Commensal microbiota is fundamental for the development of inflammatory pain
Open accessAbstract
The ability of an individual to sense pain is fundamental for its capacity to adapt to its environment and to avoid damage. The sensation of pain can be enhanced by acute or chronic inflammation. In the present study, we have investigated whether inflammatory pain, as measured by hypernociceptive responses, was modified in the absence of the microbiota. To this end, we evaluated mechanical nociceptive responses induced by a range of inflammatory stimuli in germ-free and conventional mice. Our experiments show that inflammatory hypernociception induced by carrageenan, lipopolysaccharide, TNF-α, IL-1β, and the chemokine CXCL1 was reduced in germ-free mice. In contrast, hypernociception induced by prostaglandins and dopamine was similar in germ-free or conventional mice. Reduction of hypernociception induced by carrageenan was associated with reduced tissue inflammation and could be reversed by reposition of the microbiota or systemic administration of lipopolysaccharide. Significantly, decreased hypernociception in germ-free mice was accompanied by enhanced IL-10 expression upon stimulation and could be reversed by treatment with an anti-IL-10 antibody. Therefore, these results show that contact with commensal microbiota is necessary for mice to develop inflammatory hypernociception. These findings implicate an important role of the interaction between the commensal microbiota and the host in favoring adaptation to environmental stresses, including those that cause pain.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Early evidence for a role of the enteric microbiota in the development of inflammatory somatic hyperalgesia has recently been reported.
“Early evidence for a role of the enteric microbiota in the development of inflammatory somatic hyperalgesia has recently been reported.75”
From Principles and clinical implications of the brain-gut-enteric microbiota axis (2009) · cites this paper as [75]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in <i>Tlr4</i> Gene
Poltorak, A., He, X., Smirnova, I., Liu, M.-Y., Huffel, C. V., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998) · Science · doi:10.1126/science.282.5396.2085 · Cited by 7,631 · see citing works
Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K., & Akira, S. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.7.3749 · Cited by 3,374 · see citing works
Recognition of microorganisms and activation of the immune response
Medzhitov, R. (2007) · Nature · doi:10.1038/nature06246 · Cited by 2,862 · see citing works
Dubuisson, D., & Dennis, S. G. (1977) · Pain · doi:10.1016/0304-3959(77)90130-0 · Cited by 2,534 · see citing works
Formalin test in mice, a useful technique for evaluating mild analgesics
Hunskaar, S., Fasmer, O. B., & Hole, K. (1985) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(85)90116-5 · Cited by 825 · see citing works
The pivotal role of tumour necrosis factor α in the development of inflammatory hyperalgesia
Cunha, F. Q., Poole, S., Lorenzetti, B. B., & Ferreira, S. H. (1992) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1992.tb14503.x · Cited by 792 · see citing works
Self-citationInterleukin-1β as a potent hyperalgesic agent antagonized by a tripeptide analogue
Ferreira, S. H., Lorenzetti, B. B., Bristow, A. F., & Poole, S. (1988) · Nature · doi:10.1038/334698a0 · Cited by 624 · see citing works
Self-citationA cascade of cytokines mediates mechanical inflammatory hypernociception in mice
Cunha, T. M., Verri, W. A., Jr., Silva, J. S., Poole, S., Cunha, F. Q., & Ferreira, S. H. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409225102 · Cited by 600 · see citing works
Self-citationHypernociceptive role of cytokines and chemokines: Targets for analgesic drug development?
