Do Gut Microbes play a role in Central Nervous System Disorders?

Image Courtesy  Darryl Leja, National Human Genome Research Institute, National Institutes of Health

Image Courtesy Darryl Leja, National Human Genome Research Institute, National Institutes of Health

Author: Idil Cazimoglu Edited by: Layal Liverpool

Scientists are discovering increasing connections between the brain and the bacteria that live in our guts, with implications for a number of central nervous system disorders. Several companies are harnessing this brain-gut axis for the development of novel therapeutic strategies.

Our gut provides a warm home to hundreds of species of bacteria known collectively as the gut microbiota.[1] The gut is also equipped with its very own nervous system that controls production of intestinal mucus, contraction and relaxation of intestinal muscles, and many other functions essential for digestion. This nervous system of the gut is called the enteric nervous system and is often referred to as the “second brain”.

Our enteric nervous system communicates with our central nervous system, which consists of our brain and spinal cord. This communication happens through nerves and chemical signals released into the bloodstream, collectively named the “gut-brain” axis.

These interactions between our gut and central nervous system raise the question of whether or not our gut microbes play a role in central nervous system disorders. Researchers have identified differences in the gut microbiota between healthy people and those suffering from a central nervous system disorder such as Guillain–Barré syndrome,[2],[3] autism spectrum disorders [2],[4] and Parkinson’s disease [4],[5].

Although these observations alone do not necessarily mean that the microbes play a direct role in the development or progress of these disorders, further research using animal models does support a causal link between the two.

In laboratory mice, a lack of microbiota correlates with behaviour associated with autism spectrum disorders [6] and modification of gut bacteria with antibiotics protects mice from multiple sclerosis.[7] In an experimental animal model of Parkinson’s disease, mice given a microbiota transplant from human Parkinson’s disease patients developed worse physical impairments compared to mice that received their transplant from healthy human donors. [8]

Several mechanisms have been proposed to explain how gut bacteria could impact the function of our central nervous system. Bacteria in our gut digest the food we eat into smaller compounds, such as propionic acid, which then interact with our central nervous system.[9] Excessive propionic acid from food could trigger behavioural changes associated with autism spectrum disorders.[10]

Gut bacteria also interact with our central nervous system by modulating our immune system. Research suggests that gut bacteria may induce immune cells to release cytokines that can then enter the brain.[9],[11] Bacteria may also indirectly determine our susceptibility to certain diseases by changing the permeability of our intestines to microbes and molecules, although more evidence is required to confirm this.[12]

Elucidating links between certain microbes and central nervous system disorders could help identify therapies that work by manipulating the gut microbiota. Changes in diet could favor some bacteria over others and determine which small molecules are produced as a result of digestion.

Supplementation with probiotics (live bacteria) and prebiotics (food for bacteria) could promote the growth of desired bacterial species in the gut. Fecal transplantation (stool transfer from a healthy donor to a patient) could be employed to recolonize the gut with desired bacteria.

Three companies have already set out to explore the role of gut microbiota in central nervous system disorders (among other areas) and develop therapeutics. Symbiotix Biotherapies has developed a lead product made up of specific carbohydrates, ReglemersTM, from gut bacterium Bacterioides fragilis, as an approach to treat multiple sclerosis and other immune-mediated diseases through modulation of the immune response at specific sites of inflammation in the body.

Two other companies, Kallyope and Axial Biotherapeutics, are also harnessing the gut-brain axis to develop therapeutics for central nervous system disorders, but have not publicly announced the therapeutics in their pipeline. Kallyope does not specify a focus, whereas Axial Biotherapeutics focuses on autism spectrum disorders and Parkinson’s disease.


References:

1. Gorbach SL. Microbiology of the Gastrointestinal Tract. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 95.Available from: https://www.ncbi.nlm.nih.gov/books/NBK7670/

2. Yan Wang, Lloyd H. Kasper, The role of microbiome in central nervous system disorders, Brain, Behavior, and Immunity, Volume 38, 2014, Pages 1-12, https://doi.org/10.1016/j.bbi.2013.12.015.

