Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity
Open accessAbstract
Humans are colonized by a large and diverse bacterial flora (the microbiota) essential for the development of the gut immune system. A broader role for the microbiota as a major modulator of systemic immunity has been proposed; however, evidence and a mechanism for this role have remained elusive. We show that the microbiota are a source of peptidoglycan that systemically primes the innate immune system, enhancing killing by bone marrow-derived neutrophils of two major pathogens: Streptococcus pneumoniae and Staphylococcus aureus. This requires signaling via the pattern recognition receptor nucleotide-binding, oligomerization domain-containing protein-1 (Nod1, which recognizes meso-diaminopimelic acid (mesoDAP)-containing peptidoglycan found predominantly in Gram-negative bacteria), but not Nod2 (which detects peptidoglycan found in Gram-positive and Gram-negative bacteria) or Toll-like receptor 4 (Tlr4, which recognizes lipopolysaccharide). We show translocation of peptidoglycan from the gut to neutrophils in the bone marrow and show that peptidoglycan concentrations in sera correlate with neutrophil function. In vivo administration of Nod1 ligands is sufficient to restore neutrophil function after microbiota depletion. Nod1(-/-) mice are more susceptible than wild-type mice to early pneumococcal sepsis, demonstrating a role for Nod1 in priming innate defenses facilitating a rapid response to infection. These data establish a mechanism for systemic immunomodulation by the microbiota and highlight potential adverse consequences of microbiota disruption by broad-spectrum antibiotics on innate immune defense to infection.
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Recognition of microbiota-derived PG in a NOD1-dependent manner could facilitate systemic innate immunity.
“Recognition of microbiota-derived PG in a nucleotide-binding oligomerization domain containing 1 (NOD1)-dependent manner could facilitate systemic innate immunity [110].”
From Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies (2022) · cites this paper as [110]
Peptidoglycan fragments can enter circulation and prime systemic immune responses.
“As peptidoglycan fragments can disseminate into circulation and prime systemic immune responses (37, 38)”
From <i>Enterococcus</i> peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy (2021) · cites this paper as [37]
NOD1-mediated sensing of meso-diaminopimelic acid promotes neutrophil-mediated killing of pathogens such as Staphylococcus aureus and Staphylococcus pneumoniae.
“NOD1-mediated sensing of meso-diaminopimelic acid (DAP) promotes neutrophil-mediated killing of pathogens such as Staphylococcus aureus and Staphylococcus pneumoniae [21, 22].”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [22]
In germ-free mice reconstituted with Escherichia coli, DAP is detected in blood and bone marrow over three days, indicating that bacterial ligands from the intestinal lumen can distribute systemically.
“In GF mice reconstituted with Escherichia coli, DAP was detected in the blood and BM over the course of three days, showing that bacterial ligands from the intestinal lumen can have systemic distribution and therefore, a systemic effect [22].”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [22]
Gut microbiota-induced priming of innate immune cells at the intestinal mucosa affects respiratory health, for example through NOD1-mediated activation of neutrophils required for S. pneumoniae clearance in the URT.
“gut microbiota-induced priming of innate immune cells at the intestinal mucosa was shown to affect respiratory health; for example, through NOD1 receptor-mediated activation of the neutrophils that are required for the clearance of Streptococcus pneumoniae in the URT72,166.”
From The microbiota of the respiratory tract: gatekeeper to respiratory health (2017) · cites this paper as [166]
These effects might be mediated in part by decreased Nod1 sensing of meso-DAP-containing peptidoglycan found in gut microbiota, which previously was shown to be essential for priming innate immune responses to S. pneumoniae.
“These effects might be mediated in part by decreased Nod1 sensing of meso-DAP (diaminopimelic acid)-containing peptidoglycan found in gut microbiota, which previously was shown to be essential for priming innate immune responses to S. pneumoniae”
From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [56]
Nod1 and Nod2 play a key role in mediating microbe-host cross talk, including lymphoid tissue genesis, Paneth cell function, neutrophil priming, hematopoiesis, and 5-HT signaling.
“Nucleotide-binding oligomerization domain 1 (Nod1), together with Nod2, as classic pattern recognition receptors, play a key role in mediating the microbe-host cross talk, including lymphoid tissue genesis (Bouskra et al., 2008), Paneth cell function in the intestine (Zhang et al., 2015), neutrophil priming (Clarke et al., 2010), hematopoiesis (Iwamura et al., 2017), and 5-hydroxytryptamine (5-HT)”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Clarke et al., 2010
Treatment with antibiotics has been used to deplete microbial ligands in the circulation.
“Treatment with antibiotics has been used to deplete microbial ligands in the circulation (Clarke et al., 2010; Bird, 2010; Arentsen et al., 2017; Hergott et al., 2016).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Clarke et al., 2010
Nod1 signaling primes neutrophils for optimal bactericidal activity.
“Nod1 signaling primes neutrophils for optimal bactericidal activity (Clarke et al., 2010).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Clarke et al., 2010
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- Authors
- Clarke, T. B., Davis, K. M., Lysenko, E. S., Zhou, A. Y., Yu, Y., & Weiser, J. N.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Weiser, Jeffrey N
- Venue
- Nature Medicine
- Published
- 2010-01-17
- Volume
- 16
- Issue
- 2
- Pages
- 228-231
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4497535
- OpenAlex
- W2134928825
- Cited by
- 1,154
- References
- 32
- Citations by year
- 2026: 41 · 2025: 53 · 2024: 60 · 2023: 65 · 2022: 83 · 2021: 91 · 2020: 67 · 2019: 79 · 2018: 82 · 2017: 75 · 2016: 62 · 2015: 58 · 2014: 67 · 2013: 82 · 2012: 81
- FWCI
- 36.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI038446, AI038446, R21AI044231, R01AI078538, R37AI037108, R01AI044231, R01AI037108, AI037108, AI078538, R37AI038446, AI044231)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- peptidoglycan, NOD1, gut microbiota, neutrophils, bone marrow, meso-diaminopimelic acid, commensal bacteria, Streptococcus pneumoniae, Staphylococcus aureus, pneumococcal sepsis, immunomodulation, TLR4, NOD2
- MeSH terms
- Animals, Immunity, Innate, Intestines, Peptidoglycan, Staphylococcus aureus, Streptococcus pneumoniae, Mice, Nod1 Signaling Adaptor Protein
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