August 16, 2023

expert reaction to study suggesting molecules in vegetables may help to ease lung infection

A study published in Nature looks suggests that endothelial AHR (aryl hydrocarbon receptor) activity prevents lung barrier disruption in viral infection.

Dr Neil Holden, Senior Lecturer, University of Lincoln, said:

“Whilst it presents a fascinating potential mechanism for protecting the lungs against viral infections, it is a typical early molecular mechanism paper which uses transgenic mice to elucidate the pathways – there still remains a lot of work to show that these pathways constitute a valid therapeutic target in humans with lung viral infections.”

Prof Sheena Cruickshank, Immunologist and Professor in Biomedical Sciences, University of Manchester, said:

“This is a carefully conducted and interesting study looking at the function of the Aryl Hydrocarbon Receptor (AhR) in lung endothelial cells –the cells that line the blood vessels in the lungs. The Aryl Hydrocarbon rector is an important sensor for cells to respond to stresses from the environment and/or infections and as such this is often expressed in parts of the body that are exposed to external stimuli such as the lungs and gut. Although the receptor was present in the cells lining the lung – the epithelium and some immune cells, it was mostly strongly expressed in the endothelial cells. A feature of lung viral infection can be damage to the blood vessels which worsens the outcome of the infection and an important question was if AhR is well expressed in lung vasculature can it help protect the lungs better in infection.  Dietary products can help promote the function of AhR in the gut so this study set out to see if dietary supplementation could activate AhR in the lung. The result of this mouse study shows that this did happen and that an altered diet could indeed activate AhR in the lung endothelial cells and help protect lung barrier function and the repair of the lung following infection challenge.

“However, whilst incredibly interesting it is too early to say whether such a study would translate to human disease. The study has only been performed in mice and further validation would need to be done as mouse diets and microbiomes do differ. Furthermore, the mice – as is standard were kept in pathogen-free conditions with a standardised external environment- therefore it is not clear what might happen in the presence of environmental stressors that may impact the AhR such as would happen in the environment e.g., other infections, pollution etc. Nonetheless, this doesn’t detract from this incredibly important study as if this does translate to humans it provides real hope for future cheap ways that people can improve their outcome to infection. It also reinforces the idea that our diet and microbiome are also very important in the function of our immune systems.”

Dr Claire Bourke, Sir Henry Dale Postdoctoral Research Fellow and Lecturer in Infection & Immunology, Queen Mary University of London (QMUL), said:

“The exciting part about this study is that it identifies a previously unknown way in which cells lining blood vessels in the lung can contribute to defence against lung damage by flu.  The researchers undertook a range of careful and detailed experiments to narrow the effects they saw in flu-infected mice down to this specialised group of blood vessel lining cells and pinpointed a molecular driver of the effect – activity of the aryl hydrocarbon receptor (AhR), which was previously best known about in immune and gut cells. The AhR pathway they identify is responsive to molecules that can originate in food, raising the intriguing possibility that diet could impact defences against infection in the lung. It remains to be seen whether normal diets could do this in the same way as the purified experimental diets used in this laboratory study. The researchers highlight the importance of further investigations into whether other diets and pathways could affect how blood vessel lining cells help and/or hinder the body’s response to infections.”

Dr John Tregoning, Reader in Respiratory Infections, Imperial College London, said:

Summary of study

“One of the causes of disease following influenza virus infection is damage to the lining of the lungs, this can lead to fluid leaking into the airways affecting our ability to breathe. In the published study, the research team at the Crick looked at the role of a protein called the aryl hydrocarbon receptor (Ahr for short) in this process. Ahr is described as an environmental sensor, and cells use it to detect the indole family of molecules that come from our diet, particularly broccoli and cauliflower. The researchers showed that the endothelial cells that line our airways make Ahr and it has an important protective role during lung infection. They did this in two ways, they used mice that make no Ahr or make a more active version. The mice lacking Ahr had more leaky lungs during infection and were sicker. They saw the opposite effect in the more active version, the mice were less sick following influenza virus infection. Since Ahr responds to dietary compounds, the team looked at the effect on influenza infection of spiking mouse food with a chemical derived from broccoli and known to activate Ahr, indole-3-carbinol (I3C). They compared responses to mice that were fed on a diet from which the indoles had been removed. Mice on the diet that lacked the active I3C compound had more leaky lungs after influenza infection, indicating the addition of I3C could protect against lung damage.”

Commentary

“This study is important because it shows how the cells that line the lungs protect against damage following viral infection and that protection from infectious disease is not the sole reserve of the immune system. The study shows that a compound derived from broccoli (and other cruciferous vegetables) can improve protection against viral lung damage. The study is well performed and the conclusions in the mouse model are well backed up.

“How this study translates into people during lung infection needs further work. Moving from a specific readout of airway inflammation in a mouse model given a defined dose of a specific chemical to what human food intake reduces illness following viral infection is challenging – for example how much broccoli would you need to eat to get a protective dose of precursor compound? Further work investigating supplementation of human diet with I3C during influenza infection could answer these questions.”

‘Endothelial AHR activity prevents lung barrier disruption in viral infection’ by Jack Major et al. was published in Nature at 16:00 UK time Wednesday 16 August 2023.

DOI: 10.1038/s41586-023-06287-y

Declared interests

Dr John Tregoning: “I have worked with biontech and sanofi on influenza vaccines, but have no commercial involvement.”

Dr Claire Bourke: I have no conflicts of interest to declare.

For all other experts, no reply to our request for DOIs was received.