Have you ever experienced butterflies in the stomach before an important meeting? Does attempting to “cure” the blues with Ben and Jerry’s sound familiar? If so, then you are already acquainted with the existence of a connection between our moods and our gut. Indeed, the brain and the digestive system are linked by complex pathways where information flows back and forth on a continual basis: certain feelings and thoughts can stimulate an exaggerated gut response, while sensitized nerves in the gut can trigger changes in the brain.

The Nervous System and the “Second Brain”

The nervous system is a complex network of nerves and cells that carry messages to and from the brain and spinal cord to various parts of the body, through the relaying of information by chemical messengers called neurotransmitters. The human nervous system consists of two main parts: the central nervous system (CNS) and the peripheral nervous system (PNS). The brain and the spinal cord belong to the CNS, while the PNS consists mainly of nerves connecting the CNS to every other part of the body. The PNS is comprised of the somatic nervous system (SNS) and the autonomic nervous system (ANS). The enteric nervous system (ENS) is a semi-independent part of the ANS whose function is to control the gastrointestinal (GI) system. The ENS comes complete with a network of more than 100 million neurons, neurotransmitters and proteins, combined with a complex neuronal circuitry that enables it to control the bowel and produce “gut feelings” separate from the brain’s impulses. In each situation, the gut must assess conditions such as: progress of digestion, presence of nutrients and acidity level, among others and then decide on a course of action and initiate a reflex. This amazing piece of work continues to function even when the vagus nerve – the primary neural conduit between the gut and the brain – is severed!¹ Its location in the GI tract, right next to the systems that it controls, makes perfect sense from an evolutionary standpoint.The ENS was first described by Dr. John Newport Langley in 1921 and it was coined “the second brain” by Dr. Michael D. Gershon in 1996 in reference to the complexity of its functions. When Gershon, who has been called “the father of neurogastroenterology”, suggested that the gut might in fact be using some of the same neurotransmitters as the brain, his theory was widely ridiculed. Since the early 80’s however, the concept of the enteric nervous system and the role of neurotransmitters in the gut have been accepted by the scientific community. The connection between the “two brains” is accountable for the direct relationship between emotional stress and physical distress. It explains why conditions such as anxiety, depression, irritable bowel syndrome, ulcers and Parkinson’s disease manifest symptoms both at the brain and at the gut level.

Psychology or Physiology, Which One Comes First?

Psychology clearly plays an important role in gut disorders. According to Dr. Emeran Mayer, professor of medicine, physiology and psychiatry at U.C.L.A., the majority of patients with anxiety and depression present alterations of their GI function. Dr. Mayer also reports that up to 70 percent of the patients he treats for chronic gut disorders had experienced early childhood traumas. This observation is corroborated by recent studies in animal models which demonstrate that early life stress is associated with chronic GI diseases. Stress affects the gut in several ways. In response to a perceived stressor, the brain triggers a response along two major bodily paths: the hypothalamic-pituatary-adrenal axis and the autonomic nervous system. The resulting increased secretion of cortisol, adrenaline and noradrenaline directly affects the ENS. Corticotropin-releasing-factor (CRF), a peptide found in both the brain and the gut, is another substance which appears to have major significance in the stress response. CRF increases anxiety-like behavior, abdominal pain, colon secretions, muscle contractions (motility) and increased permeability within the lining of the bowel. CRF also stimulates a type of immune cell called mast cells. Another interesting experiment on rodents demonstrates what most clinicians have already observed, namely the correlation between stress and a “leaky gut”. The study showed that when young rats were separated from their mothers, the layer of cells lining their gut weakened and became more permeable, allowing bacteria from the intestine to pass through the bowel walls and stimulate immune cells. On the flip side, several factors lend credence to physiology as the source of intestinal dysfunctions. For example, when the mast cells activate an immune response resulting in mucosal inflammation, the release of inflammatory cytokines – tumor necrosis factor α (TNF-α), interleukin (IL)-1, and IL-6 – generates an acute stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. In other words, GI inflammation triggers an increased firing of the gut’s sensory neurons, culminating in a kind of sensory hyperactivity. Serotonin provides another interesting argument supporting the gut-over-brain theory. This key neurotransmitter essential to our well-being is stored at 95 percent in the ENS where it is synthesized. Among other things, serotonin acts as a go-between, keeping the brain up to date with what is happening in the gut. Contrary to earlier assumptions, it has been found that 90 percent of the fibers in the vagus nerve carry information from the gut to the brain, and not the other way around. Finally, the emerging concept that bacteria teeming in the gut – collectively known as the microbiome – can affect not only the gut but also the mind, may shed additional light on our understanding of the gut-brain axis.

