Skip to main content

Advertisement

Log in

Gut microbiome diversity mediates the association between right dorsolateral prefrontal cortex and anxiety level

  • Original Research
  • Published:
Brain Imaging and Behavior Aims and scope Submit manuscript

Abstract

Despite the fast growing interest in the impact of microbiome–gut–brain interaction on regulating emotional behavior in animals, the underlying mechanisms on how brain anatomy together with gut microbiotic condition jointly influence emotional state in healthy human volunteers remain largely unknown and hypothetic. Here, high-resolution structural magnetic resonance imaging data, stool samples, and psychological assessment results on anxiety level were collected from 61 healthy adults. Voxel-based morphometry was used to assess gray matter (GM) volumes, whereas 16s rRNA gene sequencing was used for bacterial classification. Correlation and mediation analysis were conducted to quantify the relationships among regional GM volume, gut microbiome diversity, and anxiety level. We observed that anxiety level was negatively correlated with GM volume in the right dorsolateral prefrontal cortex and alpha diversity index of gut microbiome. Additional mediation analysis revealed the indirect effect of dorsolateral prefrontal cortex GM volume on anxiety level via gut microbiome diversity. Our findings provide potential evidence of the microbiome–gut–brain interactions and their association with anxiety, highlighting gut microbiome diversity as a mediator that influences the relationship between brain morphometry and anxiety level.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

Due to ethical concerns and proprietary nature, data used in this study can only be made available to researchers subject to a formal data sharing agreement that warrants the intended use of the data and methods that would be perfomed. Please contact the corresponding author for details of the data and the request of access.

References

  • Ait-Belgnaoui, A., Colom, A., Braniste, V., Ramalho, L., Marrot, A., Cartier, C., et al. (2014). Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice. Neurogastroenterology & Motility, 26(4), 510–520.

    Article  CAS  Google Scholar 

  • Bagga, D., Reichert, J. L., Koschutnig, K., Aigner, C. S., Holzer, P., Koskinen, K., Moissl-Eichinger, C., & Schöpf, V. (2018). Probiotics drive gut microbiome triggering emotional brain signatures. Gut Microbes, 9(6), 486–496.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barrett, J., & Armony, J. L. (2008). Influence of trait anxiety on brain activity during the acquisition and extinction of aversive conditioning. Psychological Medicine, 39(2), 255–265.

    Article  PubMed  Google Scholar 

  • Bercik, P., Denou, E., Collins, J., Jackson, W., Lu, J., Jury, J., et al. (2011). The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology, 141(2), 599-609.e3.

    Article  CAS  PubMed  Google Scholar 

  • Bishop, S. J. (2009). Trait anxiety and impoverished prefrontal control of attention. Nature Neuroscience, 12(1), 92–98.

    Article  CAS  PubMed  Google Scholar 

  • Bishop, S. J., Duncan, J., & Lawrence, A. D. (2004). State anxiety modulation of the amygdala response to unattended threat-related stimuli. The Journal of Neuroscience, 24(46), 10364–10368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bravo, J. A., Forsythe, P., Chew, M. V., Escaravage, E., Savignac, H. M., Dinan, T. G., et al. (2011). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America, 108(38), 16050–16055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bystritsky, A., Kerwin, L. E., & Feusner, J. D. (2009). A preliminary study of fMRI-guided rTMS in the treatment of generalized anxiety disorder: 6-month follow-up. The Journal of Clinical Psychiatry, 70(3), 431–432.

    Article  PubMed  Google Scholar 

  • Calhoon, G. G., & Tye, K. M. (2015). Resolving the neural circuits of anxiety. Nature Neuroscience, 18(10), 1394–1404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell-Sills, L., & Barlow, D.H. (2007). Incorporating emotion regulation into conceptualizations and treatments of anxiety and mood disorders. Handbook of emotion regulation.

  • Chen, Y., Cui, Q., Fan, Y.-S., Guo, X., Tang, Q., Sheng, W., et al. (2020). Progressive brain structural alterations assessed via causal analysis in patients with generalized anxiety disorder. Neuropsychopharmacology, 45(10), 1689–1697.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen, Y.-H., Bai, J., Wu, D., Yu, S.-F., Qiang, X.-L., Bai, H., et al. (2019). Association between fecal microbiota and generalized anxiety disorder: Severity and early treatment response. Journal of Affective Disorders, 259, 56–66.

    Article  CAS  PubMed  Google Scholar 

  • Cosoff, S. J., & Hafner, R. J. (1998). The prevalence of comorbid anxiety in schizophrenia, schizoaffective disorder and bipolar disorder. Australian and New Zealand Journal of Psychiatry., 32(1), 67–72.

