Butterflies in Your Belly: The Microbiota-Gut-Brain Axis
Most people are familiar with the feeling of having ‘butterflies in your belly’. It is a sensation associated with feelings of nervousness, anticipation, dread, and excitement. Other expressions, such as ‘gut wrenching', are common ways in which human beings experience emotions as physical sensations in the gastrointestinal system. These are not simply poetic descriptions; these sensations are the brain and gut communicating (Lyon, 2018). The microbiota, gut, and brain are connected in a bi-directional dialogue that links the emotional and cognitive areas of the Central Nervous System (CNS) with peripheral intestinal functions in the Enteric Nervous System (ENS). This microbiota-gut-brain axis plays a major role in health, and disruptions can cause gastrointestinal, inflammatory, and neurological disorders and even mental health issues. (Carabotti et al., 2015; Prins, 2011). Although the full mechanism of the microbiota-gut-brain axis is not understood, the endocrine and immune systems, hormones and metabolites produced by the gut microbiota all play a role. The interaction between the microbiota, gut, and brain gives important insights into how disruptions in gut health can lead to neurological disorders (Wang & Wang, 2016).
Much of the evidence of the link between the microbiota and the CNS health of the host has come from experiments involving ‘germ-free’ rodents (rodents that don't have a microbiota). Without a microbiota, these rodents developed a wide range of physical and psychological issues, including reduced sensory-motor functions and gastric emptying, reduced blood-brain barrier integrity, and poor immune function. These germ-free rodents also had extremely altered brain physiology compared to rodents with intact microbiota, such as structural differences in amygdala neurons, levels of the neurotransmitter serotonin in the hippocampus, and the amount of myelination of neurons in the prefrontal cortex. Due to these physiological differences, germ-free rodents exhibited stress, anxiety, depressive behaviours, and cognitive impairments (Fülling et al., 2019). Furthermore, Bercik et al. (2011) showed that when gut microbiota was transplanted from one mouse to another, the anxiety phenotype of the first mouse was also transferred. This demonstrated that the microbiota influences brain chemistry and behaviour independently from the ANS.
Figure 1: The Microbiota-Gut-Brain Axis (Cryan et al., 2019)
The Microbiota
A microbiota is the population of microorganisms in an area, and the microbiota of the gut is intrinsic to human health. A healthy and well-balanced microbiota usually means the human host will also be generally healthy (Fitzgerald et al., 2019; Jandhyala et al., 2015). The human gut microbiota is a microscopic ecological community that maintains the metabolic balance of the gastrointestinal system. An adult human body has about 100 trillion bacteria, 80% of which reside in the gut. The gut microbiota contains over 100 species of bacteria. Together with the viral and fungal species that are part of this microbiota community, there are over 5000 strains of microbes and more than 1000 species of microflora in the gut microbiota. The composition of these diverse species can change and fluctuate throughout life, with the biggest changes seen in early development and when a disease affects the body (De Vos & De Vos, 2012; Lozupone et al., 2012). The microbiota is responsible for homeostasis, nutrient metabolism, drug metabolism, immunomodulation, and protection against pathogens. Disruption of the healthy flora of the gut microbiota, known as dysbiosis, can occur in a variety of ways, such as diet and use of antibiotics and has been implicated in a wide range of health issues, including inflammatory bowel diseases, rheumatoid arthritis, metabolic diseases (e.g. diabetes, obesity), allergies, neurodevelopmental illnesses, CNS disorders (e.g. autism and Parkinson’s disease) and stress-related illnesses (Fitzgerald et al., 2019; Jandhyala et al., 2015). The microbiota could therefore become a clinical or pharmacological target to cure these diseases Lozupone et al., 2012).
One of the first observations of the microbiota interacting with the nervous system occurred when the viral pathogen that causes rabies was shown to cross the blood-brain barrier (Smith, 2015). The blood-brain is a semipermeable layer of cells that usually protects the CNS from pathogens from the general circulatory system and is usually very difficult to cross (Tsou et al., 2017). However as the rabies virus can cross this barrier it can affect the sufferer’s cognitive and emotional state and cause the aggression, confusion and fear of water which are key symptoms of rabies (Smith, 2015).