3. Nachamkin, I. Curr Infect Dis Rep (2001) 3: 116. https://doi.org/10.1007/s11908-996-0033-5

4. Gil Sharon, Timothy R. Sampson, Daniel H. Geschwind, Sarkis K. Mazmanian,The Central Nervous System and the Gut Microbiome, Cell, Volume 167, Issue 4,2016, Pages 915-932,https://doi.org/10.1016/j.cell.2016.10.027

5. Scheperjans, F. , Aho, V. , Pereira, P. A., Koskinen, K. , Paulin, L. , Pekkonen, E. , Haapaniemi, E. , Kaakkola, S. , Eerola‐Rautio, J. , Pohja, M. , Kinnunen, E. , Murros, K. and Auvinen, P. (2015), Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord., 30: 350-358. https://doi.org/10.1002/mds.26069

6.Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T. G., & Cryan, J. F. (2014). Microbiota is essential for social development in the mouse. Molecular psychiatry, 19(2), 146–148. https://doi.org/10.1038/mp.2013.65

7. Javier Ochoa-Repáraz, Daniel W. Mielcarz, Lauren E. Ditrio, Ashley R. Burroughs, David M. Foureau, Sakhina Haque-Begum, Lloyd H. Kasper. Role of Gut Commensal Microflora in the Development of Experimental Autoimmune Encephalomyelitis.The Journal of Immunology, November 15, 2009, 183 (10) 6041-6050; https://doi.org/10.4049/jimmunol.0900747

8. Timothy R. Sampson, Justine W. Debelius, Taren Thron, Stefan Janssen, Gauri G. Shastri, Zehra Esra Ilhan, Collin Challis, Catherine E. Schretter, Sandra Rocha, Viviana Gradinaru, Marie-Francoise Chesselet, Ali Keshavarzian, Kathleen M. Shannon, Rosa Krajmalnik-Brown, Pernilla Wittung-Stafshede, Rob Knight, Sarkis K. Mazmanian, Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease, Cell, Volume 167, Issue 6, 2016,Pages 1469-1480.e12, https://doi.org/10.1016/j.cell.2016.11.018

9. Aiden Haghikia, Stefanie Jörg, Alexander Duscha, Johannes Berg, Arndt Manzel, Anne Waschbisch, Anna Hammer, De-Hyung Lee, Caroline May, Nicola Wilck, Andras Balogh, Annika I. Ostermann, Nils Helge Schebb, Denis A. Akkad, Diana A. Grohme, Markus Kleinewietfeld, Stefan Kempa, Jan Thöne, Seray Demir, Dominik N. Müller, Ralf Gold, Ralf A. Linker, Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine, Immunity,Volume 43, Issue 4, 2015, Pages 817-829, https://doi.org/10.1016/j.immuni.2015.09.007.

10. Macfabe D. F. (2012). Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microbial ecology in health and disease, 23, 10.3402/mehd.v23i0.19260. doi:10.3402/mehd.v23i0.19260

11. Paul Forsythe & John Bienenstock (2010) Immunomodulation by Commensal and Probiotic Bacteria, Immunological Investigations, 39:4-5, 429-448, https://doi.org/10.3109/08820131003667978

12. Julio‐Pieper, M. , Bravo, J. A., Aliaga, E. and Gotteland, M. (2014), Review article: intestinal barrier dysfunction and central nervous system disorders – a controversial association. Aliment Pharmacol Ther, 40: 1187-1201. https://doi.org/10.1111/apt.12950


Check out the other articles in our Brain-Gut Axis Series:


Brain-Gut Axis: Microglia under focus

http://science-union.org/articlelist/2019/4/14/brain-gut-axis-microglia-under-focus

The Power of Microbiota: Drivers of the Brain-Gut Axis in Psychiatry

http://science-union.org/articlelist/2018/7/18/the-power-of-microbiota-drivers-of-the-gut-axis-in-psychiatry

SIUKatowice: The Power of Poop with Prof. Ted Dinan

http://science-union.org/articlelist/2018/5/17/siukatowice-the-power-of-poop-with-prof-ted-dinan