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Commensal bacteria make GPCR ligands that mimic human signalling molecules
Open accessAbstract
Commensal bacteria are believed to have important roles in human health. The mechanisms by which they affect mammalian physiology remain poorly understood, but bacterial metabolites are likely to be key components of host interactions. Here we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids that they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands, although future studies are needed to define their potential physiological role in humans. Our results suggest that chemical mimicry of eukaryotic signalling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a possible small-molecule therapeutic modality (microbiome-biosynthetic gene therapy).
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“Moreover, a recent paper described that commensal bacteria are able to produce G-protein-coupled receptor agonists to regulate the GI tract physiology, including metabolic hormones and glucose homeostasis [4].”
From Anxiety, depression, and the microbiome: A role for gut peptides (2018) · cites this paper as [4]
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“Although microbes secrete eCBs, their role in host physiology remains unclear (255).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [255]
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“These interactions include antibacterial activity (5), bacterial signaling (6), immune modulation (7), biofilm formation (8, 9), host colonization (10), nutrient scavenging (11), and stress protection (12).”
BackgroundForte, N. R., Fernández-Rilo, A. C., Palomba, L., Marzo, V. D., & Cristino, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051554 · Cited by 105
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Emerging targetome and signalome landscape of gut microbial metabolites
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“This is potentially of major biological relevance as GPCRs are expressed by many cell types throughout the body and exert mainly immune and metabolic functions (50, 51).”
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“In recent years, drug development based on gut microbiota has gradually attracted attention.(9,10) Urolithin B (UB) is a product of”
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“OEA is a more potent GPR119 agonist than its glycerol ester 2-Oleoyl Glycerol (2-OG) found in olive oil (322).”
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The gut microbiome, endocannabinoids and metabolic disorders
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“For example, the interaction of N -acyl-amide synthases and G-protein-coupled receptors 403 and the discovery of sialidases within the glycoside hydrolase family (GH156) 404 in gastrointestinal bacteria underscore the potential of metagenomic bioengineering to reveal previously inaccessible…”
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Human aging and disease: Lessons from age-related macular degeneration
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Impact of N-Acyl-Homoserine Lactones, Quorum Sensing Molecules, on Gut Immunity
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“Finally, according to the cell type, the receptors and their localization can be different (33, 34) but mainly involves inflammatory pathways.”
BackgroundGut Microbiota as an Endocrine Organ: Unveiling Its Role in Human Physiology and Health
Pires, L., Gonzaléz‐Paramás, A. M., Heleno, S. A., & Calhelha, R. C. (2024) · Applied Sciences · doi:10.3390/app14209383 · Cited by 89
“…by activating GPR119 on enteroendocrine L-cells, consequently in fl uencing glucose and energy metabolism. microbial N-acyl amides, Cohen et al. [105] administered an Investigating the physiological e ff ects of microbial N-acyl amides, Cohen et al. [105] administered an engineered…”
Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments
Ford, A. C., Vanner, S. J., Kashyap, P., & Nasser, Y. (2024) · Gastroenterology · doi:10.1053/j.gastro.2024.01.045 · Cited by 87
Diabesity and mood disorders: Multiple links through the microbiota-gut-brain axis
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Metadata
- Authors
- Cohen, L. J., Esterhazy, D., Kim, S.-H., Lemetre, C., Aguilar, R. R., Gordon, E. A., Pickard, A. J., Cross, J. R., Emiliano, A. B., Han, S. M., Chu, J., Vila-Farres, X., Kaplitt, J., Rogoz, A., Calle, P. Y., Hunter, C., Bitok, J. K., & Brady, S. F.
- Affiliations
- Rockefeller University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Brady, Sean F.
- ORCID
- Venue
- Nature
- Published
- 2017-08-30
- Volume
- 549
- Issue
- 7670
- Pages
- 48-53
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5777231
- OpenAlex
- W2753100975
- Cited by
- 500
- References
- 45
- Citations by year
- 2026: 44 · 2025: 47 · 2024: 60 · 2023: 53 · 2022: 52 · 2021: 44 · 2020: 64 · 2019: 62 · 2018: 55 · 2017: 18
- FWCI
- 22.22
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-04-05)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Crohn's and Colitis Foundation (370629)
- National Institute of General Medical Sciences (U01GM110714, R35GM122559)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007792, K08DK109287)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- commensal bacteria, G protein-coupled receptors, GPR119, gut microbiota metabolites, glucose homeostasis, metabolic hormones, gastrointestinal tract physiology
- MeSH terms
- Biological Mimicry, Gastrointestinal Microbiome, Amides, Animals, Bacteria, Blood Glucose, Female, Homeostasis, Humans, Ligands, Male, Symbiosis, Signal Transduction, Gastrointestinal Tract, Receptors, G-Protein-Coupled, Mice, HEK293 Cells
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