We often say “trust your gut,” or use the idiom “go with your gut feeling,” to encourage people to follow their instincts. Figures of speech aside, the question of whether the gut has anything to do with our thoughts and instincts is an interesting one.

To examine the science behind these sayings, we find that the gut and the brain– our usual suspect for sourcing feelings and thoughts– are actually deeply intertwined. Sometimes known as the “second brain”,1 the gut contains the enteric nervous system (ENS), a network of millions of nerve cells lining the gastrointestinal tract.2 While it isn’t capable of performing cognitive functions quite like the brain does, the ENS can send and receive messages from the brain through a network known collectively as the “gut-brain axis” (GBA).3

The GBA (see fig. 1) serves to tie together important functions of the brain with intestinal mechanisms. The GBA network primarily consists of the central nervous system (CNS), which includes the brain and spinal cord; the autonomic nervous system, which regulates involuntary processes like heart rate, digestion, and respiration4; the ENS, a subdivision of the autonomic nervous system; and the hypothalamic pituitary adrenal axis, which manages the body’s homeostasis and responses to stress.5 The involvement of all of these systems in the GBA allows for both neural and hormonal forms of communication: the brain can affect the function of a variety of cells in the intestine, from immune cells to muscle cells to neurons.3 All of these cells are also under the influence of the “second brain,” the gut microbiota.

The gut microbiota holds a diverse abundance of microorganisms, estimated to number over trillions in count, living in symbiosis, or mutual benefit, with their host.10 Research suggests that gut microbiota is largely impacted by diet.10 As the proverb goes: “you are what you eat.” The types of nutrients a person consumes: skewing toward animal- or plant-based, fiber heavy or light, and with or without dairy, can affect the types of bacteria living in the gut as well as the person’s overall health. Another vital function of the gut microbiota lies in the bacteria’s abilities to produce and consume mammalian neurotransmitters, chemical signalling molecules of the nervous system, including: dopamine (associated with pleasure), serotonin (associated with mood), and GABA (associated with anxiety regulation).11 Neurotransmitters are only one of many ways through which the ENS is thought to be able to interact with the CNS.

The modern idea that the gut microbiota was connected to the brain sprouted from the discovery of microorganisms in the nineteenth century.1 During this time, a French physician proposed a theory that microbes and an imbalance of these microorganisms in the body may be the cause of diseases and mental illnesses.1 However, an understanding of a relationship between the brain and digestive system existed throughout history for much longer. Use of fecal microbial transplants (FMT) has been documented since the sixteenth and seventeenth centuries in Ancient Greece and in Chinese medical practice since the fourth century CE.1 

Fecal transplant involves the transfer of healthy fecal matter, containing “good” bacteria, from a donor to a recipient who is lacking healthful bacteria due to illness or antibiotic usage.6 Restoration of gut microbial diversity through FMT in a 2014 study was found to cure overall 90% of the patients treated for Clostridium difficile infection.7 In addition to direct benefits to gut health, FMT studies provide substantive evidence for the influence of the GBA. A 2020 review of twenty-one studies relating to FMT and psychiatric illnesses found “a decrease in depressive and anxiety-like symptoms and behaviours resulting from the transplantation of healthy microbiota” and a “transmission of depressive and anxiety-like symptoms and behaviours resulting from the transplantation of microbiota from psychiatrically ill donors to healthy recipients”.8 Although there is yet no definitive concept of what a “healthy [gut] microbiome” looks like, FMT exists as a potential treatment targeting the GBA to better understand and ameliorate psychiatric illness symptoms.8 

The microbe-brain interaction is further supported by studies of dysbiosis on anxiety and depressive behaviors, as well as in autistic patients.3 Dysbiosis is an imbalance of gut microbiota which can lead to a variety of symptoms and diseases.9 It was notably observed in “functional gastrointestinal disorders (FGID) that are highly associated with mood disorders”.3 Irritable bowel syndrome (IBS) is a key example. A study found that transferring microbiota from IBS patients to previously unaffected rats resulted in development of IBS characteristics.3 

Given their functional differences, it may come as a surprise to learn that immunity of the brain also relies on the gut. CNS tissues are considered “immune privileged,” exhibiting unusually tolerant inflammatory responses.12,13 This is believed to be a result of the makeup of the CNS, which features physical barriers to infection and an absence of common elements of immune response (lymphatic involvement and immune cells/complexes).12 However, new studies have found that the “dura mater”– the outer layer of the meninges, a three membrane barrier protecting the CNS from trauma and infection– contains IgA immune cells that originate in the gut.13 When a fungus was introduced to mice in a GBA study, it was found that the mice with IgA cells were able to respond to and control the fungal infection. In the mice lacking IgA cells, the fungus was able to spread into the brain and cause a fatal infection.14 The results of this research indicate that the GBA holds a crucial role for immune response in both gut and brain.14

