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Its Not All In Your Head Mood and the Microbiome Jeremy Appleton, ND Strictly Confidential Soho Flordis International Group Strictly Confidential Soho Flordis International Group What is the Gut-Brain Axis? Neurologic Endocrine Humoral Metabolic Immune Strictly Confidential Soho Flordis International Group

How the microbiota interacts with the GBA Neurologic modulation of afferent sensory nerves directly producing molecules that can act as local neurotransmitters generating a biologically active form of catecholamines Endocrine alter nutrient availability influence the release of biologically active peptides from enteroendocrine cells galanin and ghrelin effects on HPA Axis, cortisol, etc Humoral / Metabolic SFCAs: fuel for enterocytes, affect intestinal permeability, stimulate ANS via GPR receptors SFCAs stimulate mucosal serotonin release, cross the BBB, modulate brain dev and behavior SCFAs regulate gut peptides, synthesis of serotonin Immune abnormal microbiota activates mucosal innate immune responses, which increase epithelial permeability

also affects intestinal motility and secretion, visceral sensitivity , cellular alterations SCFAs are immunomodulatory Strictly Confidential Soho Flordis International Group How the microbiota interacts with the GBA Production, expression and turnover of neurotransmitters (i.e., serotonin, GABA) and neurotrophic factor (BDNF) Protection of intestinal barrier and tight junction integrity Modulation of enteric sensory afferents Bacterial metabolites Mucosal immune regulation Brain to Gut Alteration in mucus and biofilm

production Alteration in motility Alteration of intestinal permeability Alteration in immune function Gut to Brain Strictly Confidential Soho Flordis International Group Ann Gastroenterol. 2015;28:203-9. Epithelial Barrier Function Intestinal barrier integrity is a prerequisite for mucosal function homeostasis. Disruption of epithelial barrier integrity is associated with many diseases: - infection by pathogens - obesity and diabetes - necrotizing enterocolitis

- irritable bowel syndrome - inflammatory bowel disease Modulation of intestinal barrier function is likely a primary factor in microbiota-GBA interaction. Strictly Confidential Soho Flordis International Group Br J Nutr. 2017;117(1): 93-107. Epithelial Barrier Function Strictly Confidential Soho Flordis International Group Nature Immunology. 2013;14: 660-7. Microbiome and Inflammation Gut microbiota help maintain tight junctions. Dysbiosis and associated increases in intestinal permeability are now recognized features of many diseases.

Stressful stimuli alter permeability of the intestinal epithelium. Permeability defects are thought to underlie chronic, lowgrade inflammation. Inflammatory phenotype contributes to depression by altering neurotransmitter metabolism, reducing the availability of neurotransmitter precursors, and activating the HPA axis. Bacterial-derived endotoxins (e.g., LPS) trigger immune activation. Reducing inflammation of this origin may lead to improved regulation of the HPA axis and neurotransmitter activity. Strictly Confidential Soho Flordis International Group Probiotics and Mood Systematic review by Wallace and Miley 10-study inclusion criteria - 5 studies assessed mood symptoms - 7 studies assessed anxiety symptoms - 3 studies assessed cognition The majority of the studies found positive results on all measures of depressive symptoms

Strains, dosing, and duration of treatment varied widely. No studies assessed sleep. Strictly Confidential Soho Flordis International Group Ann Gen Psychiatry. 2017;16:14. Ecologic BARRIER Strain Selection Barrier function (% TEER) Cytokine modulation MAST cell stabilization Suppression of circulating LPS Strictly Confidential Soho Flordis International Group Food Nutr Sci. 2014;5:1739-45. Strictly Confidential Soho Flordis International Group

Stressor + strain W122-S. salivarius W58-Lc. lactis W19-Lc. lactis W57-L. salivarius W24-L. salivarius W71-L. rhamnosus W62-L. plantarum W21-L. plantarum

W129-L. fermentum W79-L. casei W56-L. casei W20-L. casei W78-L. brevis W63-L. brevis W70-L. acidophilus W55-L. acidophilus W37-L. acidophilus W22-L. acidophilus

W74-L. acidophilus W54-E. faecium W108-B. longum W52-B. lactis W51-B. lactis W125-B. infantis W25-B. breve W119-B. bifidum W28-B. bifidum

W23-B. bifidum W53-B. animalis W64-Bac. coagulans stressor controle % TEER Effect of Strains on Barrier Function 110 100 90

80 70 60 50 Randomized, Controlled Clinical Trial: cognitive reactivity to sad mood * * * Strictly Confidential Soho Flordis International Group Brain Behav Immun. 2015 Aug;48:258-64.

Ecologic BARRIER One Psychiatrists Experience Scot Bay, MD Strictly Confidential Soho Flordis International Group 34 year old Female History - Chronic depression and anxiety - Concurrent IBS - Exacerbated by relationship struggles and job change Chief Complaint - Depression - Anxiety

Plan - Sertraline 100 mg qid - Trazadone 50 mg hs bid - Ecologic BARRIER 5B CFU bid Outcomes Strictly Confidential Soho Flordis International Group 14 72 year old Female History - Chronic severe depression - Medications stabilize mood with significant GI side effects Chief Complaint - Depression - Diarrhea

Plan - Duloxetine 90 mg qd - Buproprion 450 mg qd - Ecologic BARRIER 5B CFU bid Outcomes (4 weeks) - Significant improvement in diarrhea - Slight, but noticeable, improvement in mood Strictly Confidential Soho Flordis International Group 15 43 year old Female History - Recent significant psychosocial stress (divorce, move) - Medications partially effective Chief Complaint

- Anxiety Plan - Escitalopram 30 mg qd - Ecologic BARRIER 5B CFU bid Outcomes (4 weeks) - Slight, but noticeable, improvement in mood Strictly Confidential Soho Flordis International Group 16 52 year old Female History - Chronic, severe treatment-resistant depression Chief Complaint - Depression

- Delayed gastric emptying (diarrhea) Plan - Vilazodone 10 mg qd - Ecologic BARRIER 5B CFU bid Outcomes (4 weeks) - Slight, but noticeable, improvement in mood - Improvement in digestive symptoms Strictly Confidential Soho Flordis International Group 17 47 year old Male History - Chronic, severe treatment-resistant depression Chief Complaint

- Depression - Diarrhea Plan - Panlor 50 mg qd - Ecologic BARRIER 5B CFU bid Outcomes (4 weeks) - Slight, but noticeable, improvement in mood - Complete remission of diarrhea Strictly Confidential Soho Flordis International Group 18

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