The Enteric Nervous System
The ‘butterflies’ that are felt in the stomach in times of stress and anxiety are actually the activity of the enteric nervous system. The enteric nervous system (ENS) is a dense network of neurons in the gastrointestinal system that acts as an interface between the microbiota and its host. The ENS has more neurons than the spinal cord and produces over 30 neurotransmitters. Due to the high levels of neuronal activity of the gut, coupled with the fact that the ENS can operate independently from the CNS, the gut is known as the second brain of the body. The ENS regulates immune and inflammatory responses, as well as gastric motility, exocrine and endocrine secretions, and microcirculation of the gastrointestinal tract (Breit et al., 2018; Goyal & Hirano, 1996). The ENS is a branch of the autonomic nervous system (ANS) and is made up of two interconnected ganglionated plexi; the submucosal and myenteric plexus. These plexi contain sensory and motor neurons (secretomotor and vasodilation functions) and enteric neurons (regulate GI tract activity). The ENS responds to changes in the microbiota, or microbiota metabolites to facilitate gut functionality such as peristalsis and fluid movements (Cryan et al., 2019; Hyland & Cryan, 2016).
Figure 2: The Enteric Nervous System (Florjanczyk and Debevec-McKenney, n.d).
The ENS is vital to the microbiota-gut-brain axis. As the gut microbiota is in close proximity to the ENS, the gut microbiota has some influence over the neuronal signalling and function of the ENS (Hyland & Cryan, 2016). Communication between the gut and brain can occur through two distinct neuronal pathways, either directly to the ANS or bi-directionally through the ENS, which communicates the signal to the autonomic nervous system (ANS). The ANS and vagus nerve facilitate information exchange between the gut and brain (Wang & Wang, 2016).
The microbiota can influence the CNS indirectly, through the ENS. Through the intestinofugal neurons, the ENS can communicate sensory signals from the gut lumen, including signals from the microbiota. The intestinofugal neurons transmit the signal to the sympathetic ganglia through extrinsic primary afferent neurons in the spinal cord and vagus nerve of the CNS. Different microbes will have different influences on ENS activity (Cryan et al., 2019). Direct communication can occur between the gut microbiota and the brain through the vagus nerve. For example, bacterial signals from the microbiota can stimulate afferent neurons of the ENS, and the vagus nerve responds with an anti-inflammatory signal, helping to prevent pyosepticemia (blood infection) which is caused by microorganisms (Wang & Wang, 2016).
Neurological Disorders Influenced by the Gut
Hippocrates, the father of modern medicine, has been accredited with saying: “All disease begins in the gut.” There is growing evidence that his claim extends to neurological disorders as well. There is a comorbidity between gastrointestinal disorders and stress-related conditions (e.g. anxiety and depression). The influence of the gut-brain axis can also be seen in other neurological disorders such as autism, which has been linked to constipation, and multiple sclerosis, where patients experience increased intestinal permeability (Lyon, 2018; Pang & Croaker, 2010). Several clinical studies have found differences in the microbiota levels of certain species of bacteria in patients with Parkinson’s Disease (PD) compared to those without PD. The pathology of one of the hallmarks of PD, misfolded alpha-synuclein protein aggregates in the brain, begins in the GI tract. It is thought that changes in the microbiota may contribute to the accumulation of alpha-synuclein in the ENS and CNS and lead to PD (Fitzgerald et al., 2019). In Alzheimer’s, microbiota dysbiosis may result in a weakened intestinal barrier and blood-brain barrier, allowing pathogens to cross into the bloodstream and brain, causing neuroinflammation and neurodegeneration. Microbial infection may also contribute to Alzheimer's disease. Antibiotic treatment targeting the infective strains in the microbiota may provide treatments for Alzheimer's disease (Panza et al., 2019).
Figure 3: Impact of the gut microbiota on the brain (Farooq et al., 2022).
Conclusion:
Stress and nervousness can prompt an instantly familiar feeling in the gut, known as having ‘butterflies’. This feeling is caused by a stress response to the ENS that causes intestinal contraction to increase in speed and blood to be diverted from the digestive system (Lyon, 2018). The bi-directional interaction of the gut-brain axis allows for signalling from the gut to the brain and from the brain to the gut. This means that the gut can influence the brain and vice versa. Emotions and feelings of excitement or nervousness can lead to gut discomfort and ‘butterflies’, while issues in the GI tract can affect mood and cause fatigue and brain fog. This gut-brain axis also means that gut problems may be an early indicator of neurological diseases like PD. Studies have suggested that altering the gut microbiota may be a potential cure for nervous system disorders. Crosstalk between the ENS, CNS, immune system, inflammation and the bacteria, viruses and fungi that make up the gut microbiota make the microbiota-gut-brain axis incredibly difficult to study. By studying the links between the GI tract and the brain, a better understanding of neurological disorders can be found, as well as potential therapeutic targets for these diseases (Carabotti et al., 2015; Fitzgerald et al., 2019; Wang & Wang, 2016).
