A study that was designed to investigate how the immune system impacts gut bacteria has led to the discovery that two molecules, L-tyrosine and its metabolite, p-cresol sulfate (PCS), can not only provide profound protection in experimental models of asthma, but can also substantially reduce the severity of an attack. While L-tyrosine is already commercially available as a dietary supplement that is marketed to help boost alertness and attention, neither the amino acid itself nor PCS had previously been known to have an effect on asthma.
Literature studies by the Monash University researchers who led the newly reported investigation also indicated that the two metabolites are present in higher amounts in children without asthma, compared to those with the disease. And further animal studies suggested that they may have a potential role in treating acute respiratory distress syndrome (ARDS), the sometimes fatal respiratory illness that can develop in people with serious COVID-19.
The researchers say they aim to test one of the molecules in a clinical trial in asthmatics, during 2021. Study lead, Benjamin J. Marsland, PhD, professor in the department of immunology and pathology from the Monash University Central Clinical School, and colleagues at Monash University and the University of Lausanne, reported on their findings in Nature Immunology, in a paper titled, “Microbial metabolism of L-tyrosine protects against allergic airway inflammation.”
Asthma is one of the most common major noncommunicable diseases, which impacts 300 million people globally, Monash University stated, with the global market for asthma treatment standing at over $18 billion in 2019. The university’s research team, led by VESKI innovation fellow, Marsland, wanted to understand how the immune system impacts the gut microbiome. While it is known that gut bacteria have an effect on the immune system, “how the immune system influences the gut microbiome has to date been under studied,” Marsland said.
Through studying a mouse that had a limited immune system, consisting of a single type of antibody, the researchers found the gut microbiome was changed. By transferring these gut bacteria into normal mice they could identify which bacteria had an impact on the mouse immune system.
In what was an enormous surprise the researchers found that the production of a particular gut bacteria byproduct, p-cresol sulfate, led to a “profound and striking protection against asthma,” Marsland added. Part of the serendipity of the finding is that Marsland’s area of expertise is in the immunology of asthma, though he suspects this metabolite may have a role in other inflammatory diseases.
The researchers found that PCS was produced by enhanced bacterial metabolism of the amino acid L-tyrosine, which is found in dietary supplements aimed at improving attention and alertness. “We found that giving mice either L-tyrosine or PCS, provided significant protection against lung inflammation,” Marsland continued. “PCS travels all the way from the gut, to the lungs, and acts on epithelial cells lining the airways to prevent the allergic asthma response.”
Experiments by the investigators also found that the metabolites were protective in animal models of ARDS. “Although these data particularly highlighted the beneficial effects of L-tyrosine and PCS in reducing type 2 inflammation, such as that underpinning atopic asthma, it is noteworthy that they were also efficacious against neutrophilic inflammation, which is a hallmark of type 17 responses,” they wrote.
The team concluded: “Collectively, our work identifies a new pathway within the gut–lung axis, which could be targeted therapeutically to treat or prevent inflammatory diseases, such as atopic or severe neutrophilic asthma … PCS and L-tyrosine hold promise to be developed as novel therapeutics against inflammatory diseases, although their safety and efficacy need to be carefully evaluated.”
While L-tyrosine has a long history of use in dietary supplements, its potential use as a therapy could be fast-tracked into clinical trials because it is known to be safe. Marsland commented, “It’s very important that a thorough clinical study is performed in order to determine whether L-tyrosine is effective in people with asthma, and for us to determine what is the correct dose and treatment regime.”
PCS levels are known to be elevated in people with chronic kidney disease, and it’s suspected to be toxic because of these patients’ inability to clear the compound. However, the team pointed out, the results of prior studies in animals indicates that “ … it is likely that PCS has detrimental effects only when kidney function is impaired or that it is primarily a biomarker of this condition.” And notably, they pointed out, an analysis of data from two separate cohorts of children with or without asthma showed that PCS was inversely associated with asthma. “Although PCS has been reported as a uremic toxin in individuals with chronic kidney disease, it is present in the blood of healthy individuals and, notably, is one of the very few metabolites associated with protection against childhood asthma.”
The research group has started to develop a form of PCS that is a potent protector against asthma without the potential toxic side effects. More importantly, the scientists have found that inhaling PCS provides a direct protective effect against lung inflammation, opening the way for a novel inhaled preventive therapy.