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

The gut-brain axis has emerged as a complex regulator of system-wide physiology, playing essential roles to maintain homeostasis, including contributions to brain development and activity, affecting host metabolism and behavior.

The gut bacterial composition constantly fluctuates, allowing for the regular release of diverse microbe-derived compounds into the bloodstream.

Although it is known that many gut-bacterial metabolites affect distant organs such as the brain, their direct interaction with brain neurons is rarely demonstrated.

The impact of microbial metabolites on brain mechanisms are generally thought to be indirect due to interaction with, for example, the immune system or the vagus nerve.

However, my previous work has shown that microbe-derived muropeptides reach the brain and decrease the spontaneous activity of brain neurons that express the Nod2 receptor. Remarkably, this direct interaction affected appetite and thermoregulation in a sex- and age-dependent fashion.

Nevertheless, to further understand these direct interactions, some questions still need to be addressed: how does this compound reach the brain? Which factors may lead to this sex- and age-dependent neuronal activation? Are there other neuroactive bacterial compounds directly affecting brain neurons?

Therefore, using interdisciplinary approaches, I propose to (1) unravel gut-brain trafficking mechanisms, (2) define physiological factors (e.g. hormones) that shape this microbe-neuron interaction and (3) describe new bacterial compounds that affect hypothalamic circuits and their downstream effects.

This proposal will expose novel aspects of host-microbe interactions, leading to a more complete and integrated understanding of bacterial influence on host’s essential functions.

It may also lead to new therapeutic approaches for neurological disorders that exhibit specific sex prevalence and where the microbiota is a factor in disease susceptibility, such as Alzheimer’s and Parkinson’s diseases.