    Article  CAS  Google Scholar 

  • Crumeyrolle-Arias, M., Jaglin, M., Bruneau, A., Vancassel, S., Cardona, A., Daugé, V., et al. (2014). Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology, 42, 207–217.

    Article  CAS  PubMed  Google Scholar 

  • Cryan, J. F., & Dinan, T. G. (2012). Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour. Nature Reviews Neuroscience, 13(10), 701–712.

    Article  CAS  PubMed  Google Scholar 

  • Cryan, J. F., O’Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., et al. (2019). The microbiota–gut–brain axis. Physiological Reviews, 99(4), 1877–2013.

    Article  CAS  PubMed  Google Scholar 

  • Davidson, R. J. (2002). Anxiety and affective style: Role of prefrontal cortex and amygdala. Biological Psychiatry, 51(1), 68–80.

    Article  PubMed  Google Scholar 

  • Davis, M. (1992). The role of the amygdala in fear and anxiety. Annual Review of Neuroscience, 15(1), 353–375.

    Article  CAS  PubMed  Google Scholar 

  • Dilkov, D., Hawken, E. R., Kaludiev, E., & Milev, R. (2017). Repetitive transcranial magnetic stimulation of the right dorsal lateral prefrontal cortex in the treatment of generalized anxiety disorder: A randomized, double-blind sham controlled clinical trial. Progress in Neuro-Psychopharmacology and Biological Psychiatry., 78, 61–65.

    Article  PubMed  Google Scholar 

  • Forster, S., Nunez Elizalde, A. O., Castle, E., & Bishop, S. J. (2015). Unraveling the anxious mind: Anxiety, worry, and frontal engagement in sustained attention versus off-task processing. Cerebral Cortex, 25(3), 609–618.

    Article  PubMed  Google Scholar 

  • Fuster, J. M. (2002). Frontal lobe and cognitive development. Journal of Neurocytology, 31(3–5), 373–385.

    Article  PubMed  Google Scholar 

  • Gacias, M., Gaspari, S., Santos, P. M. G., Tamburini, S., Andrade, M., Zhang, F., et al. (2016). Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. eLife, 5, e13442.

    Article  PubMed  PubMed Central  Google Scholar 

  • Graff, L. A., Walker, J. R., & Bernstein, C. N. (2009). Depression and anxiety in inflammatory bowel disease: A review of comorbidity and management. Inflammatory Bowel Diseases, 15(7), 1105–1118.

    Article  PubMed  Google Scholar 

  • Heijtz, R. D., Wang, S., Anuar, F., Qian, Y., Björkholm, B., Samuelsson, A., et al. (2011). Normal gut microbiota modulates brain development and behavior. Proceedings of the National Academy of Sciences., 108(7), 3047.

    Article  CAS  Google Scholar 

  • Hoban, A. E., Stilling, R. M., Moloney, G., Moloney, R. D., Shanahan, F., Dinan, T. G., et al. (2017). Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. Microbiome, 5(1), 102.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hoban, A. E., Stilling, R. M., Ryan, F. J., Shanahan, F., Dinan, T. G., Claesson, M. J., et al. (2016). Regulation of prefrontal cortex myelination by the microbiota. Translational Psychiatry, 6(4), e774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holzer, P., Reichmann, F., Farzi, A., & Neuropeptide, Y. (2012). peptide YY and pancreatic polypeptide in the gut–brain axis. Neuropeptides, 46(6), 261–274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hori, T., Matsuda, K., & Oishi, K. (2020). Probiotics: A dietary factor to modulate the gut microbiome, host immune system, and gut–brain interaction. Microorganisms, 8(9), 1401.

    Article  CAS  PubMed Central  Google Scholar 

  • Huang, Y., Shi, X., Li, Z., Shen, Y., Shi, X., Wang, L., et al. (2018). Possible association of Firmicutes in the gut microbiota of patients with major depressive disorder. Neuropsychiatric Disease and Treatment, 14, 3329–3337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang, H.-Y., Zhang, X., Yu, Z.-H., Zhang, Z., Deng, M., Zhao, J.-H., et al. (2018). Altered gut microbiota profile in patients with generalized anxiety disorder. Journal of Psychiatric Research, 104, 130–136.

    Article  PubMed  Google Scholar 

  • Johnson, K. V. A. (2020). Gut microbiome composition and diversity are related to human personality traits. Human Microbiome Journal, 15, 100069.

    Article  Google Scholar 

  • Keogh, C. E., Kim, D. H., Pusceddu, M. M., Knotts, T. A., Rabasa, G., Sladek, J. A., et al. (2020). Myelin as a regulator of development of the microbiota-gut-brain axis. Brain, Behavior, and Immunity, 91, 437–450.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim, J. A., Szatmari, P., Bryson, S. E., Streiner, D. L., & Wilson, F. J. (2000). The prevalence of anxiety and mood problems among children with autism and Asperger syndrome. Autism, 4(2), 117–132.