Verri, W. A., Jr., Cunha, T. M., Parada, C. A., Poole, S., Cunha, F. Q., & Ferreira, S. H. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.04.001 · Cited by 538 · see citing works
Self-citationAn electronic pressure-meter nociception paw test for mice
Cunha, T. M., Verri, W. A., Jr., Vivancos, G. G., et al. (2004) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x2004000300018 · Cited by 459 · see citing works
Self-citationThe hyperalgesic effects of prostacyclin and prostaglandin E2
FERREIRA, S., Nakamura, M., & DEABREUCASTRO, M. (1978) · Prostaglandins · doi:10.1016/0090-6980(78)90199-5 · Cited by 356 · see citing works
Self-citationSchaible, H.-G., & Schmidt, R. F. (1988) · Journal of Neurophysiology · doi:10.1152/jn.1988.60.6.2180 · Cited by 342 · see citing works
Interleukin‐8 as a mediator of sympathetic pain
Cunha, F. Q., Lorenzetti, B. B., Poole, S., & Ferreira, S. H. (1991) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1991.tb12502.x · Cited by 333 · see citing works
Self-citationKhasar, S. G., McCarter, G. C., & Levine, J. D. (1999) · Journal of Neurophysiology · doi:10.1152/jn.1999.81.3.1104 · Cited by 284 · see citing works
Role of Protein Kinase A in the Maintenance of Inflammatory Pain
Aley, K. O., & Levine, J. D. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-06-02181.1999 · Cited by 261 · see citing works
The essential role of the intestinal microbiota in facilitating acute inflammatory responses
Souza, D. G., Vieira, A. T., Soares, A. C., Pinho, V., Nicoli, J. R., Vieira, L. Q., & Teixeira, M. M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.6.4137 · Cited by 247 · see citing works
Self-citationAn electronic pressure-meter nociception paw test for rats
Vivancos, G. G., Verri, W. A., Jr., Cunha, T. M., Schivo, I. R. S., Parada, C. A., Cunha, F. Q., & Ferreira, S. H. (2004) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x2004000300017 · Cited by 236 · see citing works
Self-citationCytokine‐mediated inflammatory hyperalgesia limited by interleukin‐4
Cunha, F. Q., Poole, S., Lorenzetti, B. B., Veiga, F. H., & Ferreira, S. H. (1999) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0702266 · Cited by 226 · see citing works
Self-citationMartin, H. A., Basbaum, A. I., Kwiat, G. C., et al. (1987) · Neuroscience · doi:10.1016/0306-4522(87)90360-5 · Cited by 225 · see citing works
Souza, D. G., Soares, A. C., Pinho, V., Torloni, H., Reis, L., Martins, M. T., & Dias, A. A. (2002) · American Journal of Pathology · doi:10.1016/s0002-9440(10)61122-4 · Cited by 208 · see citing works
Self-citationChemosensitivity and sensitization of nociceptive afferents that innervate the hairy skin of monkey
Davis, K. D., Meyer, R. A., & Campbell, J. N. (1993) · Journal of Neurophysiology · doi:10.1152/jn.1993.69.4.1071 · Cited by 183 · see citing works
Cytokine‐mediated inflammatory hyperalgesia limited by interleukin‐10
Poole, S., Cunha, F. Q., Selkirk, S., Lorenzetti, B. B., & Ferreira, S. H. (1995) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1995.tb14987.x · Cited by 162 · see citing works
Self-citationParada, C. A., Reichling, D. B., & Levine, J. D. (2004) · Pain · doi:10.1016/j.pain.2004.10.021 · Cited by 137 · see citing works
Cunha, F. Q., Teixera, M. M., & Ferreira, S. H. (1999) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0702601 · Cited by 134 · see citing works
Self-citationRueff, A., & Dray, A. (1993) · Neuroscience · doi:10.1016/0306-4522(93)90272-h · Cited by 97 · see citing works
Lorenzetti, B. B., Veiga, F. H., Canetti, C. D. A., et al. (2003) · PubMed · Cited by 85 · see citing works
Souza, D. G., Pinho, V., Soares, A. C., Shimizu, T., Ishii, S., & Teixeira, M. M. (2003) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705296 · Cited by 57 · see citing works
Self-citationMicrobial virulence results from the interaction between host and microorganism
Casadevall, A., & Pirofski, L. (2003) · Trends in Microbiology · doi:10.1016/s0966-842x(03)00008-8 · Cited by 40 · see citing works
Germfree animals and their significance.
