P-cresol sulfate (PCS) combat asthma and COVID-related lung diseases discovered


A study designed to study how the immune system impacts gut bacteria—has led to the extraordinary discovery of two molecules that can not only provide profound protection in experimental models of asthma but can also substantially reduce the severity of an attack.

Neither of these molecules, one of which is already commercially available as a dietary supplement, were previously known to have an effect on asthma – and they also appear, from animal studies, to have a role in treating the respiratory illness that is prevalent, and often fatal, in people with serious COVID-19.

The researchers aim to test one of the molecules in a clinical trial in 2021 in asthmatics.

As further evidence that these two molecules could potentially protect against asthma the Monash University researchers found, through studying the literature, that these metabolites are present in higher amounts in two studies of children without asthma compared to those with the disease, according to Professor Benjamin Marsland from the Monash University Central Clinical School, whose paper is published today in Nature Immunology.

Asthma is one of the most common major non-communicable diseases and it impacts 300 million people globally. The global asthma treatment market size stood at over $18 billion US in 2019.

The team led by VESKI innovation fellow, Professor 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,” he said.

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 by-product, called p-cresol sulfate (PCS), led to a “profound and striking protection against asthma.” Part of the serendipity of the finding is that Professor 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 the PCS was produced by enhanced bacterial metabolism of L-tyrosine; a well-known amino acid 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. 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”

The researchers also tested the metabolites in animal models of acute respiratory distress syndrome (ARDS), and found it to be protective. ARDS is a common killer of people with serious COVID-19.

While L-tyrosine has a long history of use in the clinic, as mentioned in dietary supplements, its potential use as a therapy could be fast tracked into clinical trials because it is known to be safe. Professor 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 however is known to be in high levels in people with chronic kidney disease and it’s suspected to be toxic because of these patient’s inability to clear it. The research group has started developing 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.

The incidence and prevalence of chronic kidney disease (CKD) are increasing rapidly worldwide [1]. With disease progression, CKD patients present several comorbidities with high morbidity and mortality rates. Patients with CKD who are undergoing maintenance hemodialysis still have a higher prevalence of neurological complications than those in the general population.

Apart from immune and cardiovascular diseases, CKD is closely associated with various central nervous system (CNS) complications, such as Parkinson’s disease, Alzheimer’s disease, cognitive dysfunction, and depression [2,3,4]. Currently, the underlying causes of disease association and the most vulnerable neurological complications are incompletely understood.

CNS diseases are accompanied by a series of biochemical and molecular changes, resulting in acute and long-term impacts on both behavioral and neurological functions. Changes in blood–brain barrier permeability, oxidative stress, neuroinflammation, neurochemicals, neurotrophins, neurogenesis, apoptosis, and synaptic connection are frequently presented in most neurological diseases [5,6].

In rodent models with CKD caused by adenine feeding or a 5/6 nephrectomy, the experimental animals have shown depression- and anxiety-like behaviors concurrent with an impaired blood–brain barrier and the cerebral activation of oxidative stress and neuroinflammation.

Those studies suggest that depression and/or anxiety may be the most vulnerable neurological complications of CKD [7,8,9]. CKD and CNS diseases share many commonalities, particularly oxidative stress and inflammation [2,3,4,5,6,7,8,9]. The integration of CKD alterations is believed to promote both the transition and pathogenesis for the development of neurological diseases. It is also likely to acquire pathogenic molecules from CKD, and then transition into neuroactive or neurotoxic surrogates.

CKD or the impairment of renal function tends to cause the retention of various solutes that are normally excreted by the kidneys, and that response negatively interacts with a body’s biological functions. The presence of CNS diseases in CKD patients undergoing maintenance hemodialysis implicates the potential pathogenic contribution of non-dialyzable solutes [2,3,4].

p-Cresol sulfate (PCS), one type of protein-bound uremic toxin, is generated by the liver and intestinal bacteria through the metabolic breakdown of tyrosine and phenylalanine. The gut-microbiota metabolite PCS progressively accumulates during the blood circulation of CKD patients due to its high albumin-binding capacity and has been identified as a potential contributor to clinical complications [10,11,12,13].

In a 5/6 nephrectomy CKD rodent model, the content of PCS is elevated in systemic circulation and the brain tissues, while the increments are decreased by uremic toxin absorbent AST-120 [9,11]. Clinically, a higher cerebrospinal fluid to plasma ratio of PCS is observed in patients diagnosed with Parkinson’s disease [14]. These findings suggest that the association between CKD and CNS diseases may be related to the accumulation, and even brain deposition, of PCS.

PCS displays diverse biological activities. Accumulating evidence has shown that PCS causes cell death and dysfunction centered around oxidative stress, inflammation, impairment of mitochondrial dynamics, and vascular disruption [15,16,17,18,19,20,21]. Thus, both the causative and pathogenic effects of PCS in CNS diseases are highly proposed.

The accumulation of uremic toxins and development of severe kidney injury are demonstrated in 5/6- but not unilateral nephrectomized mice [8,9,22]. However, chronic exogenous addition of uremic toxins produces moderate renal fibrosis without changes in serum blood urea nitrogen (BUN) and creatinine in unilateral nephrectomized mice, implying an active role of uremic toxins directly or indirectly in pathophysiological changes [22].

To extend the scope of understanding with regard to CNS complications in CKD, a unilateral nephrectomized mice model was established in order to investigate the possible pathological role PCS plays in CNS through daily administration, as well as analyze any neurobehavioral changes and molecular mechanisms involved.

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555291/

More information: Microbial metabolism of l-tyrosine protects against allergic airway inflammation, Nature Immunology (2021). DOI: 10.1038/s41590-020-00856-3 , www.nature.com/articles/s41590-020-00856-3


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