Absence of gut microbial colonization attenuates the sympathoadrenal response to hypoglycemic stress in mice: implications for human neonates
Abstract
Background Gut microbiota plays an important role during early development via bidirectional gut-brain signaling. Catecholamines provide a survival advantage allowing adaptation to common postnatal stressors. We aimed to explore the potential link between gut microbiota/gut-derived metabolites and sympathoadrenal stress responsivity.Methods The effect of insulin-induced hypoglycemia was compared in mice with (control, adapted control) and without microbiome (germ-free, GF). Counter-regulatory hormones were analyzed in urine and plasma. Adrenal gene expression levels were evaluated and correlated to cecal short chain fatty acids (SCFA) content.Results There was a significant association between absent microbiota/SCFA and epinephrine levels at baseline and after stress. Corticosterone (hypothalamic-pituitary-adrenal axis) and glucagon release (parasympathetic signaling) were similar in all groups. Hypoglycemia-induced c-Fos (marker of trans-synaptic neuronal activation) in both conditions. Delayed increases in adrenal tyrosine hydroxylase and neuropeptide Y messenger RNA were observed in GF mice. Transcriptome analysis provided insight into underlying mechanisms for attenuated epinephrine production and release.Conclusion Lack of microbiome selectively impaired adrenal catecholamine responses to hypoglycemia. We speculate that absent/delayed acquisition of flora (e.g., after antibiotic exposure) may compromise sympathoadrenal stress responsivity. Conversely, controlled manipulation of the intestinal microflora may provide a novel therapeutic opportunity to improve survival and overall health in preterm neonates.
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One previous study found that absence of gut microbial colonization selectively impaired catecholamine response to hypoglycemic stress in mice, but the molecular mechanism was not identified.
“One previous study found that the absence of gut microbial colonization selectively impaired catecholamine response to hypoglycemic stress in mice (Giri et al., 2019); however, the molecular mechanism was not identified.”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Giri et al., 2019
Absence of gut microbial colonization selectively impaired the catecholamine response to hypoglycemic stress in mice, and the transcriptome in adrenal glands was altered.
“Previous work found that the absence of gut microbial colonization selectively impaired the catecholamine response to hypoglycemic stress in mice, and the transcriptome in adrenal glands was altered (Giri et al., 2019).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Giri et al., 2019
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites
Koh, A., De Vadder, F., Kovatcheva-Datchary, P., & Bäckhed, F. (2016) · Cell · doi:10.1016/j.cell.2016.05.041 · Cited by 7,070 · see citing works
The human microbiome: at the interface of health and disease
Cho, I., & Blaser, M. J. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3182 · Cited by 3,449 · see citing works
Hsiao, E. Y., McBride, S. W., Hsien, S., Sharon, G., Hyde, E. R., McCue, T., Codelli, J. A., Chow, J., Reisman, S. E., Petrosino, J. F., et al. (2013) · Cell · doi:10.1016/j.cell.2013.11.024 · Cited by 3,283 · see citing works
Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X., Kubo, C., & Koga, Y. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.063388 · Cited by 2,735 · 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 interplay between the intestinal microbiota and the brain
Collins, S. M., Surette, M., & Bercik, P. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2876 · Cited by 1,611 · see citing works
Signals from the gut microbiota to distant organs in physiology and disease
Schroeder, B. O., & Bäckhed, F. (2016) · Nature Medicine · doi:10.1038/nm.4185 · Cited by 1,409 · see citing works
Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring
Buffington, S. A., Di Prisco, G. V., Auchtung, T. A., Ajami, N. J., Petrosino, J. F., & Costa-Mattioli, M. (2016) · Cell · doi:10.1016/j.cell.2016.06.001 · Cited by 1,163 · see citing works
Control of brain development, function, and behavior by the microbiome
Sampson, T. R., & Mazmanian, S. K. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.04.011 · Cited by 1,093 · see citing works
Microbiota and neurodevelopmental windows: implications for brain disorders
Borre, Y. E., O’Keeffe, G. W., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F. (2014) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2014.05.002 · Cited by 1,089 · see citing works
The Intestinal Microbiome in Early Life: Health and Disease