Pleasants, J. R. (1973) · PubMed · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286 · see citing works
Gut microbiota in health and disease
Sekirov, I., Russell, S. L., Antunes, L. C. M., & Finlay, B. B. (2010) · Physiological Reviews · doi:10.1152/physrev.00045.2009 · Cited by 4,182 · see citing works
The gut microbiota--masters of host development and physiology
Sommer, F., & Bäckhed, F. (2013) · Nature Reviews Microbiology · doi:10.1038/nrmicro2974 · Cited by 3,681 · see citing works
Serotonin, tryptophan metabolism and the brain-gut-microbiome axis
O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G., & Cryan, J. F. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.027 · Cited by 2,012 · see citing works
Bercik, P., Denou, E., Collins, J., Jackson, W., Lu, J., Jury, J., Deng, Y., Blennerhassett, P., Macri, J., McCoy, K. D., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.04.052 · Cited by 1,748 · see citing works
The central nervous system and the gut microbiome
Sharon, G., Sampson, T. R., Geschwind, D. H., & Mazmanian, S. K. (2016) · Cell · doi:10.1016/j.cell.2016.10.027 · Cited by 1,513 · see citing works
Gut/brain axis and the microbiota
Mayer, E. A., Tillisch, K., & Gupta, A. (2015) · Journal of Clinical Investigation · doi:10.1172/jci76304 · Cited by 1,503 · see citing works
Principles and clinical implications of the brain-gut-enteric microbiota axis
Rhee, S. H., Pothoulakis, C., & Mayer, E. A. (2009) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2009.35 · Cited by 1,342 · see citing works
Martin, C. R., Osadchiy, V., Kalani, A., & Mayer, E. A. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.04.003 · Cited by 1,284 · see citing works
Consumption of fermented milk product with probiotic modulates brain activity
Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B., Guyonnet, D., Legrain–Raspaud, S., Trotin, B., Naliboff, B., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.02.043 · Cited by 1,192 · see citing works
Commensal bacteria calibrate the activation threshold of innate antiviral immunity
Abt, M. C., Osborne, L. C., Monticelli, L. A., Doering, T. A., Alenghat, T., Sonnenberg, G. F., Paley, M. A., Antenus, M., Williams, K. L., Erikson, J., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.04.011 · Cited by 993 · see citing works
From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways
Rogers, G. B., Keating, D. J., Young, R. L., Wong, M.-L., Licinio, J., & Wesselingh, S. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.50 · Cited by 969 · see citing works
Collins, S. M., & Bercik, P. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.01.075 · Cited by 612 · see citing works
The microbiome and host behavior
Vuong, H. E., Yano, J. M., Fung, T. C., & Hsiao, E. Y. (2017) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-072116-031347 · Cited by 537 · see citing works
De Palma, G., Lynch, M. D. J., Lu, J., Dang, V. T., Deng, Y., Jury, J., Umeh, G., Miranda, P. M., Pigrau Pastor, M., Sidani, S., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf6397 · Cited by 505 · see citing works
Analysis of Gut Microbiota in Patients with Parkinson’s Disease
Petrov, V. A., Saltykova, I. V., Zhukova, I. A., Alifirova, V. M., Zhukova, N. G., Dorofeeva, Y. B., Tyakht, A. V., Kovarsky, B. A., Alekseev, D. G., Kostryukova, E. S., et al. (2017) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-017-3700-7 · Cited by 487 · see citing works
Brain gut microbiome interactions and functional bowel disorders
Mayer, E. A., Savidge, T., & Shulman, R. J. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.02.037 · Cited by 496 · see citing works
Alcock, J., Maley, C. C., & Aktipis, C. A. (2014) · BioEssays · doi:10.1002/bies.201400071 · Cited by 454 · see citing works
Neuropeptides and the Microbiota-Gut-Brain Axis
Holzer, P., & Farzi, A. (2014) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4939-0897-4_9 · Cited by 451 · see citing works
The progress of gut microbiome research related to brain disorders
Zhu, S., Jiang, Y., Xu, K., Cui, M., Ye, W., Zhao, G., Jin, L., & Chen, X. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-1705-z · Cited by 419 · see citing works
