation is of paramount importance. Oxidative stress is a pivotal contributor to colonic dysmotility and is the underlying pathology responsible for constipation symptoms. Consequently, we postulate that hydrogen therapy, an emerging and promising intervention, can serve as a safe and efficacious treatment for constipation. AIM: To determine whether hydrogen-rich water (HRW) alleviates constipation and its potential mechanism. METHODS: Constipation models were established by orally loperamide to Sprague-Dawley rats. Rats freely consumed HRW, and were recorded their 24 h total stool weight, fecal water content, and charcoal propulsion rate. Fecal samples were subjected to 16S rDNA gene sequencing. Serum non-targeted metabolomic analysis, malondialdehyde, and superoxide dismutase levels were determined. Colonic tissues were stained with hematoxylin and eosin, Alcian blue-periodic acid-Schiff, reactive oxygen species (ROS) immunofluorescence, and immunohistochemistry for cell growth factor receptor kit (c-kit), PGP 9.5, sirtuin1 (SIRT1), nuclear factor-erythroid-2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Quantitative real-time PCR and western blot analysis were conducted to determine the expression level of SIRT1, Nrf2 and HO-1. A rescue experiment was conducted by intraperitoneally injecting the SIRT1 inhibitor, EX527, into constipated rats. NCM460 cells were induced with H2O2 and treated with the metabolites to evaluate ROS and SIRT1 expression. RESULTS: HRW alleviated constipation symptoms by improving the total amount of stool over 24 h, fecal water content, charcoal propulsion rate, thickness of the intestinal mucus layer, c-kit expression, and the number of intestinal neurons. HRW modulated intestinal microbiota imbalance and abnormalities in serum metabolism. HRW could also reduce intestinal oxidative stress through the SIRT1/Nrf2/HO-1 signaling pathway. This regulatory effect on oxidative stress was confirmed via an intraperitoneal injection of a SIRT1 inhibitor to constipated rats. The serum metabolites, β-leucine (β-Leu) and traumatic acid, were also found to attenuate H2O2-induced oxidative stress in NCM460 cells by up-regulating SIRT1. CONCLUSION: HRW attenuates constipation-associated intestinal oxidative stress via SIRT1/Nrf2/HO-1 signaling pathway, modulating gut microbiota and serum metabolites. β-Leu and traumatic acid are potential metabolites that upregulate SIRT1 expression and reduce oxidative stress.
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