Arrieta, M.-C., Stiemsma, L. T., Amenyogbe, N., Brown, E. M., & Finlay, B. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00427 · Cited by 1,024 · see citing works
Overflow of catecholamine neurotransmitters to the circulation: source, fate, and functions
Esler, M., Jennings, G., Lambert, G., Meredith, I., Horne, M., & Eisenhofer, G. (1990) · Physiological Reviews · doi:10.1152/physrev.1990.70.4.963 · Cited by 794 · see citing works
Emerging Role of Endosomal Toll-Like Receptors in Rheumatoid Arthritis
Thwaites, R. S., Chamberlain, G., & Sacre, S. M. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00001 · Cited by 748 · see citing works
Prioritizing spatial accuracy in high-resolution fMRI data using multivariate feature weight mapping
Stelzer, J., Buschmann, T., Lohmann, G., Margulies, D. S., Trampel, R., & Turner, R. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00066 · Cited by 638 · see citing works
Luczynski, P., McVey Neufeld, K.-A., Oriach, C. S., Clarke, G., Dinan, T. G., & Cryan, J. F. (2016) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw020 · Cited by 632 · see citing works
Crumeyrolle-Arias, M., Jaglin, M., Bruneau, A., Vancassel, S., Cardona, A., Daugé, V., Naudon, L., & Rabot, S. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.01.014 · Cited by 581 · see citing works
Catecholaminergic systems in stress: structural and molecular genetic approaches
Kvetnansky, R., Sabban, E. L., & Palkovits, M. (2009) · Physiological Reviews · doi:10.1152/physrev.00042.2006 · Cited by 548 · see citing works
Gut microbiota and the neuroendocrine system
Farzi, A., Fröhlich, E. E., & Holzer, P. (2018) · Neurotherapeutics · doi:10.1007/s13311-017-0600-5 · Cited by 478 · see citing works
Establishment and development of intestinal microbiota in preterm neonates
Arboleya, S., Binetti, A. G., Salazar, N., Fernández, N., Sánchez, G. S., Hernández‐Barranco, A. M., Margollés, A., Reyes‐Gavilán, C. G. D. L., & Gueimonde, M. (2011) · FEMS Microbiology Ecology · doi:10.1111/j.1574-6941.2011.01261.x · Cited by 439 · see citing works
The microbiome: stress, health and disease
Moloney, R. D., Desbonnet, L., Clarke, G., Dinan, T. G., & Cryan, J. F. (2014) · Mammalian Genome · doi:10.1007/s00335-013-9488-5 · Cited by 430 · see citing works
Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc
Gallo, F. T., Katche, C., Morici, J. F., Medina, J. H., & Weisstaub, N. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00079 · Cited by 339 · see citing works
Sherwin, E., Sandhu, K. V., Dinan, T. G., & Cryan, J. F. (2016) · CNS Drugs · doi:10.1007/s40263-016-0370-3 · Cited by 308 · see citing works
Nankova, B. B., Agarwal, R., MacFabe, D. F., & La Gamma, E. F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103740 · Cited by 294 · see citing works
Self-citationEffect of Intestinal Microbial Ecology on the Developing Brain
Douglas‐Escobar, M., Elliott, E., & Neu, J. (2013) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/jamapediatrics.2013.497 · Cited by 207 · see citing works
The microbiome regulates amygdala-dependent fear recall
Hoban, A. E., Stilling, R. M., Moloney, G., Shanahan, F., Dinan, T. G., Clarke, G., & Cryan, J. F. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.100 · Cited by 197 · see citing works
Heijtz, R. D. (2016) · Seminars in Fetal and Neonatal Medicine · doi:10.1016/j.siny.2016.04.012 · Cited by 193 · see citing works
Priming for health: gut microbiota acquired in early life regulates physiology, brain and behaviour
Clarke, G., O'Mahony, S., Dinan, T., & Cryan, J. (2014) · Acta Paediatrica · doi:10.1111/apa.12674 · Cited by 179 · see citing works
Walker, W. A. (2017) · Pediatric Research · doi:10.1038/pr.2017.111 · Cited by 169 · see citing works
Microbiota regulates visceral pain in the mouse
Luczynski, P., Tramullas, M., Viola, M. F., Shanahan, F., Clarke, G. A., O’Mahony, S. M., Dinan, T. G., & Cryan, J. F. (2017) · eLife · doi:10.7554/elife.25887 · Cited by 166 · see citing works
Taborsky, G. J., & Mundinger, T. O. (2012) · Endocrinology · doi:10.1210/en.2011-2040 · Cited by 140 · see citing works
Neural pathways that control the glucose counterregulatory response
Verberne, A. J. M., Sabetghadam, A., & Korim, W. S. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00038 · Cited by 140 · see citing works
Metabolic tinkering by the gut microbiome
Selkrig, J., Wong, P., Zhang, X., & Pettersson, S. (2014) · Gut Microbes · doi:10.4161/gmic.28681 · Cited by 120 · see citing works
Vodička, M., Ergang, P., Hrnčíř, T., Mikulecká, A., Kvapilová, P., Vagnerová, K., Šestáková, B., Fajstová, A., Hermanová, P., Hudcovic, T., et al. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.07.007 · Cited by 112 · see citing works
Yu, Y., Lu, L., Sun, J., Petrof, E. O., & Claud, E. C. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00022.2016 · Cited by 96 · see citing works
Building a Beneficial Microbiome from Birth
