The sinonasal microbiota, neural signaling, and depression in chronic rhinosinusitis
Michael Hoggard BSc (hons)
School of Biological Sciences, University of Auckland, Auckland, New Zealand
Search for more papers by this authorAngela Nocera
Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA
Search for more papers by this authorKristi Biswas PhD
School of Medicine, University of Auckland, Auckland, New Zealand
Search for more papers by this authorMichael W. Taylor PhD
School of Biological Sciences, University of Auckland, Auckland, New Zealand
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
Search for more papers by this authorRichard G. Douglas MD
School of Medicine, University of Auckland, Auckland, New Zealand
Search for more papers by this authorCorresponding Author
Benjamin S. Bleier MD, FACS
Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA
Correspondence to: Benjamin S. Bleier, MD, FACS, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114; e-mail: [email protected]Search for more papers by this authorMichael Hoggard BSc (hons)
School of Biological Sciences, University of Auckland, Auckland, New Zealand
Search for more papers by this authorAngela Nocera
Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA
Search for more papers by this authorKristi Biswas PhD
School of Medicine, University of Auckland, Auckland, New Zealand
Search for more papers by this authorMichael W. Taylor PhD
School of Biological Sciences, University of Auckland, Auckland, New Zealand
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
Search for more papers by this authorRichard G. Douglas MD
School of Medicine, University of Auckland, Auckland, New Zealand
Search for more papers by this authorCorresponding Author
Benjamin S. Bleier MD, FACS
Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA
Correspondence to: Benjamin S. Bleier, MD, FACS, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114; e-mail: [email protected]Search for more papers by this authorFunding sources for the study: Garnett Passe and Rodney Williams Memorial Foundation.
Conflicts of interest: None disclosed.
Abstract
Background
The complex relationships between the human microbiota, the immune system, and the brain play important roles in both health and disease, and have been of increasing interest in the study of chronic inflammatory mucosal conditions. We hypothesized that the sinonasal microbiota may act as a modifier of interkingdom neural signaling and, subsequently, mental health, in the upper respiratory inflammatory condition chronic rhinosinusitis (CRS). In this study we investigated associations between the sinonasal microbiota; local concentrations of the neurotransmitters serotonin, dopamine, and γ-aminobutyric acid (GABA); and depression severity in a cohort of 14 CRS patients and 12 healthy controls.
Methods
Subject demographics, clinical severity scores, depression index scores, and sinonasal swab and mucus samples were collected at the time of surgery. Bacterial communities were characterized from swabs by 16S rRNA gene-targeted sequencing and quantified by quantitative polymerase chain reaction. Mucus concentrations of the neurotransmitters serotonin, dopamine, and GABA were quantified by enzyme-linked immunosorbent assay.
Results
Several commonly “health-associated” sinonasal bacterial taxa were positively associated with higher neurotransmitter concentrations and negatively associated with depression severity. In contrast, several taxa commonly associated with an imbalanced sinonasal microbiota negatively associated with neurotransmitters and positively with depression severity. Few significant differences were identified when comparing between control and CRS subject groups, including neurotransmitter concentrations, depression scores, or sinonasal microbiota composition or abundance.
Conclusion
The findings obtained lend support to the potential for downstream effects of the sinonasal microbiota on neural signaling and, subsequently, brain function and behavior.
Supporting Information
| Filename | Description |
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| alr22074-sup-0001-Figure-S1.tif1.5 MB | Supplementary figure 1. |
| alr22074-sup-0002-Figure-S2.tif2 MB | Supplementary figure 2. |
| alr22074-sup-0003-Figure-S3.tif2 MB | Supplementary figure 3. |
| alr22074-sup-0004-Figure-S4.tif964.8 KB | Supplementary figure 4. |
| alr22074-sup-0005-Table-S1.docx30.5 KB | Supplementary Table 1. Participants’ demographics and clinical scores |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Lidy Verburg-van Kemenade BM, Cohen N, Chadzinska M. Neuroendocrine-immune interaction: evolutionarily conserved mechanisms that maintain allostasis in an ever-changing environment. Dev Comp Immunol. 2017; 66: 2–23.
- 2Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012; 13: 701–712.
- 3Dinan TG, Cryan JF. Microbes, immunity, and behavior: psychoneuroimmunology meets the microbiome. Neuropsychopharmacol Rev. 2017; 42: 178–192.
- 4Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology. 2009; 136: 2003–2014.
- 5Haapakoski R, Ebmeier KP, Alenius H, Kivimäki M. Innate and adaptive immunity in the development of depression: an update on current knowledge and technological advances. Prog Neuropsychopharmacol Biol Psychiatry. 2016; 66: 63–72.
- 6Maes M, Yirmyia R, Noraberg J, et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis. 2009; 24: 27–53.
- 7Kim YK, Na KS, Myint AM, Leonard BE. The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog Neuro-Psychopharmacology Biol Psychiatry. 2016; 64: 277–284.