Forsythe, P., Sudo, N., Dinan, T., Taylor, V. H., & Bienenstock, J. (2010) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2009.05.058 · Cited by 429 · see citing works
Gut-brain Axis and migraine headache: a comprehensive review
On behalf of the School of Advanced Studies of the European Headache Federation (EHF-SAS), Arzani, M., Jahromi, S. R., Ghorbani, Z., Vahabizad, F., Martelletti, P., Ghaemi, A., Sacco, S., & Togha, M. (2020) · The Journal of Headache and Pain · doi:10.1186/s10194-020-1078-9 · Cited by 366 · see citing works
Gut Microbiota Promote Angiotensin II–Induced Arterial Hypertension and Vascular Dysfunction
Karbach, S. H., Schönfelder, T., Brandão, I., Wilms, E., Hörmann, N., Jäckel, S., Schüler, R., Finger, S., Knorr, M., Lagrange, J., et al. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.116.003698 · Cited by 378 · see citing works
Role of the microbiota in inflammatory bowel diseases
Nagalingam, N. A., & Lynch, S. V. (2012) · Inflammatory Bowel Diseases · doi:10.1002/ibd.21866 · Cited by 315 · see citing works
O’Mahony, S. M., Felice, V. D., Nally, K., Savignac, H. M., Claesson, M. J., Scully, P., Woznicki, J., Hyland, N. P., Shanahan, F., Quigley, E. M., et al. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.07.054 · Cited by 272 · see citing works
Fagundes, C. T., Amaral, F. A., Vieira, A. T., Soares, A. C., Pinho, V., Nicoli, J. R., Vieira, L. Q., Teixeira, M. M., & Souza, D. G. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1101682 · Cited by 244 · see citing works
Self-citationMicrobiota-gut-brain signalling in Parkinson's disease: Implications for non-motor symptoms
Felice, V. D., Quigley, E. M., Sullivan, A. M., O'Keeffe, G. W., & O'Mahony, S. M. (2016) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2016.03.012 · Cited by 205 · see citing works
Raison, C. L., Lowry, C. A., & Rook, G. A. W. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.161 · Cited by 169 · see citing works
Impact of stressor exposure on the interplay between commensal microbiota and host inflammation
Galley, J. D., & Bailey, M. T. (2014) · Gut Microbes · doi:10.4161/gmic.28683 · Cited by 125 · see citing works
Aguilera, M., Vergara, P., & Martínez, V. (2013) · Neurogastroenterology & Motility · doi:10.1111/nmo.12154 · Cited by 119 · see citing works
Microbial involvement in Alzheimer disease development and progression
Bulgart, H. R., Neczypor, E. W., Wold, L. E., & Mackos, A. R. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00378-4 · Cited by 116 · see citing works
Meng, H., Ba, Z., Lee, Y., Peng, J., Lin, J., Fleming, J. A., Furumoto, E. J., Roberts, R. F., Kris-Etherton, P. M., & Rogers, C. J. (2017) · European Journal of Nutrition · doi:10.1007/s00394-015-1109-5 · Cited by 52 · see citing works
Gut Microbiome and Modulation of <scp>CNS</scp> Function
Osadchiy, V., Martin, C. R., & Mayer, E. A. (2019) · Comprehensive Physiology · doi:10.1002/cphy.c180031 · Cited by 53 · see citing works
- Authors
- Amaral, F. A., Sachs, D., Costa, V. V., Fagundes, C. T., Cisalpino, D., Cunha, T. M., Ferreira, S. H., Cunha, F. Q., Silva, T. A., Nicoli, J. R., Vieira, L. Q., Souza, D. G., & Teixeira, M. M.
- Affiliations
- Departments of *Bioquímica e Imunologia and
- Universidade de São Paulo (BR)
- Departmento de Patologia Oral, Faculdade de Odontologia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, CEP 31270-901, Belo Horizonte/MG, Brazil
- Universidade Federal de Minas Gerais (BR)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-02-12
- Volume
- 105
- Issue
- 6
- Pages
- 2193-2197
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2538897
- OpenAlex
- W2076260247
- Cited by
- 289
- References
- 29
- Citations by year
- 2026: 9 · 2025: 26 · 2024: 24 · 2023: 27 · 2022: 22 · 2021: 24 · 2020: 23 · 2019: 15 · 2018: 13 · 2017: 12 · 2016: 15 · 2015: 15 · 2014: 14 · 2013: 14 · 2012: 11
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- commensal microbiota, inflammatory pain, hypernociception, germ-free mice, carrageenan, lipopolysaccharide, TNF-α, IL-1β, CXCL1, prostaglandins, dopamine, IL-10, host-microbe interactions, mechanical nociception
- MeSH terms
- Animals, Carrageenan, Germ-Free Life, Hyperalgesia, Inflammation, Interleukin-10, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review