Gasotransmitters & the Goldilocks Effect
Massive BENEFITS in getting the RIGHT Amount.
Over the last 3 decades of biomedical research we have come to better understand that 3 gasotransmitters have broad actions on health and wellbeing. These three are Nitric Oxide (NO), Hydrogen Sulfide (H2S) and carbon monoxide (CO). All are small molecules, making them highly diffusible. They are generated from dietary components (often amino acids) by a multitude of cells for a wide variety of biological actions. They regulate vascular tone (as vasodilators), are neurotransmitters regulating multiple processes but including memory and pain perception, critical components of immunity and affect inflammation in contrasting ways depending on dose and how they interact with other substrates.
Despite my pioneering work on nitric oxide, which is the dominant gasotransmitter in terms of data, knowledge and familiarity, here I would like to focus on Hydrogen Sulfide in this post. Most appreciate that H2S is rotten egg gas and that, along with its contributions to the foul odor of flatulence, gives it a less then enviable reputation. Those interested in truly ancient history know that the toxicity associated with H2S was a contributor of previous mass extinction events Mass Extinction & Hydrogen Sulfide associated with volcanic eruptions.
Which gets us back to the Title of the article, and it is truly a major factor for gasotransmitters. Too little and you are in trouble, too much and all hell can break loose . In essence the GOLDILOCKS EFFECT. Focusing on H2S what are the issues surrounding having too little and how can we resolve that?
The influence of diet is not an easy call. Firstly, the body tries to compensate for a deficit in dietary substrates by raising the production of H2S through the enzymatic pathways that drive this arm of sulfur chemistry. Some of these events are evident when the system is provoked by dietary lacks, which actually lead to enhanced H2S levels as opposed to suppressed.
Raised H2S production has been linked to:
Improved cardiovascular health (H2S as a vasodilator)
Stimulates new blood vessel regeneration
Improved cardiometabolic profiles with optimized glucose and cholesterol levels
Lowers oxidative stress and inflammation
Improved liver health, a topic of growing importance with the rates of fatty liver disease (NAFLD and NASH)
In terms of inflammation and pain management, there are several drugs in the developmental pipeline that have H2S donor groups on them. These donor groups are often added onto older NSAIDs or related anti-inflammatory drugs, with whom we have great familiarity as to their benefits and limitations. The advantage of using this odl, standard NSAIDS as a vehicle for these H2S donor moieties is that we can compare the new drugs to the old. Here the evidence suggests that not only do the new H2S donor compounds dramatically reduce toxicity eg gastritis and GI Ulcers, but they also improve the anti-inflammatory actions and importantly, pain management (Antibe Therapeutics). Given the need to find alternatives to the opioid class of therapeutics, new approaches that leverage gasotransmitters are certainly a welcome innovation.
Here is a great link to understanding the therapeutic potential of H2S in inflammation: Therapeutic Potential of H2S
LONGEVITY. Another intriguing outcome for positioning our H2S in this Goldilocks Zone is longevity. There is a multitude of studies that suggest that raised H2S levels increase longevity (Linking Diet, Longevity & H2S). There is speculation that the reduced lifespan seen with Western diets heavy in meat, eggs and dairy results from shutting down our H2S production because of excessive substrate. Have we fallen out of the Goldilocks Zone ? For some this aligns with an impetus to return to a plant-based protein diet (Meat Diets and H2S).
Of course, one cannot truly discuss Diet & Health these days without integrating the role of the microbiome into the equation. Bacteria can reduce sulfate to hydrogen sulfide (which we sometimes detect in flatulence) and here again, the challenge is to find the Goldilocks Zone, with evidence suggesting that too much results in toxicity (Sulfate Reducing Bacteria & Gut Inflammation) whereas lower amounts falling into the Goldilocks Zone being anti-inflammatory (Implications of Gut microbial & epithelial production of H2S).
It is important to emphasize that the actions/benefits/toxicity is not confined to the gut. Not only are other organs and functions targets but it can cross generations and influence DEVELOPMENTAL PROGRAMMING in the offspring. For example, a recent study in rats genetically predisposed to HYPERTENSION showed that pregnant rats fed supplemental NAC (an antioxidant and H2S donor moeity) resulted in the offspring showing increased activity of the enzymes that generate H2S from sulfur-containing amino acids. Further, the offspring exhibited an entirely different gut microbial profile, facilitating the production of H2S. The bottom line was that the offspring, unlike those whose mothers were not fed NAC, failed to develop hypertension later in life (Prevention of Hypertension by Maternal NAC Supplementation). These cross-generational actions of H2S donor supplements suggest that the enzymatic machinery was altered in an epigenomic manner to reposition the H2S generation pathway to an optimal site within the Goldilocks Zone, and thereby avoiding the inherited hypertension. Fascinating.
CONCLUSION
The gasotransmitters have remarkable impacts on our health and wellness. The robust research arising on hydrogen sulfide suggests that it too shall enter mainstream lexicons, and moving on from the derogatory description of rotten egg gas into an esteemed position as therapeutic agents. Those therapeutic approaches that help us position hydrogen sulfide into its Goldilocks Zone will have enormous impact of disease and our goals of sustained wellness.