Oral Presentation 15th Lorne Infection and Immunity 2025

Light-induced circadian rhythm disruption protects the host from Clostridioides difficile infection (#43)

Desirel Ng 1 , Steven J Mileto 1 , Diana Lopez Urena 1 , Sean W Cain 2 , Dena Lyras 1
  1. Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Melbourne, Victoria, Australia
  2. College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia

The brain, intestinal functions and gut microbiota communicate through bidirectional signalling pathways known as the gut-microbiota-brain axis to maintain health and homeostasis (1). The gut-microbiota-brain axis is also regulated by circadian rhythms, ~24-hour cycles of physiological processes synchronised with the light/dark cycle by the brain (2). However, less is known about how these systems interplay with gut infections. One bacterial pathogen is Clostridioides difficile, the leading cause of hospital-acquired diarrhoea, which colonises the colon during gut dysbiosis causing toxin-mediated damage (3). We have previously shown that C. difficile infection (CDI) can dysregulate gut circadian rhythms, suggesting that CDI may interact with brain-coordinated rhythms (López-Ureña, Mileto & Lyras, unpublished). To examine this, mice were housed in 24-hour constant light rather than standard 12-hour light/12-hour dark cycles to disrupt their circadian rhythms before infection with C. difficile. After infection, clinical scoring of cumulative CDI symptoms (e.g. diarrhoea and weight loss) in constant light-housed mice at peak infection was significantly 2.57-fold lower and delayed by ~12 hours compared to those in standard conditions. This was accompanied by reduced C. difficile toxin production and colonisation. While all infected mice in standard conditions did not survive past 36 hours post-infection, constant light enabled 40% survival with significantly reduced colon damage in surviving mice. This is the first study to construct a mouse model incorporating CDI and circadian rhythm disruption, leading us to show that constant light impacts the outcome of CDI by reducing colonisation, toxins and gut damage. These results demonstrate that circadian rhythm disruption can impact host-C. difficile interactions and may perturb rhythmic fluctuations in periods of vulnerability to infection, which is relevant to modern environments where artificial lights replace natural light cycles. Exploiting this concept via light therapy may be an innovative strategy for resolving CDI and other gut infections of healthcare concern.

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