Understanding the mechanisms of antibiotic induced weight loss and the subsequent impact on immunity

Dooley, Megan and Worthington, John (2025) Understanding the mechanisms of antibiotic induced weight loss and the subsequent impact on immunity. PhD thesis, Lancaster University.

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Abstract

Antibiotics are important drugs used to treat bacterial infections that overwhelm our immune system. Unfortunately, they do not specifically target pathogenic bacteria and therefore also affect the gut microbiota, leading to dysbiosis and unpleasant side effects such as weight changes. The exact mechanism by which antibiotics alter body weight remains unknown. Enteroendocrine peptide hormones are released in response to luminal nutrients and regulate appetite and feeding behaviour during homeostasis, but whether they play a role in antibiotic induced weight loss is unclear. Hardgrave et al. (2022) revealed that fluoroquinolone antibiotic, ciprofloxacin, causes weight loss mediated by peptide hormone, cholecystokinin (CCK). This thesis investigated whether ciprofloxacin induced weight loss can be ameliorated using CCK receptor antagonist treatment. Wildtype (WT) mice were treated with CCK receptor antagonist, devazepide, alongside ciprofloxacin treatment and a reduction in weight loss was observed compared to animals treated with ciprofloxacin alone. Whether this CCK-driven mechanism of weight loss is common to other, non-fluoroquinolone antibiotics was also investigated. WT and CCK knockout (KO) mice were treated with a human equivalent dose of doxycycline, a tetracycline antibiotic. Involvement of other enteroendocrine peptide hormones in doxycycline induced weight loss was also investigated via treatment of glucagon-like peptide-1 (GLP-1) receptor knockout mice (GLP-1rKO). Body weight and food intake were monitored throughout the course of treatment and various immune cell subsets were examined following treatment to identify alterations in immunity. Doxycycline induced weight loss was found not to be under mechanistic control of CCK, but GLP-1 was involved. GLP-1rKO animals were partially protected against doxycycline induced weight loss, particularly at the later time points of treatment. Understanding the role of enteroendocrine peptide hormones in antibiotic induced weight loss gives rise to the potential for adjunct usage of peptide hormone receptor antagonists to prevent weight loss and mitigate harmful adverse effects.