The GUTBRAIN Axis or the ENSCNS continuum Steven
The GUT-BRAIN Axis (or the ENS-CNS continuum) Steven Sandberg-Lewis, ND, DHANP ILANP Seminar October 8 & 9, 2016
Steven Sandberg-Lewis, ND, DHANP 2016
terms • Gut microbiota – the organisms themselves (about 100 trillion) • • Oral and esophageal microbiota Gastric microbiota Small bowel microbiota Colonic microbiota • Microbiome – the genome of the gut flora (about 4 million genes) • Holobiome – the concept of human genome (26, 000 genes) plus the microbiome • GI metabolome – the metabolic products of the gut flora Steven Sandberg-Lewis, ND, DHANP 2016
360 microbial genes for every 1 human gene Steven Sandberg-Lewis, ND, DHANP 2016
Metabolome (GI bacterial metabolic products) • “The gut microbiome can be viewed as an anaerobic bioreactor programmed to synthesize molecules which direct the mammalian immune system, modify the mammalian epigenome and regulate host metabolism. ” Galland L, 2014 (after Hooper LV 2004, Li M, 2008 and Jacobsen UP, 2013) Steven Sandberg-Lewis, ND, DHANP 2016
Metabolome 40% of metabolites in human blood are derived from gut flora Bacterial products Human products Steven Sandberg-Lewis, ND, DHANP 2016
Microbiota and ENS development • Gut flora needed for proper maturation of enteric neurons • Density • Activity Steven Sandberg-Lewis, ND, DHANP 2016
Enteric Nervous System http: //medweb. bham. ac. uk/research/toescu/Teaching/GIT/ENS 1. gif Steven Sandberg-Lewis, ND, DHANP 2016
Hippocrates – All disease begins in the gut Steven Sandberg-Lewis, ND, DHANP 2016
ENS to CNS through the autonomic NS • 90% of vagal impulses are from ENS to CNS • Fine tune motility, secretion and blood glucose control • Shape and consistency of bolus • Shearing forces of bolus against the mucosa stimulate serotonin release • Info on food composition (via taste receptors on enteroendocrine cells - EEC) • Stimulation of bitter receptors triggers release of ghrelin and Glucagon peptide 1 (GLP-1) • Ghrelin to CNS which upregulates hunger, etc. • Glucagon peptide 1 is a potent antihyperglycemic hormone Steven Sandberg-Lewis, ND, DHANP 2016
From http: //www. frontiersin. org/files/Articles/107295/fendo-05 -00144 -HTML/image_m/fendo-05 -00144 -g 001. jpg Steven Sandberg-Lewis, ND, DHANP 2016
From Mayer E, 2014 • Food enters the GI tract with “fine print directions” to the ENS for it’s proper digestion • Gut peptides are a “complex universal biological language that the trillions of microbes in the intestines use to communicate with the digestive system and the brain. ” Steven Sandberg-Lewis, ND, DHANP 2016
Gut peptide chart Steven Sandberg-Lewis, ND, DHANP 2016
A link between gut health and mental health Healthy gut microbiota Mental health Steven Sandberg-Lewis, ND, DHANP 2016
Links between gut health and mental health Gut infections or bacterial overgrowth Gut derived inflammatory molecules Mental health issues Oxidative stress Steven Sandberg-Lewis, ND, DHANP 2016
Bacterial overgrowth and depression “The production of small amounts of hydrogen and/or methane does not normally produce symptoms, whereas the production of higher levels can lead to a wide range of symptoms ranging from functional disorders of the bowel to low level depression. ” (de Lacy Costello BP, 2013) Steven Sandberg-Lewis, ND, DHANP 2016
Bacterial cell wall lipopolysaccharide Steven Sandberg-Lewis, ND, DHANP 2016
LPS in the bloodstream • A healthy intestinal mucus membrane prevents all but a tiny quantity of this LPS from entering the bloodstream. • The small amounts of LPS in the blood are removed when they pass through a healthy liver. Traces of bacterial LPS Steven Sandberg-Lewis, ND, DHANP 2016