    Article  Google Scholar 

  • Kim, M. J., Gee, D. G., Loucks, R. A., Davis, F. C., & Whalen, P. J. (2011). Anxiety dissociates dorsal and ventral medial prefrontal cortex functional connectivity with the amygdala at rest. Cerebral Cortex, 21(7), 1667–1673.

    Article  PubMed  Google Scholar 

  • Konopka, A. (2009). What is microbial community ecology? The ISME Journal, 3(11), 1223–1230.

    Article  PubMed  Google Scholar 

  • Kriss, M., Hazleton, K. Z., Nusbacher, N. M., Martin, C. G., & Lozupone, C. A. (2018). Low diversity gut microbiota dysbiosis: Drivers, functional implications and recovery. Current Opinion in Microbiology, 44, 34–40.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lach, G., Schellekens, H., Dinan, T. G., & Cryan, J. F. (2018). Anxiety, depression, and the microbiome: A role for gut peptides. Neurotherapeutics, 15(1), 36–59.

    Article  CAS  PubMed  Google Scholar 

  • Larsen, O. F. A., & Claassen, E. (2018). The mechanistic link between health and gut microbiota diversity. Scientific Reports, 8(1), 2183.

    Article  PubMed  PubMed Central  Google Scholar 

  • Latorre, R., Sternini, C., De Giorgio, R., & Greenwood-Van, M. B. (2016). Enteroendocrine cells: A review of their role in brain-gut communication. Neurogastroenterology and Motility, 28(5), 620–630.

    Article  CAS  PubMed  Google Scholar 

  • Liang, S., Wang, T., Hu, X., Luo, J., Li, W., Wu, X., et al. (2015). Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience, 310, 561–577.

    Article  CAS  PubMed  Google Scholar 

  • MacLeod, C., Mathews, A., & Tata, P. (1986). Attentional bias in emotional disorders. Journal of Abnormal Psychology., 95(1), 15–20.

    Article  CAS  PubMed  Google Scholar 

  • Martin, C. R., Osadchiy, V., Kalani, A., & Mayer, E. A. (2018). The brain–gut–microbiome axis. Cellular and Molecular Gastroenterology and Hepatology, 6(2), 133–148.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mayer, E. A. (2011). Gut feelings: The emerging biology of gut–brain communication. Nature Reviews Neuroscience, 12(8), 453–466.

    Article  CAS  PubMed  Google Scholar 

  • McIntyre, R. S., Subramaniapillai, M., Shekotikhina, M., Carmona, N. E., Lee, Y., Mansur, R. B., et al. (2019). Characterizing the gut microbiota in adults with bipolar disorder: A pilot study. Nutritional Neuroscience, 24, 1–8.

    Google Scholar 

  • Messaoudi, M., Violle, N., Bisson, J. F., Desor, D., Javelot, H., & Rougeot, C. (2011). Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes, 2(4), 256–261.

    Article  PubMed  Google Scholar 

  • Milham, M. P., Nugent, A. C., Drevets, W. C., Dickstein, D. S., Leibenluft, E., Ernst, M., et al. (2005). Selective reduction in amygdala volume in pediatric anxiety disorders: A voxel-based morphometry investigation. Biological Psychiatry, 57(9), 961–966.

    Article  PubMed  Google Scholar 

  • Mogg, K., & Bradley, B.P. (1999). Selective attention and anxiety: A cognitive-motivational perspective. Handbook of cognition and emotion (pp. 145–170).

  • Morawetz, C., Bode, S., Baudewig, J., Kirilina, E., & Heekeren, H. R. (2016). Changes in effective connectivity between dorsal and ventral prefrontal regions moderate emotion regulation. Cerebral Cortex, 26(5), 1923–1937.

    Article  PubMed  Google Scholar 

  • Ntranos, A., & Casaccia, P. (2018). The microbiome–gut–behavior axis: Crosstalk between the gut microbiome and oligodendrocytes modulates behavioral responses. Neurotherapeutics, 15(1), 31–35.

    Article  CAS  PubMed  Google Scholar 

  • Qin, S., Young, C. B., Duan, X., Chen, T., Supekar, K., & Menon, V. (2014). Amygdala subregional structure and intrinsic functional connectivity predicts individual differences in anxiety during early childhood. Biological Psychiatry, 75(11), 892–900.

    Article  PubMed  Google Scholar 

  • Rosen, J. B., & Schulkin, J. (1998). From normal fear to pathological anxiety. Psychological Review., 105(2), 325–350.

