Trafficking mechanisms and physiological factors mediating a direct gut microbiota-brain neuron interaction

Projektinformationen

MicrobiotaNeuroTalk

ID Finanzhilfevereinbarung: 101116569

DOI

10.3030/101116569

EK-Unterschriftsdatum 17 November 2023

Startdatum 1 Dezember 2023

Enddatum 30 November 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 875 000,00

EU-Beitrag

€ 1 875 000,00

Koordiniert durch

FUNDACAO GIMM - GULBENKIAN INSTITUTE FOR MOLECULAR MEDICINE
Portugal

Periodic Reporting for period 1 - MicrobiotaNeuroTalk (Trafficking mechanisms and physiological factors mediating a direct gut microbiota-brain neuron interaction)

Berichtszeitraum: 2023-12-01 bis 2026-05-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The microbial community of the gastrointestinal tract and the central nervous system communicate via a bidirectional network of signaling pathways known as the gut-brain axis. This axis has emerged as a complex regulator of system-wide physiology, playing essential roles in the outcomes of metabolic and neurological diseases. Thus far, most gut-brain axis mechanisms are described as indirect via bacterial interaction with, for example, the immune system or the vagus nerve. However, microbe-derived compounds are found in the brain, where these compounds can interact directly with neurons, in a direct gut-brain axis mechanism. My work was one of the first to highlight that brain neurons responded via a direct mechanism to microbe-derived compounds in an interaction that was sex- and age-dependent. However, the limited knowledge of how these compounds reach the brain, whether the gut-brain axis is affected by the individual’s physiological state (e.g. hormonal status) and its impact on the host, impairs advances for understanding host-microbe interactions and translational approaches. Therefore, this project is set up to unveil the trafficking mechanisms of gut-derived compounds to the brain and to dissect how physiological factors influence microbe-induced neuronal activation. Furthermore, this project may lead to the description of novel neuroactive microbe-derived compounds, describing their effects on the host’s metabolism and behavior. This work will advance the knowledge of how gut-commensal bacteria can interact with brain neurons, regulating host physiology and the factors that impact this interaction. This new knowledge will be a major step towards understanding novel aspects of host-microbial symbiotic relationships, opening new possibilities for developing individual-specific treatments for neurometabolic diseases and beyond.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

We have confirmed using 3D brain imaging and ClearMap analysis that sex hormones play a major role in regulating how the brain neurons respond to muramyl dipeptide (MDP). We developed in the laboratory different reporter and conditional knockout lines to evaluate the role of Nod2 in different metabolic and behaviour outcomes.
Using the reporter lines, we have detected, in different brain areas, neurons that co-express Nod2 and sex-hormone receptors. With the different conditional knockout lines we are establishing the role of neuronal Nod2 on social behaviour and stress responses.
In many of our studies we are detecting a strong sex and age-bias in the responses to gut bacteria-derived muropeptides. Moreover we are also addressing how the neuronal responses to MDP change with the circadian cycles, we were able to detect major changes and we are
currently evaluating whether muropeptide transport to the brain has a circadian regulation and whether the feeding behaviour can impact the brain response.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Our results indicate a "multi-modal" regulation of the gut-brain axis, where sex hormones, age and circadian cycle impact how brain neurons regulate their response to bacterial compounds derived from our gut-microbiota.
We are now conducting further studies to address the mechanisms, we are developing new tools and designing new experimental approaches to dissect the different compounds of this intricate communication.
Our strategy will allow us to manipulate one component at a time and evaluate the outcomes of this manipulation. With this approach we expect to dissect the implication of the different components that influence the brain neuronal response to muropeptides.
Understanding the role of each component may allow for the design and/or refinement of tools/treatments for the mitigation of the detrimental effects of several neurological and metabolic disorders.