Guerville M, 2016 • if LPS crosses the gut mucosa, it is directed via the portal vein to the liver, where major detoxification processes occur by deacetylation and excretion through the bile. If this disposal process is not sufficient, LPS enters the systemic circulation, where it is handled by numerous transport proteins that clear it back to the liver for further processing. Steven Sandberg-Lewis, ND, DHANP 2016
Systemic effects of LPS • When LPS - from gut bacteria - is absorbed into the bloodstream at slightly higher levels, it has emotional and cognitive effects (Grigoleit JS, 2011) Activation of NF-KB Impaired excretion of xenobiotic and endogenous toxins Bacterial LPS Anxiety Depression Cognitive deficits Increased visceral sensitivity Steven Sandberg-Lewis, ND, DHANP 2016
ENS to CNS - LPS (from Quig D, 2016) • There are 1 million copies of LPS in each gram negative microbe! • These are continuously shed – the bacteria do not need to die in order to give off LPS • LPS also is one of the metabolites that triggers the zonulin pathway Steven Sandberg-Lewis, ND, DHANP 2016
ENS to CNS - LPS (from Bested AC, 2013) • The adult human gut is believed to contain about one gram of LPS Steven Sandberg-Lewis, ND, DHANP 2016
ENS to CNS - LPS (from Quig D, 2016) • Bacteria need not cross the BBB to have CNS effects • LPS and inflammatory cytokines can induce transcription of IL-1 b, IL-6 and TNF alpha in discrete areas of the brain Steven Sandberg-Lewis, ND, DHANP 2016
ENS to CNS - LPS (from Mayer E, 2014) • Obese humans may have 2 -3 fold increases in LPS levels compared to lean humans • Adipose from obese humans contains up to 50% macrophages • Adipose from lean humans contains about 5% macrophages • Enterobacter derived LPS may be 1000 times more potent than LPS derived from other gram negative bacteria Steven Sandberg-Lewis, ND, DHANP 2016
Systemic inflammation and CNS inflammation • Increased systemic inflammation can trigger CNS inflammation by activating microglia. (Hannestad J, 2012) • When CNS inflammation is initiated it is difficult to turn off and may cause depression. (Fenn AM, 2013) Steven Sandberg-Lewis, ND, DHANP 2016
LPS and tryptophan metabolism Increased amygdala activity Bacterial LPS Tryptophan to serotonin inflammation Tryptophan to kynurenine Miura H, 2009, Hashimoto H, 2012 Steven Sandberg-Lewis, ND, DHANP 2016 Depression, anxiety, insomnia
Wichers MC, , 2004 and neurendoimmune. wordpress. com) Steven Sandberg-Lewis, ND, DHANP 2016
50 ways to Clog Your Liver • I started life out with a liver oh so clean, • Since then I’ve done so much to make it turn dark green, • Now that I’ve got it back to functioning again • There must be 50 ways to clog your liver… Steven Sandberg-Lewis, ND, DHANP 2016
SIg. A and LPS (from Boullier S 2009, Fernandez MI 2003) • SIg. A inactivates LPS • prevents NF-KB pathway, IFN, IL-6, TNF alpha • This inactivation occurs in endosomes Steven Sandberg-Lewis, ND, DHANP 2016
Morris G, 2016 PMID 27349436 • The composition of the microbiota largely determines the levels of tryptophan in the systemic circulation and hence, indirectly, the levels of serotonin in the brain. • Some microbiota synthesize neurotransmitters directly, e. g. , gammaamino butyric acid, while modulating the synthesis of neurotransmitters, such as dopamine and norepinephrine, and brain-derived neurotropic factor (BDNF) • The composition of the microbiota determines the levels and nature of tryptophan catabolites (TRYCATs) which in turn has profound effects on aryl hydrocarbon receptors, thereby influencing epithelial barrier integrity and the presence of an inflammatory or tolerogenic environment in the intestine and beyond. Steven Sandberg-Lewis, ND, DHANP 2016
Leclercq S, 2016 PMID 27254412 and (Galland L, 2014) • Gut bacteria strongly affect both the peripheral and central nervous systems by production of functionally active neurotransmitters: • • • Serotonin Dopamine γ-aminobutyric acid Acetylcholine Epinephrine Steven Sandberg-Lewis, ND, DHANP 2016
