The life of all cells cannot be separated from redox . During oxygen metabolism, oxygen is essential, but it also produces reactive oxygen species (ROS). It is well known that excessive reactive oxygen in cells can cause oxidative damage to biomolecules, thereby damaging key cellular processes and leading to various forms of infection. Therefore, the rapid repair of oxidative stress is crucial for cell survival.
Low molecular weight (LMW) thiol is a small molecule antioxidant required to maintain the redox homeostasis in cells. They are everywhere in nature. For example, glutathione (GSH) is the LMW thiol synthesized by eukaryotic organisms. However, the stomach disease protoplasm Helicobacter pylori ( Helicobacter pylori) that has co-evolved with human for more than 460,000 and infected more than half of the world's population, lacks the biosynthesis pathway of LMW thiol. To date, it remains an unsolved mystery how this bacteria that may cause peptic ulcers and even cancer maintains intracellular redox homeostasis in the absence of LMW thiol.
On November 7, 2022, in a new study published on "Cell" , a research team from Yale University discovered for the first time that Helicobacter pylori expresses a new transporter and uses this protein to ingest the dietary LMW thiol from the host gastrointestinal tract to maintain its own redox homeostasis. This discovery provides an important target for the development of new drugs for a variety of infectious diseases in humans.
In this new study, the team used the responsive-oriented metabolomics screening method to identify LMW thiols in Helicobacter pylori and found the unusual antioxidant ergothionein .
Ergothionine (EGT) is a natural amino acid with significant antioxidant characteristics, anti-inflammatory , cell protection and UV radiation. Although it is highly stable under physiological conditions, it can reduce strong oxidants such as hypochlorite (bleach) and peroxy nitrite .
ergothioneine is a ubiquitous component in many microorganisms cells, but is synthesized only in a few bacteria and fungi, and animals and plants can only be obtained through exogenous sources. Ergothio in the human body is mainly obtained through foods such as mushrooms, oats, and cereals. In gastrointestinal tissues, ergothione is rich in content and is widely involved in reducing disease risk.
researchers found that although H. pylori cannot synthesize ergothionein, it can express a previously unidentified ATP-binding cassette (ABC) transporter EgtUV to ingest ergothionein in the host environment, thereby resisting hypochlorous acid released by neutrophils, providing itself with its colonization advantage in the gastric mucosa.
Subsequently, the researchers evaluated the effect of ergothione intake on Helicobacter pylori colonization through mouse experiments. They found that ergothionine was present in mice’s food, stomach tissue and digested food. This suggests that Helicobacter pylori can make full use of this compound in the gastric environment and that EgtUV gives it a competitive colonization advantage.
Since gastric cells also actively ingest ergothione, the competition between the host-microbial interface in the face of this metabolite may affect the bacterial homeostasis.
Given the widespread distribution of EgtUV in gastrointestinal microorganisms, the researchers finally evaluated whether ergothioate can be metabolized by human intestinal symbionts in fecal samples from 25 healthy volunteers. The results show that the compound is catabolized by intestinal bacteria, and in some individuals, ergothionine can be converted into trimethylamine (TMA) in the host.
TMA is a precursor molecule of trimethylamine hydroxy (TMAO), a metabolite widely associated with cardiovascular disease. Therefore, ergothionein can not only enhance the antioxidant reaction of Helicobacter pylori, but also promote the production of biologically active metabolites such as TMAO that affect the physiology of the host.
The decrease in ergothione levels are usually associated with an increased risk of neurodegenerative diseases, cardiovascular diseases and autoimmune diseases. Therefore, the consumption of this nutrient by H. pylori in may have a profound impact on human health .
In summary, this study shows that the transporter EgtUV is a generally conserved mechanism for redox regulation by host-associated microorganisms (such as Helicobacter pylori). The 3-game competition of dietary ergothionine may have broadly influenced various aspects of host physiology, including inflammatory response, neurobiology, cardiovascular health, and intestinal microbial ecology.
Since the ergothionine transport mechanisms of bacteria and mammalian cells are completely different, EgtU may be a promising target for the development of broad-spectrum inhibitors that can specifically prevent the uptake of ergothionine by host gastrointestinal pathogen microorganism .
paper link:
https://doi.org/10.1016/j.cell.2022.10.008
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