DEFINING MECHANISMS UNDERPINNING ANTIBIOTIC MEDIATED DISRUPTION OF PULMONARY IMMUNE RESPONSES
Lead Research Organisation:
University of Manchester
Department Name: School of Biological Sciences
Abstract
Antibiotics are used to kill dangerous strains of bacteria that cause harmful infections, but are often inappropriately prescribed for diseases in which inflammation rather than a bacterial infection is the main cause. This includes asthma which is believed to be caused by a certain type of inflammation, driven by the immune system, called type 2 inflammation. Work in animal models shows that the harmless bacteria which normally live in tissues such as the gut and the lung are beneficial for a healthy immune system and can protect against harmful type 2 inflammation in the lung. Many of these harmless bacteria are also killed by antibiotics and there is increasing experimental evidence in animal models showing that antibiotics can in fact predispose to type 2 inflammation in the lung, contributing to conditions such as asthma.
To date, there have been no studies in humans directly investigating the effects of antibiotics on immune responses in the lung. However individuals who have taken multiple courses of antibiotics earlier in life are more likely to develop asthma. Our pilot data indicate that antibiotic use in animal models alters immune responses in the lung, specifically by activating the immune cells involved in type 2 inflammation. The aim of the current project is to study whether oral antibiotic use has similar effects in humans. We will first investigate whether antibiotics causes healthy individuals to have abnormal immune responses in the lung. We will characterise different types of immune cells from the lungs themselves, and by looking at immune cells in the bloodstream, we will be able to see how the rest of the body may be affected. We will determine whether any changes to the immune system correspond to antibiotic induced changes in populations of harmless bacteria in the gut and the lung. Next, we will investigate whether antibiotics alter immune responses in asthmatic individuals who already have type 2 inflammation in the lung. We will focus on discovering cells, molecules and pathways that are involved in antibiotic-driven alterations of immune responses. This work aims to reveal new strategies that could be used to counteract the harmful side effects of antibiotics. These new pathways also have the potential to shape more targeted treatment in type 2 inflammatory diseases such as asthma, as well as increasing our general understanding of how harmless "friendly" bacteria help control immune responses in the lung.
To date, there have been no studies in humans directly investigating the effects of antibiotics on immune responses in the lung. However individuals who have taken multiple courses of antibiotics earlier in life are more likely to develop asthma. Our pilot data indicate that antibiotic use in animal models alters immune responses in the lung, specifically by activating the immune cells involved in type 2 inflammation. The aim of the current project is to study whether oral antibiotic use has similar effects in humans. We will first investigate whether antibiotics causes healthy individuals to have abnormal immune responses in the lung. We will characterise different types of immune cells from the lungs themselves, and by looking at immune cells in the bloodstream, we will be able to see how the rest of the body may be affected. We will determine whether any changes to the immune system correspond to antibiotic induced changes in populations of harmless bacteria in the gut and the lung. Next, we will investigate whether antibiotics alter immune responses in asthmatic individuals who already have type 2 inflammation in the lung. We will focus on discovering cells, molecules and pathways that are involved in antibiotic-driven alterations of immune responses. This work aims to reveal new strategies that could be used to counteract the harmful side effects of antibiotics. These new pathways also have the potential to shape more targeted treatment in type 2 inflammatory diseases such as asthma, as well as increasing our general understanding of how harmless "friendly" bacteria help control immune responses in the lung.
Technical Summary
Antibiotics are prescribed inappropriately for conditions involving airway inflammation such as respiratory viral infections and acute exacerbations of asthma, with dysregulated type 2 inflammation driving pathology in asthma. Animal models show that the commensal microbiota in the intestine and the lung itself protect against harmful type 2 inflammation in the lung, and there is strong epidemiological evidence that antibiotic use in humans can predispose to type 2 inflammatory conditions such as asthma. Here we will test the hypothesis that collateral damage to the microbiota from antibiotics impacts pulmonary immunity in humans in a manner that is detrimental for type-2 mediated disease such as asthma.
Our pilot data demonstrate that in animal models, broad-spectrum antibiotics induce type 2 immune responses in the lung, accompanied by striking changes in energy metabolism and immune activation in alveolar macrophages. To date, there have been no studies in humans investigating the effects of antibiotics on immune responses in the lung, and it is completely unknown how the microbiota may alter cellular metabolism to regulate pulmonary immune responses in man. Here, we will translate our previous experimental findings by examining whether antibiotics can have a similar effect in humans, defining the mechanisms by which type 2 inflammation is regulated by the microbiota. We will investigate whether antibiotics might predispose to aberrant type 2 inflammation both in healthy controls and in patients with mild asthma who are already primed for overactive type 2 immunity in the lung. We will assess how changes in immune status correlate with antibiotic-induced changes in the respiratory and intestinal microbiota. This project will provide a step-change in our understanding of how type 2 inflammation is regulated in the lung, revealing novel pathways for counteracting the harmful side effects of antibiotics and for therapeutic targeting in asthma.
Our pilot data demonstrate that in animal models, broad-spectrum antibiotics induce type 2 immune responses in the lung, accompanied by striking changes in energy metabolism and immune activation in alveolar macrophages. To date, there have been no studies in humans investigating the effects of antibiotics on immune responses in the lung, and it is completely unknown how the microbiota may alter cellular metabolism to regulate pulmonary immune responses in man. Here, we will translate our previous experimental findings by examining whether antibiotics can have a similar effect in humans, defining the mechanisms by which type 2 inflammation is regulated by the microbiota. We will investigate whether antibiotics might predispose to aberrant type 2 inflammation both in healthy controls and in patients with mild asthma who are already primed for overactive type 2 immunity in the lung. We will assess how changes in immune status correlate with antibiotic-induced changes in the respiratory and intestinal microbiota. This project will provide a step-change in our understanding of how type 2 inflammation is regulated in the lung, revealing novel pathways for counteracting the harmful side effects of antibiotics and for therapeutic targeting in asthma.
