Browsing by Person "Haasis, Eva Annett Kristin"

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The role of the circadian clock, the microbiome and time-restricted feeding on the development and treatment of colitis
(2025) Haasis, Eva Annett Kristin; Lorentz, Axel
Mammals possess an internal circadian clock in almost all tissues that regulates biochemical and physiological processes over the course of 24 hours. In detail, transcription-translation feedback loops regulate the oscillation of genes over 24 hours. Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) are chronic immune activations and inflammations in the gastrointestinal tract. The etiology of IBD is not completely understood, but is associated with a disrupted circadian clock, e.g. shift work is an increased risk factor for the development of IBD. The aim of this thesis was to investigate the relationship between circadian clock and IBD. Altered light/dark cycles, consisting of four hours of light and four hours of darkness, were used to disrupt the circadian rhythm in a dextran sulfate sodium (DSS)-induced colitis mouse model and an IL-10 knockout (IL-10-/-) mouse model. Food intake is an important Zeitgeber for the circadian clock. Therefore, the potential of time-restricted feeding (TRF) to restore disturbed circadian rhythms and as a therapy for IBD should be investigated. Since fecal microbiota transplantation (FMT) could also be a possible therapy against colitis by improving the composition of the gut microbiota, the transferability of inflammatory and healthy phenotypes by fecal transplantation should be investigated. As bacterial supplementation, both a bacterium that prevents colitis and a bacterium that potentially promotes colitis were used. DSS treatment over eight days only led to early signs of inflammation and was slightly influenced by external light disruption with alternating 4 hours of light and 4 hours of darkness. The protocol for DSS treatment may not have been well suited. The same light disruption led to different results in IL-10-/- mice in two experiments. While in the first experiment an external light disruption led to an increased incidence of colitis and higher inflammation levels, these results were no longer present in the second experiment. The external light disruption led neither to an increased incidence of colitis nor to increased inflammation values. A further experiment, in which samples were taken every six hours, showed that the external light disruption had an effect in wild type (WT) animals and led to a disruption of circadian gene expression. In IL-10-/- mice, the expression of circadian genes was already disrupted at a normal light/dark rhythm of 12 hours/12 hours and further disruption by external light conditions was not possible, which could be an explanation for the different results regarding the occurrence of colitis in IL-10-/- mice with a disrupted light/dark rhythm. Eight-hour restricted feeding of IL-10-/- mice resulted in reduced incidence of colitis, low levels of inflammation and improved circadian clock expression independent of external circadian clock disruption, suggesting that TRF is an effective and useful therapeutic approach for colitis. This observation should be further tested in human studies. Administration of the fecal microbiota of mice with an inflammatory phenotype only led to increased inflammation levels, while an influence of the litter affiliation of the mice was also found in histologic scores and intestinal clock gene expression. Akkermansia muciniphila (A. muciniphila) was given as a colitis-promoting bacterium and led to increased gene expression of inflammatory markers and tight junction proteins, while Lactobacillus taiwanensis (L. taiwanensis), as a potentially colitis-preventing bacterium, improved the expression of the intestinal circadian clock. Neither FMT nor bacterial supplementation had any influence on the occurrence of colitis. The transfer of different phenotypes by FMT was only possible to a limited extent and does not appear to be an effective treatment option for colitis. A. muciniphila can be regarded as an inflammation-promoting bacterium, while a probiotic effect of L. taiwanensis could not be confirmed. In summary, this thesis has shown that a disrupted circadian clock is associated with intestinal inflammation and that TRF reduces inflammation and delays the onset of colitis, suggesting that TRF may be an effective therapy for intestinal inflammation.