- 8Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016; 16: 22–34.
- 9Lyte M. Microbial endocrinology: host-microbiota neuroendocrine interactions influencing brain and behavior. Gut Microbes. 2014; 5: 381–389.
- 10Wall R, Cryan JF, Ross RP, Fitzgerald GF, Dinan TG, Stanton C. Bacterial neuroactive compounds produced by psychobiotics. In: M Lyte, JF Cryan, eds. Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease. New York: Springer; 2014: 221–239.
10.1007/978-1-4939-0897-4_10 Google Scholar
- 11O'Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2015; 277: 32–48.
- 12De Palma G, Collins SM, Bercik P. The microbiota-gut-brain axis in functional gastrointestinal disorders. Gut Microbes. 2014; 5: 419–429.
- 13De Palma G, Collins SM, Bercik P, Verdu EF. The microbiota-gut-brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both? J Physiol. 2014; 592: 2989–2997.
- 14Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Irritable bowel syndrome: a microbiome–gut–brain axis disorder? World J Gastroenterol. 2014; 20: 14105–14125.
- 15Moloney RD, Johnson AC, O'Mahony SM, Dinan TG, Greenwood-Van Meerveld B, Cryan JF. Stress and the microbiota-gut-brain axis in visceral pain: relevance to irritable bowel syndrome. CNS Neurosci Ther. 2016; 22: 102–117.
- 16Maes M, Kubera M, Leunis J-C. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative Enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinol Lett. 2008; 29: 117–124.
- 17Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. 2011; 25: 397–407.
- 18Van Riel D, Verdijk R, Kuiken T. The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system. J Pathol. 2015; 235: 277–287.
- 19Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinology. 2012; 50(Suppl 23): 1–298.
- 20Hoggard M, Wagner Mackenzie B, Jain R, Taylor MW, Biswas K, Douglas RG. Chronic rhinosinusitis and the evolving understanding of microbial ecology in chronic inflammatory mucosal disease. Clin Microbiol Rev. 2017; 30: 321–348.
- 21Biswas K, Chang A, Hoggard M, et al. Toll-like receptor activation by sino-nasal mucus in chronic rhinosinusitis. Rhinology. 2017; 55: 59–69.
- 22Hoggard M, Biswas K, Zoing M, Wagner Mackenzie B, Taylor MW, Douglas RG. Evidence of microbiota dysbiosis in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2016; 7: 230–239.
- 23Cope EK, Goldberg AN, Pletcher SD, Lynch SV. Compositionally and functionally distinct sinus microbiota in chronic rhinosinusitis patients have immunological and clinically divergent consequences. Microbiome. 2017; 5: 53.
- 24Hoggard M, Waldvogel-Thurlow S, Zoing M, et al. Resolving the heterogeneity in chronic rhinosinusitis: inflammatory endotypes and microbial associations. unpublished data.
- 25Gliklich RE, Metson R. The health impact of chronic sinusitis in patients seeking otolaryngologic care. Otolaryngol Head Neck Surg. 1995; 113: 104–109.
- 26Bhattacharyya N. The economic burden and symptom manifestations of chronic rhinosinusitis. Am J Rhinol. 2003; 17: 27–32.
- 27Bhattacharyya N. Contemporary assessment of the disease burden of sinusitis. Am J Rhinol Allergy. 2009; 23: 392–395.
- 28Godbout JP, Glaser R. Stress-induced immune dysregulation: implications for wound healing, infectious disease and cancer. J Neuroimmune Pharmacol. 2006; 1: 421–427.
- 29Tomoum MO, Klattcromwell C, Delsignore A, Ebert C, Senior BA. Depression and anxiety in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2015; 5: 674–681.
- 30Wasan A, Fernandez E, Jamison RN, Bhattacharyya N. Association of anxiety and depression with reported disease severity in patients undergoing evaluation for chronic rhinosinusitis. Ann Otol Rhinol Laryngol. 2007; 116: 491–497.
- 31Nanayakkara JP, Igwe C, Roberts D, Hopkins C. The impact of mental health on chronic rhinosinusitis symptom scores. Eur Arch Otorhinolaryngol. 2013; 270: 1361–1364.
- 32Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 2009; 34: 447–454.
- 33Prisnie JC, Fiest KM, Coutts SB, et al. Validating screening tools for depression in stroke and transient ischemic attack patients. Int J Psychiatry Med. 2016; 51: 262–277.
- 34Herlemann DP, Labrenz M, Jürgens K, Bertilsson S, Waniek JJ, Andersson AF. Transitions in bacterial communities along the 2000 km salinity gradient of the Baltic Sea. ISME J. 2011; 541: 1571–1579.
- 35Edgar RC. Search and clustering orders of magnitude faster than BLAST. Bioinformatics. 2010; 26: 2460–2461.
- 36Caporaso GJ, Kuczynski J, Stombaugh J, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010; 7: 335–336.
