The Gut-Brain Connection: An Inside Look at Depression

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During a recent Metametrix sponsored breakfast at the IFM Symposium in Hollywood, Florida, Dr. Todd LePine gave a compelling presentation entitled The Gut-Brain Connection: An Inside Look at …

During a recent Metametrix sponsored breakfast at the IFM Symposium in Hollywood, Florida, Dr. Todd LePine gave a compelling presentation entitled The Gut-Brain Connection: An Inside Look at Depression.

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  • A presentation that confirms what Ayurveda and Chinese medicine have been saying about physical and mental health all along - physical digestion is the key to physical, emotional and mental health.

    The human system is a complex adaptive system embedded in its environment and all aspects of the environment effect it.

    The body is built on fractal patterns - the digestive system is a mirror image of the brain - each digesting different things and creating a self/non self interface - specifically the small intestine.

    Most diseases have an inflammatory basis and this more than often starts in the GI tract, the primary seat of the immune system and sense of self identity, due to dietary, emotional or mental disturbances.

    It seems that Western Medicine still hasn’t an understanding of the fractal system dynamics that underpin the universal evolutionary process but are well on their way to rediscovering it - albeit from a reductive scientific paradigm rather than from a complex adaptive / energetic/ consciousness paradigm like Ayurveda.

    I disagree with the hypothesis that diet and lifestyle are a greater predictive factor than genetics or what we refer to in Ayurveda as Prakruti - the metabolic constitutional profile of the person. I hypothesise that the reason for this assumption is that the focus has been on the sickness end of the health spectrum rather than the health end - in Ayurveda this is called Vikruti. I predict that with more experience with the health end of the spectrum it will become clearer that it is possible to predict the effects that specific foods and other environmental factors will have on genetic profiles.

    My experience is that the types of tests mentioned in this presentation are very useful to obtain patient compliance - people are far more likely to respond to 'physical evidence' in the form of a report than the implied synthesis that comes from the multifactorial diagnosis of Ayurveda. The downside is that it leads to reductive thinking rather than a systemic understanding, Having said this functional medicine is moving in the right direction and will eventually rediscover the systems side.
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  • Psycho-Neuro-Immuno-Endo-Gutologist
  • 5-HT is a major signalling molecule in the central nervous system and has been implicated in a number of diverse physiologic functions, including mood, appetite, sleep, mem- ory and learning, homeostasis, and sexual behaviors. Altered levels of 5-HT are thought to play a role in many CNS disorders including anxiety, depression, obsessive compulsive disorder, phobias, and even severe psychiatric disorders such as schizophrenia. 5-HT modulators, such as SSRIs and more specific 5-HT receptor agonists and antagonists have been successfully used to treat many of these disorders including migraine, nausea, obesity, chronic pain, hypertension, vascular disorders, and sexual dysfunction.
  • Quorum Sensing in Bacteria Bacteria Talk to Each OtherBacteria are Multi-CellularBacteria can distinguish self from othersUnderstand the role Quorum Sensing may play in “Dysbiosis”
  • The membrane is the physical structure that interfaces internal “self” and external “not-self.” It is an interface that dynamically reads and interprets environmental cues and responds by generating signals that enable the cell to function and survive. Bruce Lipton
  • The membrane is the physical structure that interfaces internal “self” and external “not-self.” It is an interface that dynamically reads and interprets environmental cues and responds by generating signals that enable the cell to function and survive. Bruce Lipton
  • Inflammatory and oxidative and nitrosative stress pathwaysunderpinning chronic fatigue, somatization andpsychosomatic symptomsMichael Maes Current Opinion in Psychiatry 2008, 21:1–9
  • . Altered levels of 5-HT are thought to play a role in many CNS disorders including anxiety, depression, obsessive compulsive disorder, phobias, and even severe psychiatric disorders such as schizophrenia. 5-HT modulators, such as SSRIs and more specific 5-HT receptor agonists and antagonists have been successfully used to treat many of these disorders including migraine, nausea, obesity, chronic pain, hypertension, vascular disorders, and sexual dysfunction.
  • . Altered levels of 5-HT are thought to play a role in many CNS disorders including anxiety, depression, obsessive compulsive disorder, phobias, and even severe psychiatric disorders such as schizophrenia. 5-HT modulators, such as SSRIs and more specific 5-HT receptor agonists and antagonists have been successfully used to treat many of these disorders including migraine, nausea, obesity, chronic pain, hypertension, vascular disorders, and sexual dysfunction.

