Hardgrave, Alex and Worthington, John and D'Elia, Riccardo and Rigby, Rachael and Benedetto, Alexandre (2023) Innate Immune Modulation by Fluoroquinolones : The Influence of Gastrointestinal Hormones. PhD thesis, Lancaster University.
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Abstract
As well as targeting bacteria directly, antibiotics have various harmful effects on host cells, often attributed to loss of commensal bacteria. Fluoroquinolone antibiotics are particularly well known for this, and have been attributed to symptoms such as tendon rupture and nerve damage. Whilst many clinical effects of fluoroquinolones are well documented, less so are the direct effects they have on immune cells and their subsequent responses. Antibiotics are known to affect weight and feeding, processes known to be modulated by intestinal hormones such as Cholecystokinin. Fluoroquinolones, typically Ciprofloxacin and Levofloxacin are used as treatments for severe acute respiratory infections, such as inhalation Anthrax and Pneumonia. We therefore focussed on the effects they can have on macrophages, key cells in lung disease. We treated bone marrow-derived macrophages with Levofloxacin and Ciprofloxacin, and studied key parameters such as activation and polarisation via flow cytometry. Moreover, we treated both wild-type and CCK knockout mice with human equivalent dose regimes of these antibiotics to assess alteration of various innate immune cell subsets in the uninfected state. We also extracted bacterial DNA from the faeces of treated mice to investigate any dysbiosis that occurs. Fluoroquinolones were found to affect Macrophage polarisation both in vitro and in vivo, causing a ‘boost’ in M1 polarisation following BMDM IFNγ stimulation, while following 14 day treatment in vivo we also saw an increase in M1 polarisation in the lung. Interestingly we found profound CCK mediated weight loss in both Ciprofloxacin and Levofloxacin treated mice versus controls, as well as dysbiosis after only 24hrs of treatment. The role of CCK in this mechanism gives rise to the possibility of introducing CCK receptor antagonist co-treatment with fluoroquinolone treatment in order to mitigate and reduce harmful side effects.