- 37Wang Q, Garrity GM, Tiedje JM, Cole JR. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol. 2007; 73: 5261–5267.
- 38Biswas K, Hoggard M, Jain R, Taylor MW, Douglas RG. The nasal microbiota in health and disease: variation within and between subjects. Front Microbiol. 2015; 9: 134.
- 39R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2015.
- 40Lam K, Schleimer R, Kern RC. The etiology and pathogenesis of chronic rhinosinusitis: a review of current hypotheses. Curr Allergy Asthma Rep. 2015; 15: 1–10.
- 41Soyka MB, Wawrzyniak P, Eiwegger T, et al. Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-γ and IL-4. J Allergy Clin Immunol. 2012; 130: 1087–1096.
- 42Rogers G, Den Beste K, Parkos CA, Nusrat A, DelGaudio JM, Wise SK. Epithelial tight junction alterations in nasal polyposis. Int Forum Allergy Rhinol. 2011; 1: 50–54.
- 43Orlandi RR, Kingdom TT, Hwang PH, et al. International Consensus Statement on Allergy and Rhinology: Rhinosinusitis. Int Forum Allergy Rhinol. 2016; 6(Suppl 1): S22–S209.
- 44Wagner Mackenzie B, Waite DW, Hoggard M, Douglas RG, Taylor MW, Biswas K. Bacterial community collapse: a meta-analysis of the sinonasal microbiota in chronic rhinosinusitis. Environ Microbiol. 2017; 19: 381–392.
- 45Ramakrishnan VR, Hauser LJ, Feazel LM, Ir D, Robertson CE, Frank DN. Sinus microbiota varies among chronic rhinosinusitis phenotypes and predicts surgical outcome. J Allergy Clin Immunol. 2015; 136: 334–342.
- 46Bailey MT, Engler H, Sheridan JF. Stress induces the translocation of cutaneous and gastrointestinal microflora to secondary lymphoid organs of C57BL/6 mice. J Neuroimmunol. 2006; 171: 29–37.
- 47Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med. 2010; 16: 228–232.
- 48Tomassen P, Vandeplas G, Van Zele T, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol. 2016; 137: 1449–1456.
- 49Wu T-H, Hu L-Y, Lu T, et al. Risk of psychiatric disorders following trigeminal neuralgia: a nationwide population-based retrospective cohort study. J Headache Pain. 2015; 16: 1–8.
- 50Rombaux P, Huart C, Levie P, Cingi C, Hummel T. Olfaction in chronic rhinosinusitis. Curr Allergy Asthma Rep. 2016; 16: 1–12.
- 51Kohli P, Naik AN, Harruff EE, Nguyen SA, Schlosser RJ, Soler ZM. The prevalence of olfactory dysfunction in chronic rhinosinusitis. Laryngoscope. 2017; 127: 309–320.
- 52Yee KK, Pribitkin EA, Cowart BJ, et al. Neuropathology of the olfactory mucosa in chronic rhinosinusitis. Am J Rhinol Allergy. 2010; 24: 110–120.
- 53Han P, Whitcroft KL, Fischer J, et al. Olfactory brain gray matter volume reduction in patients with chronic rhinosinusitis. Int Forum Allergy Rhinol. 2017; 7: 551–556.
- 54Saliba J, Fnais N, Tomaszewski M, et al. The role of trigeminal function in the sensation of nasal obstruction in chronic rhinosinusitis. Laryngoscope. 2016; 126: e174–e178.
- 55Phipps CD, Wood WE, Gibson WS, Cochran WJ. Gastroesophageal reflux contributing to chronic sinus disease in children. Arch Otolaryngol Head Neck Surg. 2000; 126: 831–836.
- 56Ciorba A, Bianchini C, Zuolo M, Feo CV. Upper aerodigestive tract disorders and gastro-oesophageal reflux disease. World J Clin Cases. 2015; 3: 102–111.
- 57Bock JM, Poetker DM. Reflux and chronic rhinosinusitis. JAMA Otolaryngol Neck Surg. 2011; 142: 633–634.
- 58Kahrilas PJ. Gastroesophageal reflux disease. JAMA. 1996; 276: 983–988.
- 59Halstead LA. Role of gastroesophageal reflux in pediatric upper airway disorders. Otolaryngol Head Neck Surg. 1999; 120: 208–214.
- 60Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes. 2013; 20: 14–21.
- 61Mawe GM, Hoffman JM. Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol. 2013; 10: 473–486.
- 62Dubin MG, Liu C, Lin SY, Senior BA. American Rhinologic Society member survey on “maximal medical therapy” for chronic rhinosinusitis. Am J Rhinol. 2007; 21: 483–488.
- 63Schwartz JS, Tajudeen BA, Cohen NA. Medical management of chronic rhinosinusitis—an update. Expert Rev Clin Pharmacol. 2016; 9: 695–704.