Transcript

  • 1. Todd R. LePine, MD May, 2009
  • 2. “What a strange machine man is! You fill him with bread, wine, fish, and radishes, and out comes sighs, laughter, and dreams.” Nikos Kazantzakis Psycho-Neuro-Immuno-Endo-Gut-Ologist
  • 3. The Gut The Inner Tube of Life
  • 4. ―Consider the lowly gut and its nervous system. The bowel just is not the kind of organ that makes the pulse race. No poet would ever write an ode to the intestine. To be frank, the popular consensus is the colon is a repulsive piece of anatomy. Its shape is nauseating, its contents disgusting and it smells bad. The bowel is a primitive, slimy, snakelike thing. Its body lies coiled within the belly and it slithers when it moves. In brief, the gut is despicable and reptilian, not unlike the brain, from which wise thoughts emerge. Clearly, the gut is an organ only a scientist would love.‖
  • 5. The enteric nervous system functions as a Brain in the Gut The Enteric Nervous System NEJM April 25, 1996
  • 6. ―The intestine is an extremely complex living system that participates in the protection of the host through a strong defense against aggressions from the external environment. This defensive task is based on 3 constituents that are in permanent contact and dialog with each other: the microflora, mucosal barrier, and local immune system.‖
  • 7. Think Differently Photo by Migraine Chick
  • 8. How do we see illness? How do we see ourselves? Photos by zedzap and SuperFantastic
  • 9. The Intestines and the Gut Microflora Microflora- Varies from person to person • > 100,000 billion bacteria (~2 lbs) • > 500 different species • 99 % of the bacteria come from 30-40 species • Intense metabolic activity, especially in the colon • Equilibrium (qualitative and quantitative) is Critically Important • ―Quorum sensing‖ i.e. communication between the bacteria
  • 10. The Rainforest within…
  • 11. So…Who‘s really in charge? http://www.microbeworld.org/
  • 12. ―The ―we‖ refers to the wild profusion of bacteria, fungi and viruses that colonize the human body. These unseen passengers number in the trillions. According to one common estimate, the human gut contains at least a kilogram of bacteria alone. They contribute so much to human biology that it is difficult to say where the body ends and the microbes begin.‖
  • 13. Nature 449, 811-818 (18 October 2007) | doi:10.1038/nature06245; Published online 17 October 2007
  • 14. ―Most of the cells in your body are not your own, nor are they even human…They are bacterial. From the invisible strands of fungi waiting to sprout between our toes, to the kilogram of bacterial matter in our guts, we are best viewed as walking "super-organisms” highly complex conglomerations of human cells, bacteria, fungi and viruses.‖
  • 15. Who Are You?
  • 16. Photo: http://commons.wikimedia.org/wiki/File:Bobtail_squid.jpg
  • 17. ―Through Bassler's discoveries, we're learning that those on the lowest rungs of the Darwinian ladder share one of the traits that has, until recently, been thought of as distinctly human: the propensity to create a continuous stream of commentary about the world. As Bassler puts it, for microbial communities, the advent of the cell-to-cell network made "the difference between subsistence farming and living in Manhattan.”
  • 18. Quorum sensing—a bacterial discussion about light. The bacterium V. fischeri emits a chemical signal, known as an acyl HSL, to announce its presence to others. In the open sea this signal rapidly dissipates (A). Within the confines of the squid light organ, however, the concentration of acyl HSL increases as the number of bacteria increases (B). When the concentration reaches a threshold level, the signal triggers the expression of genes encoding the proteins responsible for the light-generating chemical reaction (C).
  • 19. Quorum Sensing in Bacteria • Bacteria Talk to Each Other • Bacteria are Multi-Cellular • Bacteria can distinguish self from others • The role of Quorum Sensing in ―Dysbiosis?‖