Commensal Gut Microbiota

We are all born with a sterile gut, but over time it gets colonized by a diverse and distinct brew of bacterial species determined by genetics and by bacteria surrounding us. The incredible 100 trillion microbes – more than ten times the amount of cells in our entire body! – that make the GI tract their playground, are absolutely critical to our health. Over the last few years, increasing evidence from studies in rodents are pointing to an effect of commensal gut microbiota on the CNS. Researchers have found that the gut microbiome can influence neural development, brain chemistry, and a wide range of behavioral phenomena including emotional behavior, pain perception and the stress response. In a 2011 study, Bienenstock and colleagues fed a broth enhanced with the probiotic Lactobacillus rhamnosusto a group of mice, and plain broth to the control group. After 28 days, the researchers subjected the mice to a battery of tests to detect signs of anxiety and depression. What they discovered is that mice who had been fed the probiotic solution demonstrated less fear-response behaviors and anxiety compared to the control group. In the mice that were fed L. rhamnosus, some brain regions showed an increase in the number of receptors for gamma-aminobutyric acid (GABA), the main CNS inhibitory neurotransmitter. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. Probiotic-fed mice also produced lower levels of the stress hormone corticosterone than control mice. Interestingly, when the vagus nerve was severed, the effects of gut bacteria on brain biochemistry, stress response and behavior evaporated. The researchers concluded that “these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.” In another study, Bercik and colleagues investigated the role of Bifidobacterium longum in tempering anxiety and depression related to GI disorders.16 They first infected mice with the parasite Trichuris muris, which caused moderate gut inflammation and anxiety-like behavior linked to decreased hippocampal brain-derived neurotrophic factor (BDNF). Lower hippocampal BDNF has been associated with anxiety and depressive behavior. The administration of the probiotic (B. longum) normalized both behavior and BDNF level. This result demonstrates that a member of the intestinal microbiota may affect the brain biochemistry and behavior in adult mice. Some studies also suggest that gut bacteria are closely tied to early brain development and subsequent behavior.

Happy Gut, Happy Mind

Given the intimate feedback loop between the gut and the brain, we must consider addressing GI dysfunctions when treating mood imbalances and behavioral or developmental issues. The use of high quality probiotics including Lactobacillus rhamnosus and Bifidobacterium longum along with digestive support such as DPP-IV enzyme and L-glutamine are proven strategies. Restoring mood balance is also crucial in achieving GI health. Adaptogenic herbs including as Siberian ginseng, ashwagandha, Rhodiola or holy basil combined with adrenal tissue extracts can support a healthy stress response, while substances such as GABA, L-theanine, inositol, SAMe and B complex vitamins can help achieve a balanced mood.

References

1. Gershon MD. The Second Brain: The Scientific Basis of Gut Instinct and a Groundbreaking New Understanding of Nervous Disorders of the Stomach and Intestines. HarperCollins Publishers, Inc., New York, NY; 1998.

2. Rubin RP. A Brief History of Great Discoveries in Pharmacology: In Celebration of the Centennial Anniversary of the Founding of the American Society of Pharmacology and Experimental Therapeutics. Pharmacological Reviews. 2007; 59: 289-359.

3. American Association of Anatomists. Available at: http://www.anatomy.org/content/michael-gershon Accessibility verified February 20th, 2012.

4. Mayer EA, Naliboff BD, Santo V, et al. Stress and the Gastrointestinal Tract. V. Stress and irritable bowel syndrome. AJP – GI. 2000; 280: G519-G524.

5. Bradford K, Elizabeth J, Presson AP, et al. Association between early adverse life events and irritable bowel syndrome. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association. 2012; 10(4): 385-390.

6. Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000;47:861-869

7. Martinez V, Taché Y. Corticotropin-releasing factor and the brain-gut motor response to stress. Can J Gastroenterol. 1999;13 Suppl A:18A-25A.

8. Mayer EA., Saper CB, Ladd CO, et al. Long-term behavioral and neuroendocrine adaptations to adverse early experience. in The biological basis for mind body interactions. 2000; 122: 79–101.

9. Malaviya R, Abraham SN. Mast cell modulation of immune responses to bacteria. Immunol. Rev. 2001; 179: 16– 24.

10. Theoharis C, Theoharidesa BC, David E. Critical role of mast cells in inflammatory diseases and the effect of acute stress. Journal of Neuroimmunology. 2004; 146:1– 12

11. Perlstein RS, Whitnall MH, Abrams JS, et al. Synergistic roles of interleukin-6, interleukin-1, and tumor necrosis factor in adrenocorticotropin response to bacterial lipopolysaccharide in vivo. Endocrinology. 1993; 132:946–952.

12. Dreyfus CF, Bornstein M B, Gershon MD. Synthesis of serotonin by neurons of the myenteric plexus in situ and in organotypic tissue culture. Brain Research. 1977;128:125–139

13. Gershon MD. The Second Brain: The Scientific Basis of Gut Instinct and a Groundbreaking New Understanding of Nervous Disorders of the Stomach and Intestines. 1998

14. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011; 108:16050-160505.

15. Harter MC, Conway KP, Merikangas KR. Associations between anxiety disorders and physical illness. Eur Arch Psychiatry Clin Neurosci. 2003;253:313–320.

16. Bercik, P., Verdu, E.F., Foster’ J.A., Macri, J., Potter’ M., Huang, X., Malinowski, P., Jackson, W., et al. Chronic Gastrointestinal Inflammation Induces Anxiety-Like Behavior and Alters Central Nervous System Biochemistry in Mice. Gastroenterology. 2010 Dec;139(6):2102-2112

17. Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety. Nat Neurosci 2007;10:1089–1093.

18. Hejtz R.D, Wang S, Anuar F, et al. The normal gut microbiota modulates brain development and behavior. Proceedings of the National Academy of Sciences of the USA. 2011; 108: 3047-3052.

19. Valicenti-McDermott M., McVicar K, Rapin I, et al. Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. J Dev Behav Pediatr. 2006; 27:S128-36.

20. Adams JB, Johansen LJ, Powell LD, et al. Gastrointestinal flora and gastrointestinal status in children with autism — comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 2011; 11: 22.

21. Reichelt, KL, Tveiten D, Knivsberg A. et al. Peptides’ role in autism with emphasis on exorphins. Microbial Ecology in Health & Disease. 2012:23

22. Whiteley P, Shattock P, Knivsberg AM, et al. Gluten and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2012; 6:344.