Adam Penrose

Deep connections and therapeutic challenges of the Enteric Nervous System

The gut-brain axis is a biochemical signaling system which serves as a line of communication between the Gastrointestinal Tract (GI Tract) and the Central Nervous System (CNS). The gut can release hormones into the blood stream which indirectly cause the CNS to communicate to the conscious brain: communications which are interpreted as hunger, satiety, well-being, over-fullness, and even specific cravings. This system of crosstalk is called the Enteric Nervous System (the ENS) which is referred to in jargon as the ‘” second brain’ based on its size, complexity, and similarity-in neurotransmitters and signaling molecules- with the brain,” (Mayer, 2011).

Figure 1: The complex and interconnected nature of the Central Nervous System, Peripheral Nervous System, and Enteric Nervous System (Image Source Mayer, 2011). Internal, External and cerebral responses interact in mesencephalic (facial), medullary (adrenal), spinal, mesenteric (GI tract), and Enteric (gut) axes.

A general limbic system response to emotional stress involves the hypothalamus releasing corticotropic releasing factor into the hypophyseal portal system, stimulating the pituitary gland to secrete adrenocorticotropic hormone. Adrenocorticotropic hormone, or ACTH, is a corticoid hormone which is carried in the blood on lipid proteins to prevent its aggregation due to plasma’s polar character. The ACTH travels in the blood to the adrenal medulla, which releases cortisol and affects the intestine through CRH receptors. In response, the intestine can use efferent autonomic pathways with multiple targets back to several targets including muscle layers, the central nervous system, the hypothalamus, and salivary glands (Carabotti et al., 2015).  Some patients with irritable bowel syndrome responded with an improvement of symptoms after CRH receptor antagonists were administered, decreasing the power ACTH has on their intestinal movements. (Fukudo, 2007.)

Beyond just circulatory signal molecules, there is a proposed monosynaptic connection between the Nucleus Tractus Solitarius (a sensory nucleus in the hindbrain) and the dorsal nucleus of the vagus. To test this connection, researchers injected GABA-receptor antagonists and observed physiological changes in animals. As can be expected, they saw a decrease in Intragastric pressure (IGP) and mean arterial blood pressure. This indicates some connection between gastric activity and CNS activity- a connection that can be intuited from common sense and knowledge of physiology, but nuances in this line of communication can cause several complex and interrelated issues when pathological (Herman et al. 2008).

This general phenomenon of interconnectedness is well documented in several fields of academic endeavor including gastroenterology, psychiatry, psychology, nutrition, and social research. The deeply integrated nature of the gut and the brain lead some to ask: could the gut offer unique opportunities to treat psychiatric disorders? Could psychiatric disorders lead to gastroenterological disease?

Postnatal inoculation of infants’ internal environment through maternal care has been shown to be essential to their physiological stress responses, as studied in mice (Sudo et al., 2004). Several earlier studies have asserted that this early postnatal inoculation is essential to Central and Enteric Nervous System development in general, particularly their responses to stress and gut-brain cross talk (Barbara et al., 2005). There turns out to be some evidence for gastrointestinal probiotic treatment of psychiatric disorders due to this connection between gut hormones and stress response.

Treatment options include microbes for anxiety, depression, cognitive function, Autism spectrum and obsessive-compulsive disorders, and stress response. The researchers believe that a lot of the neuroactive functions of these bacteria are because of their production of GABAergic hormones and chemicals, which have a strong effect on anxiety and stress. They concluded that inoculations of “B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei were most effective in improving CNS function, including psychiatric disease associated functions (anxiety, depression, mood, stress response) and memory abilities. Doses between 109 and 1010 CFU and durations of 2 weeks in animals and 4 weeks in humans have shown sufficient effects.”

Microbes are fairly inexpensive to cultivate and grow, inoculations of known and tested microbes are relatively safe, and the treatment is noninvasive. These could be the future of psychiatric treatment, and gut flora profiles could soon be a diagnostic tactic in determining root causes of psychiatric disabilities.