    Article  CAS  PubMed  Google Scholar 

  • Rothhammer, V., Mascanfroni, I. D., Bunse, L., Takenaka, M. C., Kenison, J. E., Mayo, L., et al. (2016). Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nature Medicine, 22(6), 586–597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rotzinger, S., & Vaccarino, F. J. (2003). Cholecystokinin receptor subtypes: Role in the modulation of anxiety-related and reward-related behaviours in animal models. Journal of Psychiatry and Neuroscience, 28(3), 171–181.

    PubMed  PubMed Central  Google Scholar 

  • Scult, M. A., Knodt, A. R., Swartz, J. R., Brigidi, B. D., & Hariri, A. R. (2017). Thinking and feeling: Individual differences in habitual emotion regulation and stress-related mood are associated with prefrontal executive control. Clinical Psychological Science: A Journal of the Association for Psychological Science., 5(1), 150–157.

    Article  Google Scholar 

  • Shan, B., Ai, Z., Zeng, S., Song, Y., Song, J., Zeng, Q., et al. (2020). Gut microbiome-derived lactate promotes to anxiety-like behaviors through GPR81 receptor-mediated lipid metabolism pathway. Psychoneuroendocrinology, 117, 104699.

    Article  CAS  PubMed  Google Scholar 

  • Shin, M., & Kemps, E. (2020). Media multitasking as an avoidance coping strategy against emotionally negative stimuli. Anxiety, Stress, & Coping, 33, 1–12.

    Article  Google Scholar 

  • Spampinato, M. V., Wood, J. N., De Simone, V., & Grafman, J. (2009). Neural correlates of anxiety in healthy volunteers: A voxel-based morphometry study. The Journal of Neuropsychiatry and Clinical Neurosciences, 21(2), 199–205.

    Article  PubMed  Google Scholar 

  • Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X.-N., et al. (2004). Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. The Journal of Physiology., 558(1), 263–275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takada, M., Nishida, K., Kataoka-Kato, A., Gondo, Y., Ishikawa, H., Suda, K., et al. (2016). Probiotic Lactobacillus casei strain Shirota relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models. Neurogastroenterology and Motility: THe Official Journal of the European Gastrointestinal Motility Society, 28(7), 1027–1036.

    Article  CAS  Google Scholar 

  • Tao, M., & Gao, J. (1994). Reliability and validity of Zung’s Self-Rating Anxiety Scale (SAS). Chinese Journal of Nervous and Mental Diseases, 5, 301–303.

    Google Scholar 

  • Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B., et al. (2013). Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology, 144(7), 1394–401.e4.

    Article  CAS  PubMed  Google Scholar 

  • van de Wouw, M., Boehme, M., Lyte, J. M., Wiley, N., Strain, C., O’Sullivan, O., et al. (2018). Short-chain fatty acids: Microbial metabolites that alleviate stress-induced brain–gut axis alterations. The Journal of Physiology, 596(20), 4923–4944.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu, R., Wu, B., Liang, J., He, F., Gu, W., Li, K., et al. (2020). Altered gut microbiota and mucosal immunity in patients with schizophrenia. Brain, Behavior, and Immunity., 85, 120–127.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, F., Chen, H., Zhang, R., Liu, Y., Kong, N., Guo, Y., et al. (2020). 5-Fluorouracil induced dysregulation of the microbiome-gut-brain axis manifesting as depressive like behaviors in rats. Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease., 1866(10), 165884.

    Article  CAS  Google Scholar 

  • Zung, W. W. (1971). A rating instrument for anxiety disorders. Psychosomatics, 12(6), 371–379.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank all the participants and researchers of the study.

Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81871432, 62036003, and U1808204), the Sichuan Science and Technology Program (Grant Nos. 2018TJPT00160, 2019YJ0180), and the Fundamental Research Funds for the Central Universities (Grant Nos. 2672018ZYGX2018J079, ZYGX2019Z017).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xujun Duan.

Ethics declarations

Conflict of interest

The authors report no potential conflicts of interest.

Ethical approval

This study was approved by the research ethical committee of University of Electronic Science and Technology of China. Written informed consents were obtained from participants after fully explaining the purpose of this study. All participants were allowed to withdraw from the study at any moment.

Informed consent

All the participants signed a written informed consent after fully understanding the purpose of this study. Written informed consent for publication was obtained from all participants.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 32 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, X., Li, L., Ling, Z. et al. Gut microbiome diversity mediates the association between right dorsolateral prefrontal cortex and anxiety level. Brain Imaging and Behavior 16, 397–405 (2022). https://doi.org/10.1007/s11682-021-00513-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11682-021-00513-9

Keywords

Navigation