  • 20. ―Given that eukaryotic cell-to-cell signaling typically occurs through hormones, and that bacterial cell-to-cell signaling occurs through QS, we speculate that QS might be a ‗‗language‘‘ by which bacteria and host cells communicate.‖
  • 21. ―More than just an accumulation of bacteria, biofilms are complex structures in which the bacteria are likely to use a substantially different set of genes than in their free-floating form‖ T.J. Silhavy from ScienceDaily
  • 22. ―The membrane is the physical structure that interfaces internal ―self‖ and external ―not-self.‖ It is an interface that dynamically reads and interprets environmental cues and responds by generating signals that enable the cell to function and survive.‖ Bruce Lipton, PhD
  • 23. Increased epithelial permeability may be important in the development of chronic gut T cell–mediated inflammation…. Pro-inflammatory cytokines then further increase epithelial permeability, setting up a vicious cycle of chronic inflammation SCIENCE 2005
  • 24. Am J Physiol Gastrointest Liver Physiol 280: G7–G13, 2001.
  • 25. Therefore, vitamin D deficiency may compromise the mucosal barrier, leading to increased susceptibility to mucosal damage and increased risk of Inflammatory Bowel Disease
  • 26. ―these findings provide evidence that astroglial-like cells in both brain and gut contribute interchangeably to barrier functions, suggesting a previously unrecognized paradigm whereby cellular interactions previously thought to be unique to the blood–brain barrier, also regulate gut epithelial permeability.‖
  • 27. The cytokine network. Image of the global network of cytokine interactions between the 14 immune cells (red nodes) and the 15 non-immune body cells (blue nodes). The black edges represent mutual connections; the grey edges represent one-way connections. Frankenstein et al. Biology Direct 2006 1:32 doi:10.1186/1745-6150-1-32
  • 28. During an immune response the brain and the immune system ―talk to each other‖ and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic pituitary- adrenal (HPA) axis and the sympathetic nervous system (SNS). Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES., Pharmacol Rev. 2000 Dec;52(4):595-638.
  • 29. The results show that intestinal mucosal dysfunction characterized by an increased translocation of gram-negative bacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. It is suggested that the increased LPS translocation may mount an immune response and thus IRS activation in some patients with MDD and may induce specific ―sickness behaviour‖ symptoms.
  • 30. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms Michael Maes Current Opinion in Psychiatry 2008, 21:1–9
  • 31. ―Induction of indoleamine 2,3-dioxygenase, which converts tryptophan into kynurenine, may play a role in the pathophysiology of depression through its induction of neurotoxic kynurenine metabolites. Therefore, we proposed a shift in the serotonergic hypothesis of depression from tryptophan depletion to neurotoxicity‖ (Maes et al. 1994-2006)
  • 32. Lord RS, Bralley JA, eds. Laboratory Evaluations for Integrative and Functional Medicine. Duluth, GA: Metametrix Institute; 2008.
  • 33. Lord RS, Bralley JA, eds. Laboratory Evaluations for Integrative and Functional Medicine. Duluth, GA: Metametrix Institute; 2008.
  • 34. 59 yo female with Scleroderma, silicon breast implants, recurrent herpes to sacral area, depression and insomnia secondary to pain
  • 35. Nicholson focuses on these chemicals both because little is known about them and because they appear to be highly relevant: recent research suggests that gut microbes play a crucial role in human health and disease. They help us absorb nutrients and fight off viruses and ―bad‖ bacteria; disrupting intestinal colonies, such as with a course of antibiotics, often leads to digestive sickness. In fact, Nicholson says, “almost every sort of disease has a gut bug connection somewhere.”
  • 36. THE PROLIFERATION OF HUMAN MICROBIOME PROJECTS MetaHIT (EU & China) Canadian $31 million Human MetaGenome Microbiome Initiative Consortium (Japan) $10 million MicroObes (France) $5 million $3 million Meta-GUT China) Human Microbiome Project (USA) $1.5 million $115 million Human Gastric Microbiome (Singapore) Austrailian Urogenital Microbiome Consortium $750,000 All figures are estimates of cost in US dollars $600,000 Photo by Kathryn
