The International Journal of Molecular Sciences recently published a review of the role of gut bacteria-derived hydrogen sulfide gas (H2S) in multiple disease axes, including gut-immune, gut-heart, and gut-endocrine axes. While H2S is produced endogenously by human cells and acts as a signaling molecule with multiple physiological effects, the role of bacterially produced H2S is less well understood, yet it is thought to modulate intestinal barrier function, mucosal healing in the gut, and potentially to a variety of diseases, including SIBO, colon cancer, atherosclerosis, neurodegenerative disease, metabolic disease, and more.
Endogenously synthesized H2S is produced by vitamin B6-dependent enzymes (cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), 3-mercaptopyruvate sulfotransferase (3-MST)), and selenium-binding-protein 1 (SELENBP1), as well as the mitochondrial enzyme (cysteinyl-tRNA synthetase 2 (CARS2)), utilizing L-cysteine and homocysteine (or derivatives) as substrates. As a signaling molecule, H2S is produced in many cell types, including enterocytes, cardiovascular endothelial cells, pancreatic beta cells, etc., and influences cardiovascular, neurological, immune, metabolic, and other functions, and, similar to nitric oxide, is a critical gaseous signaling molecule.
H2S’s physiological effects are complex, with concentration-dependent and compartment-dependent actions. For example, the large intestine has a very high concentration of H2S that would otherwise be lethal to bacteria, even species that produce H2S, because the colon has a large detoxification capacity and converts H2S to the nontoxic thiosulfate (or trimethylsulfonium ion after multiple methylation steps). Indeed, colonocytes can use H2S as an energy source in the respiratory chain’s ATP production, and low concentrations of H2S can be beneficial, supporting the integrity of the gut’s epithelial layer and promoting the resolution of intestinal inflammation and healing of mucosal ulcers, preventing bacterial adherence to biofilms, etc.
Yet higher amounts of H2S, particularly in the small intestine, can be detrimental, inhibiting mitochondrial respiration, increasing inflammation and oxidative stress, and even a breakdown of the mucous barrier and the protective mucin in the biofilm. In a study recently published in the Journal of Clinical Gastroenterology, H2S, measured by at-home breath-testing, was associated with unique symptoms. In this study, over 3000 participants completed symptom surveys, and had levels of 3 gases – hydrogen, methane, and H2S – measured after receiving either glucose or lactulose. While methane was associated with constipation, H2S was associated with more severe diarrhea and abdominal pain, in support of the concept of intestinal sulfide overproduction (ISO), parallel to intestinal methanogen overgrowth (IMO, due to intestinal colonization with methanogens).
The importance of H2S, especially H2S generated by the microbiome, is only now gaining attention, and clear guidelines for diagnosis and treatment do not exist. Dietary changes do seem to alter H2S production (e.g., animal vs. plant-based), but not uniformly. ISO appears to have effects beyond the gut as well. As described in the recent review, H2S plays a role in neurological function; it can cross the blood-brain barrier, enhance NMDA receptors, etc., and it seems plausible that H2S is part of the brain-gut axis at least in part by modulating neuroinflammation, with changes in either H2S levels or the abundance of bacterial producers of H2S associated with Alzheimer’s disease, Parkinson’s disease, and ischemic stroke. H2S also influences vasodilation and plays a role in hypertension and atherosclerosis, suggesting a better understanding of bacterial synthesis of H2S has broad implications for health and disease.