Science - USA (2022-04-15)

RESEARCH ARTICLE SUMMARY

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NEUROIMMUNOLOGY

Bacterial sensing via neuronal Nod2 regulates

appetite and body temperature

Ilana Gabanyi, Gabriel Lepousez, Richard Wheeler, Alba Vieites-Prado, Antoine Nissant,
Sébastien Wagner, Carine Moigneu, Sophie Dulauroy, Samia Hicham, Bernadette Polomack,
Florine Verny, Philip Rosenstiel, Nicolas Renier, Ivo Gomperts Boneca,
Gérard Eberl†, Pierre-Marie Lledo*†

INTRODUCTION:Compounds released by the
microbiota are found in the bloodstream and
can modulate physiological processes in the
host, such as immunity, metabolism, and brain
functions. Microbial metabolites, including
short-chain fatty acids and tryptophan deriv-
atives, regulate many processes through recep-
tors that are widely expressed. However, the
structural components of microbes are de-
tected by pattern recognition receptors (PRRs)
that signal the presence of viruses, bacteria, or
fungi on mucosal surfaces, in tissues, and in
cells. Bacterial components have been found
to modulate brain activity, and PRRs are asso-
ciated with brain disorders. Whether brain
neurons can directly sense bacterial compo-
nents and whether bacteria can regulate phys-
iological processes through regulation of brain
neurons remains to be demonstrated.

RATIONALE:Mice that lack neuronal expression

of Nod2—a PRR recognizing fragments of the

bacterial cell wall termed muropeptides—

develop alterations in food intake, nesting be-

havior, and body temperature control. We used

brain imaging to identify regions affected by

the oral administration of muropeptides and

measured the modulation of neuronal activ-

ity by muropeptides. We also developed mice

that lack Nod2 expression in subsets of neu-

rons and in regions of the hypothalamus that

regulate feeding behavior and body tempera-

ture,soastoassesstheimpactofthegut-brain

axis on the regulation of host metabolism. Finally,

we used patch-clamp recordings to assess wheth-

er neurons directly respond to muropeptides.

RESULTS:Using reporter mice and in situ hy-

bridization techniques, we found that Nod2 was

expressed in neurons of several brain regions

including the hypothalamus. Older female mice

lacking expression of Nod2 in inhibitoryg-

aminobutyric acid transporter–positive (GABAergic)

neurons ate more and consequently gained

more weight than normal mice. Oral adminis-

tration of muramyl dipeptide (MDP), a muro-

peptide ligand of Nod2, reduced feeding but

only when activating Nod2 in GABAergic neu-

rons. These mice also showed a reduced pro-

pensity to build nests, a behavioral trait related

to heat conservation, as well as reduced tem-

perature regulation in response to the circadian

rhythm, fasting, and adrenergic stimulation.

MDP, administered orally or as muropep-

tides produced by intestinal bacteria, reached

the brain and regulated neurons in diverse

brain areas of older female mice, including the

arcuate nucleus of the hypothalamus, which is

involved in the regulation of feeding behavior

and body temperature. The activity of GABAergic

neurons of the arcuate nucleus was depressed

upon feeding and was similarly depressed

upon oral administration of MDP. Infusion

of MDP in single neurons and patch-clamp

recording of neuron excitability demonstra-

ted that MDP-mediated control of GABAergic

neurons was cell-autonomous.

We next tested whether the expression of

Nod2 in hypothalamic GABAergic neurons was

necessary to control food intake and body tem-

perature. Indeed, the ablation of theNod2gene

in hypothalamic neurons alone using the local

injection of a Cre-expressing virus led to weight

gain in older mice. Moreover, this treatment

alterednestbuildingbehaviorandbodytem-

perature control. The intestinal microbiota is

the most probable source of Nod2 ligand in this

context, as oral antibiotic treatment abrogated

the Nod2-mediated control over feeding.

CONCLUSION:Our study shows that structural

components of the bacterial microbiota can be

directly sensed by hypothalamic neurons to

regulate feeding behavior, nesting behavior,

and body temperature. In this way, intestinal

bacteriamaybeusedbythebrainasanin-

direct measure of food intake or as a direct

measure of bacterial expansion or death attrib-

utable to food intake. In the latter scenario,

bacterial expansion or death may be associated

with perturbation of intestinal homeostasis

or a risk of pathogenesis. Alternatively, resident

bacteria may regulate food intake to protect

their intestinal niche.

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RESEARCH

SCIENCEscience.org 15 APRIL 2022•VOL 376 ISSUE 6590 263

The list of author affiliations is available in the full article online.

*Corresponding author. Email: [email protected] (I.G.); gerard.

[email protected] (G.E.); [email protected] (P.-M.L.)

These authors contributed equally to this work.

Cite this article as I. Gabanyiet al.,Science 376 , eabj3986

(2022). DOI: 10.1126/science.abj3986

READ THE FULL ARTICLE AT

https://doi.org/10.1126/science.abj3986

Decreased firing activity

Hypothalamus

Muropeptides

Inhibitory

neuron

Nod2

MDP

Metabolic control via the gut-brain axis.Food consumption induces expansion of the intestinal microbiota.
This expansion is followed by an increase in muropeptide release from the gut bacteria. When they reach
the brain, these muropeptides target a subset of inhibitory hypothalamic neurons. In older females, activation
of neuronal Nod2 receptors by muropeptides decreases neuronal activity, which in turn helps to regulate
satiety and body temperature.