Komplikationen verhindern

Brain-Gut-Interaction

In experimentellen und klinischen Untersuchungen wird den Fragen, ob Schlaganfall sich auf das Darmmikrobiom auswirkt und ob das Darmmikrobiom sich auf den Outcome  nach Schlaganfall auswirkt, nachgegangen.
Fortsetzung/Projektbeschreibung

AG Dirnagl
AG Meisel

Projektbeschreibung

The microbiota within the gut are a microbial metabolic organ, composed of trillions of mostly anaerobic bacteria that coevolved with our own physiology. About 500 to 1000 bacterial species colonize the human gut, with a combined genome 100 times larger than our own. It has long been established that these microbiota play a major role in metabolic as well as immunological homeostasis. Due to advances in DNA-sequencing we are now able to study these bacteria, most of which cannot be cultured, and their impact on health and disease. It is now emerging that the intestinal microbiome is also an important modifier of the pathophysiology of numerous diseases, from obesity to multiple sclerosis. Gut metagenomics in combination with germ free animals (gnotobionts), selective bacterial colonization, as well as transgenic animals allow the dissection of the contribution of the intestinal microbiome to disease, including brain pathology. After brain lesion (e.g. stroke) the brain engages in intense signalling with the immune system, with deleterious as well as protective consequences. The intestinal immune system is the largest and most complex part of the immune system. Altered systemic immunity after brain lesion may affect bacterial microbiota, and lead to the translocation of bacteria and their products via mucosal barrieres, further impacting on the immune system, and providing co-stimulation in immune-brain cell interaction. Besides via the immune system, direct impact of brain lesions on bacterial microbiota is expected via the sympathetic nervous system as well as the N.vagus. The autonomic nervous thus provides a further route for brain-gut communication after lesion, as it provides a neural link to the enteric nervous system.

Thus, based on our previous results on brain-immune interactions and autonomic nervous system activation after stroke, and the recent advances in studying gut microbiota, this project explores the following novel, hitherto completely unexplored but clinically highly relevant hypotheses:

  • Stroke changes the gut microbiome
  • The gut microbiome affects outcome after stroke
  • Gut microbiome impacts on outcome after CNS lesion via a) effects on the immune system, including costimulation by bacterial products; b) direct humoral/metabolic signaling; and c) effects on enteral nervous system.

We have collected preliminary experimental evidence that stroke alters the gut microbiome, but it is unclear whether this occurs in patients, and what effect on the course and outcome of the disease this might have. In the clinical part of this project we hypothesize that

  • cerebral ischemia induces changes in the human gut microbiome, and that
  • the gut microbiome of stroke patients differs from the non-stroke population.

These hypotheses will be tested in mouse models of experimental stroke by characterizing changes in the gut microbiome, gut morphology (including the gut associated lymphoid system), gut function (permeability), and bacterial translocation in relation to stroke phenotype (infarct volumes, behaviour, post-stroke infection etc.). In a second step we will manipulate gut microbiota in these models (gnotobionts) and / or gut decontamination, recolonization with specific microbiota). The clinical part of the project we are currently performing an observational study (Influence of Stroke on the Composition of Intestinal Microbiota, GUTSTROKE, ClinicalTrials.gov Identifier: NCT02008604). The aim of this study is to verify the hypothesis that the microbial colonisation of the gut is changed in patients after stroke and that the gut microbiome of severely affected stroke patients differs from that of patients with only a short disruption of blood circulation in the brain (transient ischemic attack, TIA). For this, the composition of gut microbiota in stool samples will be analyzed by 454 pyrosequencing. Further, the correlation of stroke-associated changes in the microbiome with immunological parameters will be analyzed.

Principal Investigators

  • Katarzyna Winek
  • Andreas Meisel
  • Ulrich Dirnagl

Collaboration Partners

  • Andreas Nitsche, Robert-Koch-Institut, Berlin, Germany
  • Stefan Bereswill, Markus Heimesaat; Department of Microbiology and Hygiene, Charité – Universitätsmedizin Berlin, Germany

 

 

Zurück zur Übersicht
Logo Charité Berlin Logo Centrum für Schlaganfallforschung Berlin
© 2018 CSB | TYPO3 Website von Kombinat Berlin