- R. D. Lisk, R. A. Pretlow 3rd, S. M. Friedman, Hormonal
stimulation necessary for elicitation of maternal nest-building
in the mouse (Mus musculus).Anim. Behav. 17 , 730– 737
(1969). doi:10.1016/S0003-3472(69)80020-5; pmid: 5378004 - S. Suyama, T. Yada, New insight into GABAergic neurons in the
hypothalamic feeding regulation.J. Physiol. Sci. 68 , 717– 722
(2018). doi:10.1007/s12576-018-0622-8; pmid: 30003408 - S. F. Morrison, Central neural control of thermoregulation and
brown adipose tissue.Auton. Neurosci. 196 , 14–24 (2016).
doi:10.1016/j.autneu.2016.02.010; pmid: 26924538 - Y. Chen, Y.-C. Lin, T.-W. Kuo, Z. A. Knight, Sensory detection of
food rapidly modulates arcuate feeding circuits.Cell 160 ,
829 – 841 (2015). doi:10.1016/j.cell.2015.01.033;
pmid: 25703096 - Z. Huanget al., Antibody neutralization of microbiota-derived
circulating peptidoglycan dampens inflammation and
ameliorates autoimmunity.Nat. Microbiol. 4 , 766–773 (2019).
doi:10.1038/s41564-019-0381-1; pmid: 30833732 - F. De Vadderet al., Microbiota-generated metabolites promote
metabolic benefits via gut-brain neural circuits.Cell 156 ,
84 – 96 (2014). doi:10.1016/j.cell.2013.12.016; pmid: 24412651 - J. Bretonet al., Gut commensal E. coli proteins activate host
satiety pathways following nutrient-induced bacterial growth.
Cell Metab. 23 , 324–334 (2016). doi:10.1016/
j.cmet.2015.10.017; pmid: 26621107 - T. Arentsen, R. Khalid, Y. Qian, R. Diaz Heijtz, Sex-dependent
alterations in motor and anxiety-like behavior of aged
bacterial peptidoglycan sensing molecule 2 knockout mice.
Brain Behav. Immun. 67 , 345–354 (2018). doi:10.1016/
j.bbi.2017.09.014; pmid: 28951252 - M. M. Puscedduet al., Nod-like receptors are critical for gut-
brain axis signalling in mice.J. Physiol. 597 , 5777–5797 (2019).
doi:10.1113/JP278640; pmid: 31652348 - G. Peiet al., Cellular stress promotes NOD1/2-dependent
inflammation via the endogenous metabolite sphingosine-1-
phosphate.EMBO J. 40 , e106272 (2021). doi:10.15252/
embj.2020106272; pmid: 33942347 - L. M. Cox, H. Abou-El-Hassan, A. H. Maghzi, J. Vincentini,
H. L. Weiner, The sex-specific interaction of the microbiome in
neurodegenerative diseases.Brain Res. 1724 , 146385 (2019).
doi:10.1016/j.brainres.2019.146385; pmid: 31419428 - M.-C. Audet, Stress-induced disturbances along the gut
microbiota-immune-brain axis and implications for mental
health: Does sex matter?Front. Neuroendocrinol. 54 , 100772
(2019). doi:10.1016/j.yfrne.2019.100772; pmid: 31302116 - K. M. Culbert, C. L. Sisk, K. L. Klump, A Narrative Review of Sex
Differences in Eating Disorders: Is There a Biological Basis?
Clin. Ther. 43 , 95–111 (2021). doi:10.1016/
j.clinthera.2020.12.003; pmid: 33375999 - A. Franceschini, L. Fattore, Gender-specific approach in
psychiatric diseases: Because sex matters.Eur. J. Pharmacol.
896 , 173895 (2021). doi:10.1016/j.ejphar.2021.173895;
pmid: 33508283 - M. S. Thionet al., Microbiome Influences Prenatal and Adult
Microglia in a Sex-Specific Manner.Cell 172 , 500–516.e16
(2018). doi:10.1016/j.cell.2017.11.042; pmid: 29275859
37. F. Kühnet al., Intestinal alkaline phosphatase targets the gut
barrier to prevent aging.JCI Insight 5 , e134049 (2020).
doi:10.1172/jci.insight.134049; pmid: 32213701
38. E. Jašarević, K. E. Morrison, T. L. Bale, Sex differences in the
gut microbiome-brain axis across the lifespan.Philos. Trans. R.
Soc. London Ser. B 371 , 20150122 (2016). doi:10.1098/
rstb.2015.0122; pmid: 26833840
39. Z. S. Ma, W. Li, How and Why Men and Women Differ in Their
Microbiomes: Medical Ecology and Network Analyses of the
Microgenderome.Adv. Sci. 6 , 1902054 (2019). doi:10.1002/
advs.201902054; pmid: 31832327
40. S. L. Padillaet al., AgRP to Kiss1 neuron signaling links
nutritional state and fertility.Proc. Natl. Acad. Sci. U.S.A. 114 ,
2413 – 2418 (2017). doi:10.1073/pnas.1621065114;
pmid: 28196880
41. G. Neal-Perry, E. Nejat, C. Dicken, The neuroendocrine
physiology of female reproductive aging: An update.Maturitas
67 , 34–38 (2010). doi:10.1016/j.maturitas.2010.04.016;
pmid: 20570066
42. F. Mauvais-Jarvis, D. J. Clegg, A. L. Hevener, The role of
estrogens in control of energy balance and glucose
homeostasis.Endocr. Rev. 34 , 309–338 (2013). doi:10.1210/
er.2012-1055; pmid: 23460719
43. M. E. Griffin, C. W. Hespen, Y. C. Wang, H. C. Hang, Translation
of peptidoglycan metabolites into immunotherapeutics.
