Decoding a direct dialog between the gut microbiota and the brain

Date:
April 15, 2022
Source:
Institut Pasteur
Summary:
Gut microbiota by-products circulate in the bloodstream, regulating
host physiological processes including immunity, metabolism and
brain functions. Scientists have discovered that hypothalamic
neurons in an animal model directly detect variations in bacterial
activity and adapt appetite and body temperature accordingly. These
findings demonstrate that a direct dialog occurs between the
gut microbiota and the brain, a discovery that could lead to new
therapeutic approaches for tackling metabolic disorders such as
diabetes and obesity.



FULL STORY ==========================================================================
Gut microbiota by-products circulate in the bloodstream, regulating
host physiological processes including immunity, metabolism and brain functions.

Scientists from the Institut Pasteur (a partner research organization
of Universite' Paris Cite'), Inserm and the CNRS have discovered that hypothalamic neurons in an animal model directly detect variations
in bacterial activity and adapt appetite and body temperature
accordingly. These findings demonstrate that a direct dialog occurs
between the gut microbiota and the brain, a discovery that could lead
to new therapeutic approaches for tackling metabolic disorders such as
diabetes and obesity. The findings are due to be published in Scienceon
April 15, 2022.


==========================================================================
The gut is the body's largest reservoir of bacteria. A growing body of
evidence reveals the degree of interdependence between hosts and their
gut microbiota, and emphasizes the importance of the gut-brain axis. At
the Institut Pasteur, neurobiologists from the Perception and Memory Unit (Institut Pasteur/CNRS)[1], immunobiologists from the Microenvironment
and Immunity Unit (Institut Pasteur/ Inserm), and microbiologists from
the Biology and Genetics of the Bacterial Cell Wall Unit (Institut Pasteur/CNRS/Inserm)[2] have shared their expertise to investigate how
bacteria in the gut directly control the activity of particular neurons
in the brain.

The scientists focused on the NOD2 (nucleotide oligomerization domain)
receptor which is found inside of mostly immune cells. This receptor
detects the presence of muropeptides, which are the building blocks of the bacterial cell wall. Moreover, it has previously been established that
variants of the gene coding for the NOD2 receptor are associated with
digestive disorders, including Crohn's disease, as well as neurological diseases and mood disorders. However, these data were insufficient to demonstrate a direct relationship between neuronal activity in the brain
and bacterial activity in the gut. This was revealed by the consortium
of scientists in the new study.

Using brain imaging techniques, the scientists initially observed that the
NOD2 receptor in mice is expressed by neurons in different regions of the brain, and in particular, in a region known as the hypothalamus. They subsequently discovered that these neurons' electrical activity is
suppressed when they come into contact with bacterial muropeptides from
the gut. "Muropeptides in the gut, blood and brain are considered to be
markers of bacterial proliferation," explains Ivo G. Boneca, Head of the Biology and Genetics of the Bacterial Cell Wall Unit at the Institut
Pasteur (CNRS/Inserm). Conversely, if the NOD2 receptor is absent,
these neurons are no longer suppressed by muropeptides.

Consequently, the brain loses control of food intake and body
temperature. The mice gain weight and are more susceptible to developing
type 2 diabetes, particularly in older females.

In this study, the scientists have demonstrated the astonishing fact that neurons perceive bacterial muropeptides directly, while this task was
thought to be primarily assigned to immune cells. "It is extraordinary
to discover that bacterial fragments act directly on a brain center as strategic as the hypothalamus, which is known to manage vital functions
such as body temperature, reproduction, hunger and thirst," comments Pierre-Marie Lledo, CNRS scientist and Head of the Institut Pasteur's Perception and Memory Unit.

The neurons thus appear to detect bacterial activity (proliferation and
death) as a direct gauge of the impact of food intake on the intestinal ecosystem.

"Excessive intake of a specific food may stimulate the disproportionate
growth of certain bacteria or pathogens, thus jeopardizing intestinal
balance," says Ge'rard Eberl, Head of the Microenvironment and Immunity
Unit at the Institut Pasteur (Inserm).

The impact of muropeptides on hypothalamic neurons and metabolism raises questions on their potential role in other brain functions, and may help
us understand the link between certain brain diseases and genetic variants
of NOD2. This discovery paves the way for new interdisciplinary projects
at the frontier between neurosciences, immunology and microbiology,
and ultimately, for new therapeutic approaches to brain diseases and
metabolic disorders such as diabetes and obesity.

[1] This research unit is also known as the "Genes, Synapses and Cognition Laboratory" (Institut Pasteur/CNRS). Paris Brain Institute (CNRS/Inserm/ Sorbonne Universite'/AP-HP) also contributed to these findings.

[2] The CNRS unit's name is the "Integrative and Molecular Microbiology
Unit" and the Inserm unit's name is the "Host-Microbe Interactions and Pathophysiology Unit" (Institut Pasteur/CNRS/Inserm).


========================================================================== Story Source: Materials provided by Institut_Pasteur. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Ilana Gabanyi, Gabriel Lepousez, Richard Wheeler, Alba
Vieites-Prado,
Antoine Nissant, Se'bastien Wagner, Carine Moigneu, Sophie Dulauroy,
Samia Hicham, Bernadette Polomack, Florine Verny, Philip Rosenstiel,
Nicolas Renier, Ivo Gomperts Boneca, Ge'rard Eberl, Pierre-Marie
Lledo.

Bacterial sensing via neuronal Nod2 regulates appetite and body
temperature. Science, 2022; 376 (6590) DOI: 10.1126/science.abj3986 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220415100551.htm

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