Science - USA (2022-04-15)

15 APRIL 2022 • VOL 376 ISSUE 6590 249

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signals, including from the intestines, to the

central nervous system), immune factors

(e.g., circulating cytokines and chemokines

released within the gut), and signaling hor-

mones or metabolites. Microbial products,

such as metabolites, fatty acids (acetate, pro-

pionate, and butyrate), and even neurotrans-

mitters (dopamine and serotonin), influence

brain cells, including neurons and microglia,

in multiple brain structures. Hence, it is not

surprising that the alteration of these com-

munication pathways is associated with a

range of neurodevelopmental and psychiatric

disorders (1, 4).

Although the signaling pathways involved

in gut-brain communication remain to be

fully elucidated, peptidoglycans have been

detected in the bone marrow, blood, and ce-

rebrospinal fluid (CSF) of healthy humans,

rodents, and nonhuman primates, where

specific receptors or other proteins can de-

tect their presence ( 1 , 3 ). Indeed, peptidogly-

cans bind to pattern-recognition receptors

(PRRs), cytosolic nucleotide-binding oligo-

merization domain-like receptors (NOD1

and NOD2), and membrane-bound Toll-like

receptors (TLRs) and peptidoglycan recogni-

tion proteins (PGRPs). Gabanyi et al. show

that NOD2 is expressed by neurons in the

mouse brain, including the hypothalamus, in

a region- and sex-dependent manner. They

further show that intestinal bacteria–derived

peptidoglycans called muropeptides (MDPs)

bind to NOD2 and decrease the activity of

inhibitory neurons from the arcuate nucleus

(ARC) and ultimately decrease appetite in old

female mice.

The ARC lies at the floor of the hypothala-

mus and is adjacent to the median eminence,

a structure that is permeable to blood-borne

metabolites, hormonal signals, and presum-

ably bacterial products ( 5 ). The ARC con-

tains agouti-related peptide/neuropeptide-Y

(AgRP/NPY)–expressing neurons that signal

hunger and promote feeding, which Gabanyi

et al. also found to express the vesicular g-

aminobutyric acid transporter (VGAT) and

NOD2 and are inhibited upon exposure to

MDPs. Deletion of Nod2 in VGAT+ neurons

in the ARC or the dorsomedial hypothalamus

(DMH) resulted in reduced weight, feeding

behavior, and nest-building; impaired tem-

perature regulation; and decreased life span

in female mice (see the figure).

In contrast to hunger AgRP/NPY neurons,

pro-opiomelanocortin (POMC)–expressing

neurons signal satiety, and their activation

stops feeding. These two neuronal popula-

tions act as “first-order” sensors of energy

status and integrate peripheral signals, in-

cluding the hormones leptin, ghrelin, and

insulin, to regulate feeding and energy ex-

penditure. Thus, besides MDP inhibition of

feeding-promoting cells (AgRP/NPY VGAT+)

reported by Gabanyi et al., it remains unclear

whether other microbiota-derived molecules

modulate POMC neurons or other hypotha-

lamic cells, including tanycytes, a type of glial

cell that modulates food intake and energy

homeostasis. In this context, second-order

neural circuits of the lateral hypothalamus

that act as metabolic sensors and control

food intake or energy homeostasis, some of

which include feeding-promoting VGAT+

neurons ( 6 ), may represent other possible

peptidoglycan targets that warrant further

investigation.

In addition to regulating energy homeo-

stasis, the hypothalamus is critical for fight-

or-flight responses (including stress and

anxiety), reproduction, sleep-wake states,

and goal-directed behaviors toward natural

(food, sex) and artificial (drug) rewards ( 7 ).