Clin. Transl. Immunol. 8 , e1095 (2019). doi:10.1002/cti2.1095;
pmid: 31798878
44. D. Kimet al., Nod2-mediated recognition of the microbiota is
critical for mucosal adjuvant activity of cholera toxin.
Nat. Med. 22 , 524–530 (2016). doi:10.1038/nm.4075;
pmid: 27064448
45. F. Barreauet al., CARD15/NOD2 is required for Peyer’s
patches homeostasis in mice.PLOS ONE 2 , e523 (2007).
doi:10.1371/journal.pone.0000523; pmid: 17565376
46. E. Casanovaet al., A CamKIIaiCre BAC allows brain-specific
gene inactivation.Genesis 31 , 37–42 (2001). doi:10.1002/
gene.1078; pmid: 11668676
47. R. Wheeler, F. Veyrier, C. Werts, I. G. Boneca, inGlycoscience:
Biology and Medicine, N. Taniguchiet al., Eds. (Springer, 2015),
pp. 737–747.
48. D. Mengin-Lecreulx, E. Siegel, J. van Heijenoort, Variations in
UDP-N-acetylglucosamine and UDP-N-acetylmuramyl-
pentapeptide pools in Escherichia coli after inhibition of protein
synthesis.J. Bacteriol. 171 , 3282–3287 (1989). doi:10.1128/
jb.171.6.3282-3287.1989; pmid: 2656647
49. F. B. Wientjes, C. L. Woldringh, N. Nanninga, Amount of
peptidoglycan in cell walls of gram-negative bacteria.
J. Bacteriol. 173 , 7684–7691 (1991). doi:10.1128/
jb.173.23.7684-7691.1991; pmid: 1938964
50. K. P. Nguyen, T. J. O’Neal, O. A. Bolonduro, E. White, A. V. Kravitz,
Feeding Experimentation Device (FED): A flexible open-source
device for measuring feeding behavior.J. Neurosci. Methods
267 , 108–114 (2016). doi:10.1016/j.jneumeth.2016.04.003;
pmid: 27060385
51. N. Renieret al., Mapping of Brain Activity by Automated
Volume Analysis of Immediate Early Genes.Cell 165 ,
1789 – 1802 (2016). doi:10.1016/j.cell.2016.05.007;
pmid: 27238021- L. A. Gunaydinet al., Natural neural projection
dynamics underlying social behavior.Cell 157 , 1535– 1551
(2014). doi:10.1016/j.cell.2014.05.017;
pmid: 24949967 - T. Bacchetti De Gregoris, N. Aldred, A. S. Clare, J. G. Burgess,
Improvement of phylum- and class-specific primers for
real-time PCR quantification of bacterial taxa.
J. Microbiol. Methods 86 , 351–356 (2011). doi:10.1016/
j.mimet.2011.06.010; pmid: 21704084
ACKNOWLEDGMENTS
We thank S. Saha, E. de Launoit, and T. Topilko for their help in
conducting and/or analyzing experiments; G. Chevalier for his
preliminary work onNod2GFPmice; and D. Mucida and
G. M. Silva for their insightful discussions and critical reading
and editing of the manuscript. We would also like to thank
P. Campagne from the Hub of Bioinformatics and Biostatistics
of the Institut Pasteur for his advice on the statistical tests
used in this work and the members of the Animalerie Centrale
of the Institut Pasteur for maintenance and care of the mice
used in this work. We also thank the members of the
Microenvironment & Immunity Unit, the laboratory for
Perception & Memory, the Stroma, Inflammation & Tissue
Repair Unit, and the Biology and Genetics of the Bacterial Cell
Wall Unit, for their support and feedback.Funding:Institutional
support was provided by Institut Pasteur, CNRS, and Inserm.
Also supported by Pasteur-Roux postdoctoral fellowships from
the Institut Pasteur (I.G.), a Human Frontier Science Program
fellowship (I.G.), Agence Nationale de la Recherche grant
ANR-16-CE15-0021 (I.G.B., P.-M.L., G.C. and G.E.), DFG CRC1182
project C2 (P.R.), and life insurance company“AG2R-La-
Mondiale”(P.-M.L.).Author contributions:Conceptualization:
I.G. Formal analysis: I.G., A.V.-P. Funding acquisition: I.G., G.L.,
I.G.B., G.E., P.-M.L. Investigation: I.G., G.L., N.R., A.V.-P., R.W.,
C.M., A.N., S.D., B.P., F.V. Methodology: I.G., G.L., N.R., S.W.,
A.V.-P., A.N., R.W. Project administration: I.G. Resources:
S.H., P.R., I.G.B. Supervision: G.L., I.G.B., G.E., P.-M.L.
Validation: I.G., N.R., A.V.-P., G.L., R.W. Visualization: I.G.,
A.V.-P. Writing–original draft: I.G. Writing–review and editing:
I.G., G.L., N.R., I.G.B., G.E., P.-M.L., R.W., P.R.Competing
interests:The authors declare no competing interests.Data
and materials availability:All data are available in the main
text or the supplementary materials.SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abj3986
Figs. S1 to S8
Tables S1 and S2
MDAR Reproducibility Checklist11 May 2021; accepted 25 February 2022
10.1126/science.abj3986Gabanyiet al.,Science 376 , eabj3986 (2022) 15 April 2022 12 of 12
RESEARCH | RESEARCH ARTICLE