Final Report, ECCO Grant for Silke Kiessling
Silke Kiessling, ECCO Grant Awardee
Induction of circadian microbial function in chronic intestinal inflammation
© Silke Kiessling
Background & aim of research
Impaired clock gene expression has been observed in biopsies from patients with Inflammatory Bowel Disease (IBD). Disruption of circadian rhythms, which occurs in shift workers, has been linked to an increased risk of gastrointestinal diseases, including IBD. The intestinal clock balances gastrointestinal homeostasis by regulating the microbiome. We aimed to characterise intestinal immune functions in mice lacking the intestinal clock and in IBD-relevant mouse models under different feeding conditions in order to assess the functional impact of the intestinal clock in the development of gastrointestinal inflammation.
Methodology used in the research
Tissues and faecal samples from intestinal clock-deficient mice (Bmal1IEC-/-) and mouse models for colitis (IL-10-/-, Bmal1IEC-/-xIL-10-/-, DSS administration) under ad libitum and restricted feeding (RF) conditions were used to determine the causal role of the intestinal clock in colitis. Experiments involving faecal microbiota transfer into germ-free recipients were used to directly test the role of microbial rhythmicity in the progression and development of IBD.
Main findings/results of the research
Lack of the intestinal clock promoted gut inflammation and dramatically reduced survival in colitis models. Germ-free Bmal1IEC-/- hosts colonised with disease-associated microbiota exhibited increased inflammatory responses, suggesting the importance of the intestinal clock for IBD development. RF in IL-10-/- mice restored the colon clock and related immune functions, improved the inflammatory responses and rescued the histopathological phenotype. In contrast, RF failed to improve IBD symptoms in Bmal1IEC-/-xIL-10-/- mice, demonstrating the significance of the intestinal clock in gating the effect of RF.
Conclusions and perceived impact of the findings
We obtained evidence that inflammation-associated intestinal clock dysfunction triggers host immune imbalance and promotes the development and progression of IBD-like colitis. Enhancement of intestinal clock function by RF modulates the pathogenesis of IBD and thus could become a novel strategy to ameliorate the symptoms in IBD patients.
Plan of publication
- Altaha, B., M. Heddes, V. Pilorz, Y. Niu, E. Gorbunova, M. Gigl, K. Kleigrewe, H. Oster, D. Haller and S. Kiessling (2022). "Genetic and environmental circadian disruption induce weight gain through changes in the gut microbiome." 66: 101628. Mol Metab IF: 8.6
- Heddes, M., B. Altaha, Y. Niu, S. Reitmeier, K. Kleigrewe, D. Haller and S. Kiessling (2022). "The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis” 13(1): 6068. Nat Commun IF: 17.7
- Yunhui Niu, Marjolein Heddes, Baraa Altaha, Michael Birkner, Karin Kleigrewe, Chen Meng, Dirk Haller, View ORCID ProfileSilke Kiessling, Targeting the intestinal circadian clock by meal timing ameliorates gastrointestinal inflammation, BioRxiv 2023 currently submitted
- Marjolein Heddes, Yunhui Niu, Baraa Altaha, Karin Kleigrewe, Chen Meng, Dirk Haller, Silke Kiessling, The Intestinal Clock Regulates Host Metabolism through the Fiber-Dependent Microbiome and Macronutrient Transcriptome, BioRxiv currently submitted