Hector Warnes: The gut-brain axis

An impressive body of evidence has shown how commensal and or pathogenic microorganisms that inhabit our body, and in particularly the gut, do have an impact on our health: complex interaction signaling mind, brain, gut and its microbiome. Dysbiosis refers to an imbalance of microorganisms in the intestinal tract. In a recent recent review by Kilcolt-Glaser JK, Derry HM and Fagundes CP (2015), the authors include in the pathogenesis of depression an inflammatory response activated by childhood adversity, stressors and diet which can influence the gut microbiome and promote intestinal permeability. Another excellent review was published by Leonard B. Weinstock (2013) covering a wider area of medical illnesses. A more molecular study appeared in 2016 published by Saxena  and Sharma.

The treatment of patients with hepatic encephalopathy, irritable bowel syndrome, recurrent pyelonephritis, irritable colon, autism spectrum disorder, fibromyalgias, chronic pain, candidiasis, chronic inflammation, autoimmune disorder, celiac disease, attention deficit hyperactivity disorder and depressive anxious disorder with multiple somatization and resistance to most usual therapies have led to a probable "shift of paradigm" in the bilateral relationship between the brain and the gut. It has even been suggested that intestinal bacterial overgrowth is linked to vascular disease via vitamin K2 dependent mechanisms.

Since Elie Metchnikoff (winner of the 1908 Nobel Prize for his work on phagocytosis), the probiotic effects of lactobacillus bulgaricus have been demonstrated. Metchnikoff put forward the hypothesis that aging is caused by putrefactive activity in the gut.

 In 1932, Baruch was able to produce an experimental catatonia in animals using a neurotropic toxin of the intestinal colibacillus apart of the already discovered similar effect of  bulbocapnine (a simil-apomorphine).

In hepatic encephalopathy due to liver cirrhosis and portal hypertension, a few neurologists who were not able to improve agitation, tremors, ataxia, neurocognitive dysfunction, confusion, agrypnia, fluctuation of the level of consciousness and marked emotional lability of these patients, decided to refer them to psychiatrists. In collaboration with a hepatologist, we were able to bring patients to remission by modifying the putrefactive bacteria in the gut which were releasing neurotoxic substances and treat them with probiotics, low doses of anti-psychotic agents, rifaximin (an antibiotic), lactulose and occasionally low doses of mirtazepine when the depression became manifest. Obviously, the neurotoxic substances bypassing the portal circulation and the liver that were released by the gut's bacteria into the general circulation and which entered the CNS attributed to increased permeability of the blood-brain barrier and increased cerebral blood flow. These gut bacterias, such as clostridium difficile, colibacillus, helicobacter pylori, salmonella and others, could release phenols, ammonia and indoles by digestion of proteins and were also capable of releasing neuroactive substances, such as gamma-aminobutyric acid, catecholamine, acetylcholine and serotonin, which acted on the brain-gut axis.

Mayer et al. (2006), with great clarity, wrote about the mechanism involved: "Reflex response within the brain gut-axis mediated by vagal afferents, and efferents of the autonomic nervous system, play a crucial role in the maintenance of homeostasis during physiological perturbations caused by food intake, contractile activity and metabolic products of the enteric flora." It appears that the insular cortex plays an important role in the perceptions of all sensations arising from the body.

Wang and Kasper (2014) included in this system not only the central nervous, neuroendocrine and neuroimmune systems, but also the hypothalamic, pituitary adrenal axis (HPA axis), sympathetic and parasympathetic branches of the autonomic nervous system, the enteric nervous system, the vagus nerve and the gut microbiota.

Dinan et al. (2013), who pioneered research in this area on the impact of microbiota on brain and behaviour, suggest that bioactive compounds are synthesized from tryptophan by bacteria in the gut. Further, that indole is produced from tryptophan by bacteria into 3 indolpropionic acid (IPS), a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals lactobacillus species which metabolize tryptophan into indole 3 aldehyde (I3A). Indole itself acts as a glucagon-like peptide (GLP-1). Holzer, Reichmann and Farzi (2012) have shown that “neuropeptide YY is influenced by the intestinal microbiota and neuropeptide Y is an immunomodulator that displays proinflamatory action, regulating food intake, energy homeostasis,  anxiety, mood and stress resilience.”

So far, for the microbiota or intestinal flora's potentially pathogenic effect, the question arises about how this system interacts with the hormonal and neuropeptide system released by the gastrointestinal mucosa and muscle layers. These gut hormones and peptides are released into plasma after a physiological stimulus and are also capable of acting on distant tissue. These peptides, with a neurocrine, neuromodulatory and neurotransmitter role, have been investigated and have been considered to be of pathogenic importance. They are more familiar to us and could be listed as substance P, bombesin, cholecystokinin, neurotensin, somatostatin, vasoactive intestinal polypeptide, endorphins, gastrin, enteroglucagon, neurokinins, cytokines, ghrelin and so on.