  • 37. THE PROLIFERATION OF HUMAN MICROBIOME PROJECTS The NIH‘s five-year Human Microbiome Project will spend much of its money identifying which bacteria are lodged where in the body and compiling a reference set of MetaHIT (EU & China) their genetic sequences. Metagenomics of Canadian $31 million Human MetaGenome the Human Intestinal Microbiome Initiative Tract (MetaHIT), will Consortium (Japan) focus on microbial inhabitants (France) gut, the $10 million MicroObes of the $5 million $3 million main repository of the microbiota, and how they contribute to obesity and inflammatory Meta-GUT China) bowel disease. Human Microbiome $1.5 million Project (USA) NATURE|Vol 453|29 May 2008 $115 million Human Gastric Microbiome (Singapore) Austrailian Urogenital Microbiome Consortium $750,000 All figures are estimates of cost in US dollars $600,000 Photo by Kathryn
  • 38. ―The bacterial flora of the gut may also have an important role; encephalopathy develops in patients with cirrhosis after meals rich in protein when the gut flora produces amino compounds, which are absorbed from the gut and, bypassing the liver, act as false transmitters in the brain. Specific food residues are broken down by the colonic microflora with the production of chemicals, which, in susceptible individuals with low concentrations of relevant hepatic enzymes, pass into the systemic circulation to produce distant symptoms.‖ Hunter, JO Lancet. 338:495-496 (1991)
  • 39. The human gut might best be described as a “continuous-flow microbial growth chamber”
  • 40. Dietary Precursors for Bacterial Products in Urine Lord RS, Bralley JA, eds. Laboratory Evaluations for Integrative and Functional Medicine. Duluth, GA: Metametrix Institute; 2008.
  • 41. Lord RS, Bralley JA, eds. Laboratory Evaluations for Integrative and Functional Medicine. Duluth, GA: Metametrix Institute; 2008.
  • 42. ―And you can geographically map people according to their metabolic patterns,‖ The patterns do not seem to follow genetics, Nicholson said. ―It has to do with their diet and lifestyle and also gut microorganisms,‖ Nicholson said.
  • 43. ―In terms of relaxing blood vessels, it looks like hydrogen sulfide might be as important as nitric oxide,‖ Snyder says, referring to the first gasotransmitter that two decades ago was discovered to regulate blood pressure.
  • 44. Functional GI Tests • Traditional Digestive Stool Analysis • Intestinal permeability testing • Hydrogen breath test for bacterial overgrowth • Food Antibody Testing • Urinary Organic acids for dysbiosis • GI Effects test using PCR technology
  • 45. Characteristics of IgE and IgG- Mediated Reactions to Food Lord RS, Bralley JA, eds. Laboratory Evaluations for Integrative and Functional Medicine. Duluth, GA: Metametrix Institute; 2008.
  • 46. Elevated IgG1 & 4 Food Antibodies Functional Measure of Leaky Gut Milk Protein Antigen — IgG1 & 4 Complex Insoluble Large Complex
  • 47. If you don’t look inside… How do you know what is really going on?
  • 48. There‘s Gold hidden in there!!
  • 49. What Patient Populations Benefit from GIfx Stool Analysis? • Inflammatory bowel issues • Skin conditions • Fatigue of unknown origin • Depression • Autoimmune Disorders • Change in bowel habits • Refractory Obesity
  • 50. To the researchers' surprise, after 2 months, the newly infected mice were 42% fatter, even though they had eaten 29% less than the bacteria- free mice. And fast metabolism wasn't the answer, as the metabolism of the bacteria-free mice was 27% slower than that of their microbe-carrying counterparts.
  • 51. Metametrix Tests to look inside for contributing factors in depression • IgG 4 Food Allergy • RBC Essential Fatty Acids Profile • Comprehensive • Amino Acid Profile Organix Profile: • TRIAD Profile • Neurotransmitter • GI Effects Test metabolites, Methylation markers, functional B-vitamin markers, dysbiosis markers
  • 52. The road to health is paved with good intestines…