It is a federation of nuclei that encompass

multiple cell populations with complex neu-

rochemical profiles and electrophysiological

fingerprints that form an intricate local and

extensive network of excitatory and inhibi-

tory cells, each of which has a specific role

in homeostatic functions. Notably, the hypo-

thalamus modulates other vital functions, in-

cluding the quantity and the quality of sleep

( 8 ), both of which are modulated by micro-

bial products ( 9 ). Peptidoglycan fragments

are detected in the CSF and brain of sleep-

deprived animals and urine of sleep-deprived

humans. Consistently, administration of pep-

tidoglycan fragments increased the duration

of non–rapid eye movement (NREM) sleep

in rodents and nonhuman primates ( 10 ) and

enhanced the amplitude of slow waves—a

marker of sleep pressure and sleep quality—

during episodes of NREM sleep. Similarly,

such modulation of hypothalamic VGAT+

neurons may be involved in arousal control

because these neurons have also been impli-

cated in the control of wakefulness ( 11 ).

The microbiota provides potential biologi-

cal markers of microbiota-brain interactions

and candidates for the development of thera-

peutic strategies for the treatment of neuro-

developmental, psychiatric, and metabolic

disorders. A major challenge in identifying

these mechanisms is the multiple brain tar-

gets and the diversity of hypothalamic cel-

lular pathways. Thus, a better understanding

of the cellular cross-talk between appetite

and body temperature, as well as other hy-

pothalamic circuits that share functions—in-

cluding those that regulate sleep and body

temperature ( 12 ), sleep and appetite ( 13 ), re-

productive and aggressive behaviors ( 14 ), or

arousal and reward processing ( 15 )—will be

essential to reveal the mechanisms and ther-

apeutic relevance of potential treatments. j

REFERENCES AND NOTES

1. A. Gonzalez-Santana, R. Diaz Heijtz, Trends Mol. Med. 26 ,
   729 (2020).


2. J. Nagpal, J. F. Cryan, Neuron 109 , 393 0 ( 202 1).


3. I. Gabanyi et al., Science 376 , 263 (2022).


4. K. Berding, J. F. Cryan, Curr. Opin. Psychiatry 35 , 3 (2022).


5. A. Jais, J. C. Brüning, E n d o c r. Rev. 43 , 314 (2022).


6. J. H. Jennings et al., Cell 160 , 516 (2015).


7. G. D. Stuber, R. A. Wise, Nat. Neurosci. 19 , 198 (2016).


8. A. Adamantidis, L. de Lecea, Trends Endocrinol. Metab. 19 ,
   362 (2008).


9. M. Sgro et al., Sleep 45 , zsab268 (2022).


10. J. M. Krueger, J. R. Pappenheimer, M. L. Karnovsky, Proc.
    Natl. Acad. Sci. U.S.A. 79 , 6102 (1982).


11. C. G. Herrera et al., Nat. Neurosci. 19 , 290 (2016).


12. T. M. Takahashi et al., Nature 583 , 109 (2020).


13. L. T. Oesch et al., Proc. Natl. Acad. Sci. U.S.A. 117 , 19590
    ( 2020 ).


14. H. Lee et al., Nature 509 , 627 (2014).


15. T. Sakurai, N a t. Rev. Neu rosc i. 15 , 719 (2014 ).

AC KNOWLEDGMENTS

A.A. is supported by the Swiss National Science Foundation,

the European Research Council, the Inselspital, and the

University of Bern.

10.1126/scienceBecky

Bacteria

Physiological

outputs

Cell

populations

Satiety

Body

temperature

Feeding

Arousal or sleep?

Fight or flight?

Reproduction?

VMH

ARC

DMH

PVN

V G AT

neuron

POMC

neuron

Leptin,

ghrelin

Insulin

Median eminence

Hypothalamus

DMH, dorsomedial hypothalamus; POMC, pro-opiomelanocortin; PVN, paraventricular nuclei; VGAT, vesicular γ-aminobutyric acid transporter; VMH,

ventromedial hypothalamus.

AgRP/NPY

PGN neuron

fragments

The gut microbiota–hypothalamus connection

Peptidoglycan (PGN) fragments from bacterial cell walls circulate and reach the brain, where they decrease

the activity of feeding-promoting agouti-related peptide/neuropeptide-Y (AgRP/NPY) neurons in the arcuate

nucleus (ARC) and thus food intake. This adds to the multiple peripheral signals that are detected by hypo-

thalamus cells to control appetite and energy homeostasis, as well as other physiological outputs.