Bacterial peptidoglycan traverses the placenta to induce fetal neuroproliferation and aberrant postnatal behavior
Open accessAbstract
Maternal infection during pregnancy is associated with adverse outcomes for the fetus, including postnatal cognitive disorders. However, the underlying mechanisms are obscure. We find that bacterial cell wall peptidoglycan (CW), a universal PAMP for TLR2, traverses the murine placenta into the developing fetal brain. In contrast to adults, CW-exposed fetal brains did not show any signs of inflammation or neuronal death. Instead, the neuronal transcription factor FoxG1 was induced, and neuroproliferation leading to a 50% greater density of neurons in the cortical plate was observed. Bacterial infection of pregnant dams, followed by antibiotic treatment, which releases CW, yielded the same result. Neuroproliferation required TLR2 and was recapitulated in vitro with fetal neuronal precursor cells and TLR2/6, but not TLR2/1, ligands. The fetal neuroproliferative response correlated with abnormal cognitive behavior in CW-exposed pups following birth. Thus, the bacterial CW-TLR2 signaling axis affects fetal neurodevelopment and may underlie postnatal cognitive disorders.
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Preclinical evidence suggests that GM-mediated mechanisms are likely involved in modulating brain processes, including brain biochemistry, response to stress, pain interpretation, feeding, emotional behaviors, and cognition.
“Preclinical evidence suggests that GM-mediated mechanisms are likely involved in modulating brain processes, including brain biochemistry, response to stress, pain interpretation, feeding, emotional behaviors, and cognition (57–64).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [64]
Offspring exposed to maternal peptidoglycans exhibited decreased cognitive function related to TLR-2-mediated neuroproliferation via FoxG1 induction in the cortex.
“The offspring exhibited decreased cognitive function related to TLR-2-mediated neuroproliferation via FoxG1 induction in the cortex.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [64]
Microbial peptidoglycans can traverse the mouse placenta, such that maternal administration of peptidoglycans could be detected in the fetal brain.
“Humann et al. showed that microbial PGs can traverse the mouse placenta, such that maternal administration of PGs could be detected in the fetal brain (64).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [64]
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- Authors
- Humann, J., Mann, B., Gao, G., Moresco, P., Ramahi, J., Loh, L. N., Farr, A., Hu, Y., Durick-Eder, K., Fillon, S. A., Smeyne, R. J., & Tuomanen, E. I.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Tuomanen, Elaine I.
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 19
- Issue
- 3
- Pages
- 388-399
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC4787272
- OpenAlex
- W2296178950
- Cited by
- 100
- References
- 53
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 11 · 2023: 12 · 2022: 5 · 2021: 11 · 2020: 15 · 2019: 14 · 2018: 7 · 2017: 6 · 2016: 4
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-06-08)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Lebanese Syrian Associated Charities
- U.S. Public Health Service (R01-27913)
- RIKEN
- National Cancer Institute (R25CA23944, R25CA023944, P30CA021765)
- National Institute of Allergy and Infectious Diseases (R01AI027913, R01AI128756)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- bacterial peptidoglycan, placenta, TLR2 signaling, maternal infection, fetal brain development, FOXG1, TLR2/6, TLR2/1, antibiotic therapy
- MeSH terms
- Animals, Bacterial Infections, Behavior, Animal, Brain, Cognition Disorders, Female, Maternal-Fetal Exchange, Neurons, Peptidoglycan, Pregnancy, Cell Proliferation, Toll-Like Receptor 2, Mice
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