The microflora occupy specific roles in the gut ecosystem- Mackie et al. determined that specific species exist in specific portions of the GI tract, and evolved to do so for important reasons. The large intestine is the “primary site of microbial colonization because of slow turnover, and is characterized by large numbers of bacteria (10¹⁰-10¹¹/g or mL content).” Moving up the tract, the small intestine has a characteristically diverse bacteria scene, which resides in recesses and brush borders of the absorptive surface. The small intestine has very specific absorptive needs, and this diversity reflects the reliance on bacteria to assist in this metabolism and macromolecule breakdown. The stomach and proximal small intestine contain low diversity and populations of microbes due to their acidic pH and digestive enzyme concentration.

Neonatal infants are inoculated with the beginnings of their gut microflora initially during vaginal birth- there is a marked decrease of GI health in infants born via C-section. After birth, inoculation continues through breast-feeding and continued parental physical contact. Finally, the general environment coaxes into action the infant’s immune system and completes the gut inoculation. (Mackie et al., 1999)

The gut microbiome’s effects on the host’s health are not a one-way street. A recent study found that host genetics, which lead to specific pathways and products, have a strong effect on gut microflora diversity. A study found associations between genes and microflora by doing genome-wide analyses, and found several notable correlations. Activation of C-type lectin pathways produced at 2p13.3 and 12p13 and other pathways which can be heritably up or down regulated have a strong correlation with gut flora diversity- hosts can control their microbe levels to quite a high degree (Bonder et al., 2016).

Some ways of testing for diversity of gut microbiota include fecal immunochemical tests (FIT tests). These tests are typically used for screening colon cancer, but can be used to assay the diversity of an internal ecosystem. After a bowel movement, patients brush the surface of their stool and then dip the brush into toilet water. This clears away most non-organic matter from the brush, which is then used as a transfer tool to inoculate a test card. The test card is sealed and sent to a lab for assay, which can take place either by epigenetic analysis of SSU RNA or through old fashioned wet- biology; streaking cultures for isolation before staining and differentially plating them.

CITATIONS:

Barbara, G., Stanghellini, V., Brandi, G., Cremone, C., Di Nardo, G., De Giorgio, R., and R. Corinaldesi. 2005. Interactions between commensal bacteria and gut sensorimotor function in health and disease- microflora and motility. American Journal of Gastroenterology 100: 2560-2568.

Bonder, M.J., Kurilshikov, A., Tigchelaar, E.F>, Mujagic, Z., IMhann, F., Vila, A.V., Deelen, P., Vatanen, T., Schirmer, M., Smeekens, S.P., Zhernakova, D.V., Jankipersadsing, S.A., Jaeger, M., Oosting, M., Cenit, M.C., Masclee, A.A., Swertz, M.A., Li, Y., Kumar, V., Joosten, L., Hamsen, H., Weersma, R.K., Franke, L., Hofker, M.H., Xavier, R.J., Jonkers, D., Netea, M.G., Wijmenga, C., Fu, J., Zhernakova, A. 2016. The effect of host genetics on gut microbiome. Natural Genetics 48: 1407-1412.

Carabotti, M., Scirocco, A., Maselli, M.A., and C. Severi. 2015. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of Gastroenterology 28: 203-209.

Fukudo, S. 2007. Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation. Journal of Gastroenterology 42: 48-51.

Herman, M.A., Cruz, M.T., Sahibzada, N., Verbalis, J., and R.A. Gillis. 2008. GABA signaling in the nucleus tractus solitaries sets the level of activity in dorsal motor nucleus of the vagus cholinergic neurons in the vagovagal circuit. American Journal of Physiology 296: 101-111.

Mackie, R.I., Sghir, A., and H.R. Gaskins. 1999. Developmental microbial ecology of the neonatal gastrointestinal tract. American Journal of Clinical Nutrition 69: 1035-1045.

Mayer, E.A. 2011. Gut feelings: the emerging biology of gut-brain communication. Nature Reviews Neuroscience 12: 453-467.

Sudo, N., Chida, Y., Aiba, Y., Sonoda, Junko., Oyama, N., Yu, X., Kubo, C., and Y., Koga. 2004. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. Journal of Physiology 558: 263-275.