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Crosstalk between microbiota metabolites and immune cells, the missing link to brain damage.

Periodic Reporting for period 1 - MetaBiota (Crosstalk between microbiota metabolites and immune cells, the missing link to brain damage.)

Período documentado: 2017-05-01 hasta 2019-04-30

Stroke is a frequent and devastating disease: accounting for almost 1.5 million of people suffering a stroke each year in Europe with only 15% of stroke patients being eligible for a specific treatment. Despite considerable advances in prevention and care, stroke remains one of the most common causes of death and the leading cause of long-term disabilities (Benjamin et al., Circulation 2019). With the ageing population, patients living with stroke are estimated to increase within the next 15 years of almost one million across the EU (Wilkins et al., The Burden of Stroke in Europe, 2017). Thus, there is a pressing need for a better comprehension of the underlying cellular and molecular mechanisms occurring during a stroke to prevent the cascade of deleterious events and to ameliorate recovery.

Stroke is a neuroinflammatory disease that is characterized by the recruitment of circulating immune cells to the injured brain. Previous studies have focused on how to modulate the peripheral immune system to improve stroke outcome. The gut contains the largest number of immune cells in our body and immune cell function is regulated by the gut microbiota. Thus, research has recently investigated the critical role of the gut microbiota as immunomodulators and the possible role of the microbiome to influence brain function.


Experimental findings suggest that the composition of the microbiota is changing after stroke (also know as dysbiosis) and induces detrimental effects on the ischemic brain. I have shown together with others that the function of immune cells is modulated by the gut microbiota and that intestinal immune cells migrate from the gut to the brain where they contribute to neuroinflammation and secondary brain injury (Benakis et al. Nat. Med. 2016, Singh et al. J. Neurosci. 2016). In particular, modification of the gut microbiota composition towards an anti-inflammatory response in the gut is neuroprotective, and re-establishing the dysbiotic microbiota in mice subjected to stroke by fecal transfer from an non-stroke animal improves outcome, showing a direct connection along the gut-brain axis via intestinal immune cells (Benakis et al., Nat Med 2016; Singh et al., J Neurosci 2016; Sadler et al., Brain Behav Immun 2018).

It is still not known which bacterial species and bacterial products are involved in this gut-to-brain communication. Interestingly, gut-to-brain communication may occur via the production of metabolites from the gut resident bacteria. Indeed, there is accumulating evidence showing that metabolites derived from the gut microbiota influence brain diseases via the regulation of intestinal immune cell function.

The key objective of my project is to investigate whether metabolites produced by gut bacteria can influence stroke outcome via the regulation of immune cells in the gut.
The overall objective of my project is to test how immune cells are regulated by bacterial metabolites, in particular the tryptophan metabolism and its related metabolites known as AhR ligands in a mouse model of stroke. To answer this question, I developed three objectives:

Objective 1) Identify key metabolites of the tryptophan pathway that are altered after stroke by analysing the metabolites (metabolomics) and the bacteria in the gut (metagenomics).
The main results of this first objective are: a) tryptophan metabolism derived from the gut bacteria (also known as indole metabolites) is altered after stroke. b) the microbiota composition related to tryptophan metabolism is altered after stroke.

Objective 2) Test how AhR influences immune cell function and stroke outcome.
Ahr is present in immune cells and is regulated by tryptophan. I tested how the function of different immune cell populations are modified by the absence of AhR.
The main result of this second objective is: Dendritic cells–which are key intermediates between bacteria and adaptive immunity–are regulated in an Ahr-dependent manner after stroke.

Objective 3) Therapeutic efficacy in experimental stroke of tryptophan metabolites
I investigated whether an indole metabolite (IPYA) has an impact on immunity in the gut and modifies stroke outcome. I could not find an effect of IPYA on these two parameters. I am currently investigating whether a) dietary tryptophan supplementation by the diet and b) small molecule inhibitors of AhR have an impact of dendritic cell population and stroke outcome.


As a final report of this project, the overview of my results are the following: I have found that tryptophan metabolism is altered after stroke and that dendritic cells–which are key intermediate between bacteria and adaptive immunity–are regulated in an AhR-dependent manner after stroke and and influence the outcome of stroke.


Exploitation and dissemination of the results:
1) The results of this project will be published in peer-reviewed journal. Importantly, upon completion of the analysis, the data regarding the tryptophan metabolomics and metagenomics after stroke will be available at public repositories (http://www.metabolomicsworkbench.org) in accordance with good scientific practice.

2) I have been very active in disseminating my pre-publication results to the scientific community as poster and oral presentation in international (Stroke conference, Brain conference) and European (Neurorepair and Neuroprotection symposium) conferences. Also I participated at the Mind Mood Microbes conference this year in Amsterdam, where I gave an interview that could be find here: https://mindmoodmicrobes.org/videos-pro.php

3) I have started a new collaboration with a company in Boston, leader in developing probiotics, with whom we will test engineered bacteria that are selected to induce an anti-inflammatory response. I aim to use these bacteria to test their impact on stroke outcome. We are currently establishing an amendment between the company and our university to be able to test this hypothesis.
Findings derived from this study may allow for the identification of microbial metabolite-based therapies to alleviate the neuroinflammatory response to stroke and improve recovery.

Targeting the gut microbiota as a therapeutic approach has a strong socio-economic impact since one can postulate that diet interventions modifying the tryptophan pathway can ameliorate the health condition of patients who had a stroke and significantly reduced the number of patients with post-stroke deleterious outcomes. Importantly, findings from this proposal can have a wider impact on other brain diseases with immuno-components, such as multiple sclerosis, Parkinson disease and Alzheimer disease.
Project hypothesis