Thanks to the GBA, brain and gut immunity are codependent. A study of traumatic brain injury (TBI) in mice found that brain injury caused chronic changes in the intestines that increased the likelihood of future infections.15,16 When mice with TBI were treated with a gut infection, the study found a worsening of brain inflammation and greater loss of neurons than in uninfected mice.16 These findings highlight an increased risk of mortality after brain trauma, dependent on gut health, while expanding the possibilities for treating patients with TBI.15 

GBA research is integral to developing treatments for diseases involving the brain and/or the intestinal tract. In afflictions ranging from psychiatric (e.g. stress or anxiety) to intestinal (e.g. IBS) study of the gut can benefit our understanding of what is occurring in the brain and vice versa. From dietary nutrient distribution10 to FMT treatments,8 the GBA proves a critical set of pathways with which to consider the impacts of a healthy gut microbiota and nervous system. 

So, to return to the question of whether “gut feelings” can tell us anything important, given the benefits to be gained from taking care of our gut microbiota: we should definitely “listen to our guts.”

References

[1] Moore, A. et al. “Contextualising the microbiota-gut-brain axis in history and culture.” Microbial Ecology in Health and Disease, vol. 29 (2), 2018,
doi: 10.1080/16512235.2019.1546267

[2] “The Brain-Gut Connection.” Johns Hopkins Medicine, 2020, www.hopkinsmedicine.org/health/wellness-and-prevention/the-brain-gut-connection. 

[3] Carabotti, M. et al. “The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.” Annals of gastroenterology, vol. 28 (2), 2015, pp. 203-209. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367209/. 

[4] Waxenbaum, J. et al. “Anatomy, Autonomic Nervous System.” In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020.  https://www.ncbi.nlm.nih.gov/books/NBK539845/. 

[5] Heaney, Jennifer. “Hypothalamic-Pituitary-Adrenal Axis.” SpringerLink, Springer, New York, NY, 1970, link.springer.com/referenceworkentry/10.1007/978-1-4419-1005-9_460. 

[6] Villines, Zawn. “What Is a Fecal Transplant? Everything You Need to Know.” Medical News Today, MediLexicon International, 2019, www.medicalnewstoday.com/articles/325128. 

[7] Youngster, I. et al. “Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study.” Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, vol. 58,11 (2014): 1515-22. doi:10.1093/cid/ciu135

[8] Chinna Meyyappan, A. et al. “Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review.” BMC psychiatry, vol. 20,1 299. 15 Jun. 2020, doi:10.1186/s12888-020-02654-5

[9] “Dysbiosis.” ScienceDirect, 2020, www-sciencedirect-com.proxy.library.emory.edu/topics/medicine-and-dentistry/dysbiosis. 

[10] Thursby, Elizabeth, and Nathalie Juge. “Introduction to the human gut microbiota.” The Biochemical journal, vol. 474,11 1823-1836. 16 May. 2017, doi:10.1042/BCJ20160510

[11] Strandwitz, Philip. “Neurotransmitter modulation by the gut microbiota.” Brain research, vol. 1693, Pt B (2018): 128-133. doi:10.1016/j.brainres.2018.03.015

[12] Forrester, J. et al. “CNS infection and immune privilege.” Nature Reviews Neuroscience, vol. 19, pp. 655–671, 2018. https://doi.org/10.1038/s41583-018-0070-8. 

[13] Fitzpatrick, Z., Frazer, G. et al. “Gut-educated IgA plasma cells defend the meningeal venous sinuses.” Nature, vol. 587, 2020, pp. 472–476. https://doi-org.proxy.library.emory.edu/10.1038/s41586-020-2886-4.

[14] “The Gut Trains the Immune System to Protect the Brain.” Neuroscience News, 4 Nov. 2020, https://neurosciencenews.com/gut-immune-brain-17249/.  

[15] Ma, E., Smith, A. et al., “Bidirectional Brain-Gut Interactions and Chronic Pathological Changes after Traumatic Brain Injury in Mice.” Brain, Behavior, and Immunity, vol. 66, 2017, pp. 56-69. https://doi.org/10.1016/j.bbi.2017.06.018. 

[16]“Traumatic Brain Injury Causes Intestinal Damage.” Neuroscience News, 8 Dec. 2017, https://neurosciencenews.com/tbi-intestines-8137/.