Enterocromaffin cells are neuroendocrine cells found in the gastric mucosa beneath the epithelium that stimulate the production of gastric acid via the release of histamine and the pituitary adenyl cyclase activating peptide. Hyperplasia or tumors of these cells lead to the Zollinger-Ellison syndrome, which often becomes chronic and incapacitating.
Endocrine cells lining the stomach and proximal small intestine serve as a source of ghrelin that circulates in the blood playing a role in gastrointestinal motility, cardiovascular immunologic and regulatory activity of the energy balance. Nogueiras et al. (2008) have shown how ghrelin, leptin and proopiomelanocortin act on the hypothalamic arcuate nucleus in various functions (orexigenic, anorexigenic and regulatory Growth Hormone secreting activity).

A number of the neuroendocrine-peptides were first discovered in the brain and all act as neurotransmitters in gastrointestinal tissue and other peripheral tissues. The Carcinoid syndrome is associated with flushing, anxiety, distress, diarrhea, wheezing, weight loss, pellagra, dermatitis and more severe complications due to a hyper secretion of serotonin which appears to play a role in its pathogenesis, along with other molecules like bradykinin, kallikrein, noradrenaline, histamine, vasoactive peptides and prostaglandins.

The Serotonin syndrome described by H. Sternbach is not a rare complication of serotonin re-uptake inhibitor anti-depressants (often in combination with other compounds). The Zollinger-Ellison, Carcinoid and Serotonin syndromes share a few common symptoms and signs, such as confusion, agitation, hyperthermia, twitching of the muscles, heavy sweating, diarrhea, headaches, etc. The Serotonin syndrome, which in rare occasions could be fatal, ought to be distinguished from the neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic toxicity and heat stroke. The association of substance P with pain syndromes and of cholecystokinin with panic disorders have been well researched.

As far as I am aware, the gut brain-axis has not been experimentally or clinically distinguished as to whether we are dealing with an overgrowth of microbiota or to the enteroendocrine-peptide cells of the intestinal mucosa and smooth muscles. As discussed above, the latter are also capable of releasing multiple peptides and neurohormones in a feedback loop. It is beyond the scope of my expertise to discuss these three systems (gut's flora, intestinal mucosa and brain-mind) in relation with the neuropsychopharmacological response to treatment of each particular patient.

References:

Baruch H. Pathogénie du Syndrome catatonique et la catatonie experimental. Paris: G. Doin;, 1932

Baruch H. La psychiatrie et la science de l'homme. Paris: Éditions du Levain; 1961.

Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropics. Biological Psychiatry 2013; 74: 720-6.

Holzer, P. Reichmann F. and Farzi A. Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 2012;.45: 261-74.

Kilcolt-Glaser JK, Derry HM, Fagundes CP. Inflammation: Depression fans the flames and feasts on the heat. Am. J. Psychiatry 2015; 172: 1075-91.

Mayer EA, Knight R. Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain. Paradigm shift in neuroscience. Journal of Neuroscience 2014; 34 15490-6.

Mayer EA, Naliboff BD, Craig AD. Neuroimaging of the brain-gut axis from basic understanding to treatment of functional GI Disorders. Gastroenterology 2006; 131:1925-42.

Nogueiras, R. Tschöp MH, Zigman J.   CNS regulation of energy metabolism: ghrelin versus leptin. Ann N Y Acad Sci. 2008 Apr; 1126:14-9.

Podolsky SH. Metchnikoff and the microbiome. Lancet 2012; 380: 1810-6.
Quigley EM. Gut bacteria in health and disease. Gastroenterol Hepat. (NY) 2013; 9: 560-9.

Saxena, R., and V. K. Sharma. "A Metagenomic Insight Into the Human Microbiome: Its Implications in Health and Disease." (2016). Elsevier; 2016, PP.107-17.

Soga J. Yakuwa, Y. Osaka M. Carcinoid syndrome: a statistical evaluation of 748 reported cases. Journal of Experimental and Clinical cancer research. 1999; 18: 133-41.

Sternbach, H. The Serotonin Syndrome.. Am J Psychiatry 1991; 148: 705-13.

Wall R, Cryan VF, Ross RP, Fitzgerald GF, Dinan TG, Stanton C. Bacterial neuroactive compounds produced by psychobiotics.  Adv Exper Med Biol 2014; 817: 221-39.

Wang Y, Kasper LH. The role of microbrome in central nervous disorders. Brain Behav Immun 2014; 38: 1-12.

Weinstock L B. Small intestinal bacterial overgrowth disorders (SIBO). Gastroenterology.  2013; 14: 2-12).