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Microbes & Immunity Identifying hydrogenase orthologs in the human proteome

(SCFAs), such as butyrate, acetate, and propionate, during Emerging research suggests that H acts as an effective
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the fermentation of indigestible dietary fibers. SCFAs antioxidant and anti-inflammatory agent, with numerous
strengthen the gut epithelial barrier, thereby reducing studies showing that H , whether produced endogenously
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the translocation of bacterial endotoxins that can trigger by microbes or administered exogenously, can reduce
systemic inflammation and immune dysregulation. oxidative stress, inflammation, and modulate immune
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Furthermore, SCFAs exhibit potent anti-inflammatory responses, 10-14 For instance, H has been shown to stimulate
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properties and are known to regulate regulatory T cells, the production of butyrate, an essential SCFA known for
which play a crucial role in maintaining immune tolerance its anti-inflammatory properties, The ability of the gut
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and preventing excessive immune responses. 3 microbiota to modulate H production and utilization is
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In addition to the favorable effects of microbial crucial for maintaining gut health. Methanobrevibacter
metabolites on adaptive immunity, the intestinal smithii, for example, uses H to reduce carbon dioxide into
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microbiome is pivotal in reducing oxidative stress, a major methane (CH ), a less reactive byproduct, thus preventing
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contributor to inflammation and cellular damage. The excess accumulation of H . Interspecies H transfer
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immune system relies on a delicate balance of oxidative plays a key role in sustaining gut microbial diversity
and antioxidative processes to function effectively. and contributes to overall gut health. In addition, recent
Oxidative stress, a phenomenon that can lead to erratic studies indicate that H positively affects mitochondrial
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immune signaling, occurs when the production of structure and function, enhancing adenosine triphosphate
reactive oxygen species (ROS) exceeds the body’s ability production, mitigating oxidative stress, and stabilizing
to detoxify them. ROS, including superoxide and hydroxyl membrane potential. 15-18 These findings suggest that H
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radicals, are highly reactive molecules that participate in supports favorable energy dynamics in somatic cells.
a network of signaling pathways. Furthermore, ROS are Over the past decade, H has gained interest as a
known to influence cellular stress responses, including modulator of oxidative stress and inflammation, 10-12,16
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the expression of proinflammatory chemokines and with several studies showing that H can attenuate
cytokines, as well as apoptosis. While ROS signaling is inflammation in various models of intestinal diseases,
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essential for immune responses, such as the destruction of including colitis and inflammatory bowel disease. For
pathogens, excessive levels can damage healthy cells and example, a study conducted by Song et al. demonstrated
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tissues, leading to inflammation and impaired immune that H -rich water, which mimics the effects of microbial-
responses. Disruption of this balance may result in produced H , significantly reduced colonic inflammation
1,2
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either an overactive immune response, contributing to 2
autoimmune diseases, or a weakened somatic response, in a mouse model of ulcerative colitis by decreasing
increasing susceptibility to infections. Many microbial levels of proinflammatory cytokines such as tumor
metabolites, including hydrogen (H ) and glutathione, act necrosis factor-alpha (TNF-α). Significant increases in
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as antioxidants, either by directly neutralizing ROS and glutathione concentration and inhibition of pathogenic
preventing oxidative damage or by activating signaling bacteria, including Enterococcus faecalis, Clostridium
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pathways, such as nuclear factor erythroid 2-related factor perfringens, and Bacteroides fragilis, were also noted. As
2, which promotes the expression of antioxidant enzymes a non-polar, electrochemically neutral, and lightweight
and enhances cellular defenses against oxidative stress. 5 (molecular weight: 2.016 g/mol) diatomic molecule,
H can traverse biological membranes and target
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The gastrointestinal tract hosts more than 10 intracellular compartments, playing a crucial role in the
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microorganisms, collectively referred to as the gut interaction between intestinal microbes and the immune
microbiota. This diverse array of archaea, bacteria, system.
bacteriophage, fungi, and viruses contributes to various
physiological processes, including immune function. Many reports describe the anti-inflammatory effects of
1,6
During the fermentation of undigested carbohydrates by H treatments, supported by scientific evidence indicating
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commensal bacteria, H gas is produced as a metabolic that H suppresses biological markers of oxidative stress
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byproduct. This H can be absorbed into the bloodstream and pro-inflammatory peptides (for example, TNF-α),
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and expelled via the lungs, or it can be utilized by interleukins (IL; for instance, IL-6 and IL-1ß), and nuclear
methanogens and sulfate-reducing bacteria through a factor kappa B (NFκB). 10-12,16 These protective mechanisms
process known as interspecies H transfer. It is estimated involve not only interactions with multiple cellular
7-9
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that the intestinal microbiome can produce approximately processes, as described above but also the regulation of p38
13 L of H each day, with around 71% of commensal bacteria mitogen-activated protein kinase (MAPK)/extracellular
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capable of metabolizing H indicating the potential signal-regulated kinase signaling cascades responsible for
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2,
significance of H in regulating intestinal immune function. initiating the biosynthesis of proinflammatory cytokines. 20,21
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Volume 1 Issue 2 (2024) 82 doi: 10.36922/mi.4544