From igem. org Steven Sandberg-Lewis, ND, DHANP 2016
Bailey MT, 2011 PMID: 21040780 • Stressed mice exhibit immediate changes in cecal flora • Reduced Bacteroides and increased Clostridium • Increase in circulating cytokines (IL-6 and MCP-1) • Cytokine levels were reduced when the mice were treated with antibiotics prior to the stress Steven Sandberg-Lewis, ND, DHANP 2016
Leclercq S, 2016 PMID 27254412 • “Recent experimental and clinical data converge on the hypothesis that imbalanced gut microbiota in early life may have long-lasting immune and other physiologic effects that make individuals more susceptible to develop PTSD after a traumatic event and contribute to the disorder. This suggests that it may be possible to target abnormalities in these systems by manipulation of certain gut bacterial communities directly through supplementation or indirectly by dietary and other novel approaches. ” Steven Sandberg-Lewis, ND, DHANP 2016
ENS to CNS - SCFA (Saint-Georges-Chaumet Y, 2015) (also Ash M, 2016) • SCFA produced by bacterial fermentation of soluble fiber and mucin • Mediates microbial/nitochondria/host cross-talk • Systemic absorption • Crosses BBB • Modulates CNS inflammation Steven Sandberg-Lewis, ND, DHANP 2016
ENS to CNS - SCFA • SCFA and secondary bile metabolites • React with receptors on enteroendocrine cells • Altered serotonin levels • Anxiety • Sleep alterations • Pain sensitivity alterations Steven Sandberg-Lewis, ND, DHANP 2016
Nice quote “I strongly feel that it is the engagement of the gut and its microbiome that plays a major role in determining the intensity duration and uniqueness of our emotional feelings” Emeran A Mayer, MD Gastrointestinal Functional & Motility Disorders Professor, Medicine, Physiology & Psychiatry, UCLA School of Medicine Steven Sandberg-Lewis, ND, DHANP 2016
Bacterial overgrowth, insulin and the brain Steven Sandberg-Lewis, ND, DHANP 2016
Elevated blood insulin High blood pressure metabolic syndrome Elevated blood fats Elevated blood sugar Increased waist circumference Steven Sandberg-Lewis, ND, DHANP 2016
Waist circumference /visceral fat Less than 35” – women Less than 40” - men more than 35” – women more than 40” - men Steven Sandberg-Lewis, ND, DHANP 2016
Visceral fat • Visceral fat is the largest endocrine producing “gland” in the body leptin adiponectin resistin visfatin tumor necrosis factor-alpha interleukin-6 Steven Sandberg-Lewis, ND, DHANP 2016
Blood sugar, bacteria and brain issues High carbohydrate diet Insulin resistance Brain degeneration SIBO Cherbuin N, 2012 Free radicals Steven Sandberg-Lewis, ND, DHANP 2016
Blood sugar surges after high carbohydrate meals Blood sugar surges Depletion of: Serotonin Epinephrine Norepinephrine Dopamine B vitamins Magnesium stress on the liver stress on the nervous system Insulin resistance Neurodegeneration and depression glycation Geroldi C, 2005 Perlmutter D, 2013 Steven Sandberg-Lewis, ND, DHANP 2016
Normal vs ideal values marker normal range ideal glycated hemoglobin (Hgb. A 1 c) below 5. 7 4. 8 -5. 4 5. 7 -6. 4 = prediabetes >6. 5 = diabetes fasting insulin < 22 Steven Sandberg-Lewis, ND, DHANP 2016 <4
Anxiety and depression in GI disorders • 84. 1% showed state anxiety • 67% showed trait anxiety • 27% showed current depression • The number of gastrointestinal diseases was directly correlated to state anxiety (p < 0. 001) and trait anxiety (p = 0. 04). • Females showed higher levels of anxiety and depression than males (p < 0. 001). (Addolorato G, 2008) Steven Sandberg-Lewis, ND, DHANP 2016
Anxiety and depression in GI disorders • State anxiety was related to food allergies (p < 0. 001) and bacterial overgrowth (SIBO) (p = 0. 001) • Trait anxiety was related to IBS (p < 0. 001), food allergies (p = 0. 001) and SIBO (p = 0. 001). • Current depression was related to IBS (p < 0. 001), celiac disease (p = 0. 01), and SIBO (p = 0. 02). (Addolorato G, 2008) Steven Sandberg-Lewis, ND, DHANP 2016