Bibliographical References
Bercik, P., Denou, E., Collins, J. N., Jackson, W. M., Lu, J., Jury, J., Deng, Y., Blennerhassett, P., Macri, J., McCoy, K. D., Verdu, E. F., & Collins, S. M. (2011). The Intestinal Microbiota Affect Central Levels of Brain-Derived Neurotropic Factor and Behavior in Mice. Gastroenterology, 141(2), 599-609.e3. https://doi.org/10.1053/j.gastro.2011.04.052
Breit, S., Kupferberg, A., Rogler, G., & Hasler, G. (2018). Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders. Frontiers in Psychiatry, 9. https://doi.org/10.3389/fpsyt.2018.00044
Carabotti, M., Scirocco, A., Maselli, M., & Severi, C. (2015). The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. PubMed, 28(2), 203–209. https://pubmed.ncbi.nlm.nih.gov/25830558
Cryan, J. F., O’Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F., Boehme, M., Codagnone, M. G., Cussotto, S., Fülling, C., Golubeva, A. V., Guzzetta, K. E., Vaidya, V. A., Long-Smith, C. M., Lyte, J. M., Martin, J., Molinero-Perez, A., Moloney, G. M., Morelli, E., Morillas, E., Dinan, T. G. (2019). The Microbiota-Gut-Brain Axis. Physiological Reviews, 99(4), 1877–2013. https://doi.org/10.1152/physrev.00018.2018
De Vos, W. M., & De Vos, E. (2012). Role of the intestinal microbiome in health and disease: from correlation to causation. Nutrition Reviews, 70, S45–S56. https://doi.org/10.1111/j.1753-4887.2012.00505.x
Fitzgerald, E. E., Murphy, S., & Martinson, H. M. (2019). Alpha-Synuclein Pathology and the Role of the Microbiota in Parkinson’s Disease. Frontiers in Neuroscience, 13. https://doi.org/10.3389/fnins.2019.00369
Fülling, C., Dinan, T. G., & Cryan, J. F. (2019). Gut Microbe to Brain Signaling: What Happens in Vagus. . .. Neuron, 101(6), 998–1002. https://doi.org/10.1016/j.neuron.2019.02.008
Goyal, R. K., & Hirano, I. (1996). The Enteric Nervous System. The New England Journal of Medicine, 334(17), 1106–1115. https://doi.org/10.1056/nejm199604253341707
Hyland, N. P., & Cryan, J. F. (2016). Microbe-host interactions: Influence of the gut microbiota on the enteric nervous system. Developmental Biology, 417(2), 182–187. https://doi.org/10.1016/j.ydbio.2016.06.027
Jandhyala, S. M., Talukdar, R., Subramanyam, C., Vuyyuru, H., Sasikala, M., & Reddy, D. N. (2015). Role of the normal gut microbiota. World Journal of Gastroenterology, 21(29), 8787. https://doi.org/10.3748/wjg.v21.i29.8787
Lozupone, C. A., Stombaugh, J., Gordon, J. I., Jansson, J. K., & Knight, R. (2012). Diversity, stability and resilience of the human gut microbiota. Nature, 489(7415), 220–230. https://doi.org/10.1038/nature11550
Lyon, L. (2018). ‘All disease begins in the gut’: was Hippocrates right? Brain, 141(3), e20. https://doi.org/10.1093/brain/awy017
Pang, K. H., & Croaker, G. D. H. (2010). Constipation in children with autism and autistic spectrum disorder. Pediatric Surgery International, 27(4), 353–358. https://doi.org/10.1007/s00383-010-2680-8
Panza, F., Lozupone, M., Solfrizzi, V., Watling, M., & Imbimbo, B. P. (2019). Time to test antibacterial therapy in Alzheimer’s disease. Brain. https://doi.org/10.1093/brain/awz244
Prins, A. (2011). The brain-gut interaction: the conversation and the implications. South African Journal of Clinical Nutrition, 24(sup-1), 8–14. https://journals.co.za/doi/abs/10.10520/EJC65261
Smith, P. (2015). The tantalizing links between gut microbes and the brain. Nature, 526(7573), 312–314. https://doi.org/10.1038/526312a
Tsou, Y. H., Zhang, X., Zhu, H., Syed, S., & Xu, X. (2017). Drug Delivery to the Brain across the Blood–Brain Barrier Using Nanomaterials. Small, 13(43), 1701921. https://doi.org/10.1002/smll.201701921
Wang, H., & Wang, Y. (2016). Gut Microbiota-brain Axis. Chinese Medical Journal, 129(19), 2373–2380. https://doi.org/10.4103/0366-6999.190667