Castanys‐Muñoz, E., Martín, M. J., & Vázquez, E. (2016) · Advances in Nutrition · doi:10.3945/an.115.010694 · Cited by 93 · see citing works
Cavadas, C., Céfaï, D., Rosmaninho‐Salgado, J., Vieira‐Coelho, M. A., Moura, E., Busso, N., Pedrazzini, T., Grand, D., Rotman, S., Waeber, B., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600913103 · Cited by 54 · see citing works
Patel, P., Nankova, B. B., & LaGamma, E. F. (2005) · Developmental Brain Research · doi:10.1016/j.devbrainres.2005.08.005 · Cited by 41 · see citing works
Self-citationO'Neill, H. M., Lally, J., Galić, S., Pulinilkunnil, T., Ford, R. J., Dyck, J. R. B., van Denderen, B. J., Kemp, B. E., & Steinberg, G. R. (2015) · Physiological Reports · doi:10.14814/phy2.12444 · Cited by 32 · see citing works
Cytokine Interactions with Adrenal Medullary Chromaffin Cells
Douglas, S. A., Sreenivasan, D., Carman, F. H., & Bunn, S. J. (2010) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-010-9593-x · Cited by 28 · see citing works
Neuropeptide Y Gates a Stress-Induced, Long-Lasting Plasticity in the Sympathetic Nervous System
Wang, Q., Wang, M., & Whim, M. D. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.3132-12.2013 · Cited by 26 · see citing works
Lab mice's ancestral ‘Eve’ gets her genome sequenced
Reardon, S. (2017) · Nature · doi:10.1038/nature.2017.22974 · Cited by 10 · see citing works
Kudrick, N., Chan, O. T. M., Gamma, E. F. L., Kim, J. L., Tank, A. W., Sterling, C. R., & Nankova, B. B. (2015) · Physiological Reports · doi:10.14814/phy2.12307 · Cited by 8 · see citing works
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Trujillo-Vargas, C. M., Schaefer, L., Alam, J., Pflugfelder, S. C., Britton, R. A., & de Paiva, C. S. (2019) · The Ocular Surface · doi:10.1016/j.jtos.2019.10.006 · Cited by 87 · see citing works
Mir, H.-D., Milman, A., Monnoye, M., Douard, V., Philippe, C., Aubert, A., Castanon, N., Vancassel, S., Guérineau, N. C., Naudon, L., et al. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104750 · Cited by 70 · see citing works
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Tanelian, A., Nankova, B. B., Miari, M., Nahvi, R. J., & Sabban, E. L. (2022) · Neurobiology of Stress · doi:10.1016/j.ynstr.2022.100461 · Cited by 51 · see citing works
Self-citationKurhaluk, N., Kołodziejska, R., Kamiński, P., & Ткаченко, Г. М. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262311706 · Cited by 41 · see citing works
Assessment of gut microbiota fecal metabolites by chromatographic targeted approaches
Fiori, J., Turroni, S., Candela, M., & Gotti, R. (2019) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2019.112867 · Cited by 33 · see citing works
Without a bug’s life: Germ-free rodents to interrogate microbiota-gut-neuroimmune interactions
Spichak, S., Guzzetta, K. E., O’Leary, O. F., Clarke, G. A., Dinan, T. G., & Cryan, J. F. (2018) · Drug Discovery Today Disease Models · doi:10.1016/j.ddmod.2019.08.002 · Cited by 28 · see citing works
Butterflies in the gut: the interplay between intestinal microbiota and stress
Lai, T.-T., Liou, C.-W., Tsai, Y.-H., Lin, Y.-Y., & Wu, W. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-023-00984-6 · Cited by 26 · see citing works
LaGamma, E. F., Hu, F., Cruz, F. P., Bouchev, P., & Nankova, B. B. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100376 · Cited by 16 · see citing works
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Jiang, Y. P., Pan, W., Wu, W., Wang, W., Sun, S., & Wang, J. (2019) · BMC Pediatrics · doi:10.1186/s12887-019-1844-5 · Cited by 15 · see citing works
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- Authors
- Giri, P., Hu, F., La Gamma, E. F., & Nankova, B. B.
- Affiliations
- Westchester Medical Center (US)
- New York Medical College (US)
- Corresponding author
- Nankova, Bistra B.
- ORCID
- Nankova, Bistra B.
- Venue
- Pediatric Research
- Published
- 2019-01-14
- Volume
- 85
- Issue
- 4
- Pages
- 574-581
- ISSN
- 0031-3998 (ISSN-L)
- 1530-0447
- OpenAlex
- W2910231929
- Cited by
- 15
- References
- 43
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 1
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Pediatric Research (publishedVersion)
- PubMed (publishedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- gut microbiota, germ-free mice, insulin-induced hypoglycemia, sympathoadrenal response, epinephrine, catecholamines, short-chain fatty acids, tyrosine hydroxylase, neuropeptide Y, c-fos, hypothalamic-pituitary-adrenal axis, glucagon, gut-brain axis, neonatal stress, preterm infants, antibiotic exposure
- MeSH terms
- Gastrointestinal Microbiome, Adrenal Glands, Animals, Corticosterone, Epinephrine, Glucagon, Humans, Hypoglycemia, Infant, Newborn, Mice, Inbred C57BL, Sympathetic Nervous System, Mice
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