Molecular and functional analysis of the GUT circadian clock

• Applicant: Dr. Silke Kiessling
• Subject Area: Nutritional Sciences
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 387083114

• Final Report Year: 2023

Final Report Abstract

Disruption of the circadian (approx.. 24 h) body clock, which occurs in shift work, has been linked to an increased risk of inflammatory bowel disease (IBD). Although gut immune homeostasis is controlled by the circadian system, it remains unclear whether the gut clocks itself plays a role in the development of gut inflammation. In a genetic mouse model for colitis we found a disrupted clock in the inflamed colon, which led us to investigate the cause and effect relationship between colon clock disruption and colon inflammation. Next-generation sequencing analysis in mice with a genetically dysfunction gut clock identified that the gut clock controls genes involved in immune/inflammatory responses and bacteria defence. Therefore we hypothesize that a dysfunctional gut clock might impact the development or progression of gut inflammation. Indeed, in gut clock deficient mice chemically and genetically induced colitis severely reduced survival, enhanced inflammation, determined by histological scoring, qPCR of inflammatory markers and immune cell infiltration (macrophages and neutrophils) measured by flow cytometry as well as reduced body weight. These results clearly demonstrate that lack of the gut clock promotes the sensitivity to acute and chronic colon inflammation. The gut microbiome represent another important factor in the development of gut inflammation. Microbiota sequencing analysis of gut clock deficient mice revealed that the gut clock is responsible for the oscillation of 80% of the rhythmic bacteria residing in the gut. Fecal microbiota transfer of disease-associated microbiota into germ free (GF) gut clock deficient recipients further supported that the host gut clock plays an important role in microbiotainduced IBD development. Moreover, restoring the gut clock in an IBD-related mouse model by night restricted feeding (RF) significantly enhanced survival and reduced gut inflammation. This effect on the severity and progression of was gated by the gut clock, because RF failed to ameliorate the colitis symptoms and survival in IBD-related mice with an additionally defective gut clock. These results demonstrate that a functional gut clock is essential to maintain gastrointestinal homeostasis and represents a major player in IBD. Taken together, our findings indicate that enhancing intestinal clock function by meal-timing could become a novel strategy to ameliorate the symptoms in IBD patients.

Publications

• Arrhythmic Gut Microbiome Signatures Predict Risk of Type 2 Diabetes. Cell Host & Microbe, 28(2), 258-272.e6.
  Reitmeier, Sandra; Kiessling, Silke; Clavel, Thomas; List, Markus; Almeida, Eduardo L.; Ghosh, Tarini S.; Neuhaus, Klaus; Grallert, Harald; Linseisen, Jakob; Skurk, Thomas; Brandl, Beate; Breuninger, Taylor A.; Troll, Martina; Rathmann, Wolfgang; Linkohr, Birgit; Hauner, Hans; Laudes, Matthias; Franke, Andre; Le Roy, Caroline I.; ... & Haller, Dirk
  
• Comparing Circadian Rhythmicity in the Human Gut Microbiome. STAR Protocols, 1(3), 100148.
  Reitmeier, Sandra; Kiessling, Silke; Neuhaus, Klaus & Haller, Dirk
  
• Genetic and environmental circadian disruption induce weight gain through changes in the gut microbiome. Molecular Metabolism, 66, 101628.
  Altaha, Baraa; Heddes, Marjolein; Pilorz, Violetta; Niu, Yunhui; Gorbunova, Elizaveta; Gigl, Michael; Kleigrewe, Karin; Oster, Henrik; Haller, Dirk & Kiessling, Silke
  
• The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis. Nature Communications, 13(1).
  Heddes, Marjolein; Altaha, Baraa; Niu, Yunhui; Reitmeier, Sandra; Kleigrewe, Karin; Haller, Dirk & Kiessling, Silke
  
• The Intestinal Clock Regulates Host Metabolism through the Fiber-Dependent Microbiome and Macronutrient Transcriptome. Cold Spring Harbor Laboratory.
  Heddes, Marjolein; Niu, Yunhui; Altaha, Baraa; Kleigrewe, Karin; Meng, Chen; Haller, Dirk & Kiessling, Silke
  
• Targeting the intestinal circadian clock by meal timing ameliorates gastrointestinal inflammation. Cellular & Molecular Immunology, 21(8), 842-855.
  Niu, Yunhui; Heddes, Marjolein; Altaha, Baraa; Birkner, Michael; Kleigrewe, Karin; Meng, Chen; Haller, Dirk & Kiessling, Silke