Hiatal Hernia and Hiatal Hernia Syndrome Steven Sandberg-Lewis, ND, DHANP 2016
Incidence in the U. S. • Sliding hiatal hernia affects over 40% of the U. S. population (Merck Manual 2006) • 15% of the U. S. population (http: //medicine. yale. edu) • The frequency of hiatus hernia increases with age, from 10% in patients younger than 40 years to 70% in patients older than 70 years. (http: //emedicine. medscape. com/article/178393 overview#aw 2 aab 6 b 2 b 3 aa) Steven Sandberg-Lewis, ND, DHANP 2016
More common in the Western world • Low fiber diet and the resulting chronic constipation and straining during bowel movements, may explain the higher incidence of this condition (Burkitt et al, 1973) Steven Sandberg-Lewis, ND, DHANP 2016
considered asymptomatic by most physicians unless it causes reflux • “In most patients, hiatus hernias cause no symptoms. This is especially true of sliding hernias. When symptoms occur, they may only be heartburn and regurgitation, when stomach acid refluxes back into the esophagus. . ” From http: //www. ecaware. org/what-is-esophageal-cancer/risk-factors/hiatus-hernia/ Steven Sandberg-Lewis, ND, DHANP 2016
Hiatal hernia syndrome Clinical picture (revised from Ralph Failor, ND) • • • fatigue easy satiety pallor chest oppression non-cardiac chest pain stitching pains averse to constriction “spare tire” bulge *fullness in the ears excessive belching flatulence mental dullness shallow breathing ANXIETY reflux dysphagia, globus full feeling at the base of the throat regurgitation tickling non-productive cough atrial fibrillation Steven Sandberg-Lewis, ND, DHANP 2016
Case example • 55 yo female : She was a night shift nurse for 20 years • Clinical picture over the last 8 years: • • severe nausea abdominal pain constipation loss of appetite 20 pound weight loss in the last 6 months chronic arthritis and cervical stenosis fibromyalgia with a long history of narcotic use Steven Sandberg-Lewis, ND, DHANP 2016
Case example • Results of lactulose SIBO breath test: • 53 PPM rise in hydrogen • normal is less than a 20 PPM rise • 2 PPM rise in methane • normal is less than 12 PPM rise, but any level >3 can cause constipation Steven Sandberg-Lewis, ND, DHANP 2016
Case example Response to treatment: • Mid-way through the course of antibiotics her appetite returned and she had less nausea. The abdominal pain is gone. Since then it has consistently gotten better and better. • How is the nausea? “Much less severe - down from 10 to a 2 and I don’t need to take zofran. ” The nausea was “paralyzing” and triggered “severe waves of anxiety. ” “The anxiety is gone. ” Steven Sandberg-Lewis, ND, DHANP 2016
Case example • How is the depression? “I have stopped crying. I used to cry easily and frequently throughout the day. I have stopped taking zofran and ambien because I don’t need them. I still take the wellbutrin and occasional ly take tramadol for the neck pain. ” Steven Sandberg-Lewis, ND, DHANP 2016
Case example • She is much more able to do things - went to a barn dance, spends the day active with her kids and is not exhausted at night or the next day. She can clean her house and do ADLs. Overall her energy is much improved. • She is preparing SIBO food guide meals. She juices green drinks and generally eats proteins and cooked vegetables. Steven Sandberg-Lewis, ND, DHANP 2016
Case example • Energy was 0 -4/10 and now it is an 8/10. She had an eight year history of very low energy. • The patient and her daughter notice a dramatic increase in cognitive clarity. She has been traveling and is very excited about doing things. She is going to visit her parents in Chicago and Phoenix next week. Steven Sandberg-Lewis, ND, DHANP 2016
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