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2016-11-30prezinde-170202064827.pdf

  1. 1. Gut Microbiota and Probiotic Science Foundation [India] 3rd – 4th December 2016, ITC Grand Chola, Chennai, India 8TH India Probiotic Symposium Probiotics in Health - Emerging Opportunities Raphaël MORIEZ , PhD Department of Life Sciences - Clinical Studies & Biometry Nutribiotic & Microbes for Health Team Centre de Recherche Daniel Carasso, Palaiseau GUT-BRAIN AXIS & PROBIOTICS © Reproduction, even partial, is not authorized I R.MORIEZ
  2. 2. Gut-Brain Axis is more than an emerging concept Social Networks Personal Development Press International Best Seller Academic Press Scientific Press Biomedical Publications GUT-BRAIN AXIS| R. MORIEZ
  3. 3. To have in mindbefore the presentation…. • Gut-Brain axis - a misleading term differentially used to named: => Neuroanatomical pathways between Gastrointestinal tract & brain [pathway of visceral pain…] => Neuro -endocrine -immune communications between GI tract & brain... • Gut-Brain axis is more complex, and is an INTEGRATIVE SYSTEM, BIDIRECTIONAL that integrates all dimensions of the host and of it’s microbiota Brain-Gut Axis  Brain-Gut-Intestinal Microbiota Axis GUT-BRAIN AXIS| R. MORIEZ
  4. 4. • Introduction to the Gut-Brain axis with preclinical and clinical data • Probiotics are an interesting route to consider in the management of syndromes/pathologies associated with Gut- Brain axis dysfunction TODAY’sTALK GUT-BRAIN AXIS| R. MORIEZ
  5. 5. ❸ Neuroanatomical pathway of gut-brain axis ❹ Neuroendocrine HPA axis pathway ❺Gut immune system & neuroimmune pathways ❻ Gut microbiota & metabolism system ❼ Intestinal barrier & blood brain barrier ❷ Gut microbiota ❶ Brain How the Gut-Brain Axis works GUT-BRAIN AXIS| R. MORIEZ
  6. 6. • enteric NS • parasympathetic NS • sympathetic NS • CRF, ACTH, cortisol • mast cells, macrophages.. • Cytokines, PGs… • Proteases • GABA, Dopamine, serotonin… • LPS, SCFA… • Epithelial/Enteroendocr ne cells • Tight Jcts/permeability How the Gut-Brain Axis works– The key Actors ❸ Neuroanatomical pathway of gut-brain axis ❹ Neuroendocrine HPA* axis pathway ❺Gut immune system & neuroimmune pathways ❻ Gut microbiota & metabolism system ❼ Intestinal barrier & blood brain barrier ❷ Gut microbiota ❶ Brain *Hypothalamic–pituitary–adrenal GUT-BRAIN AXIS| R. MORIEZ
  7. 7. life style diet dietary proteins antibiotic xenobiotic food allergies infections How the Gut-Brain Axis works– The key Actors & Modulators ❷ gut microbiota ❶ brain ❸ neuroanatomical pathway of gut-brain axis ❹ neuroendocrine HPA axis pathway ❺gut immune system & neuroimmune pathways ❻ gut microbiota & metabolism system ❼ intestinal barrier & blood brain barrier life style stress hormones aging genetic diet infections / chronic pathologies & treatments • enteric NS • parasympathetic NS • sympathetic NS • CRF, ACTH, cortisol • mast cells, macrophages.. • Cytokines, PGs… • Proteases • GABA, Dopamine, serotonin… • LPS, SCFA… • Epithelial/Enteroendocrine cells • Tight Jcts/permeability GUT-BRAIN AXIS| R. MORIEZ
  8. 8. Differents approaches to demonstrate Gut-Brain axis interaction PreclinicalResearch Cryan & Dinan, Nature Neurosci Rev (2012) GUT-BRAIN AXIS| R. MORIEZ
  9. 9. Differents approaches to demonstrate Gut-Brain axis interaction PreclinicalResearch Cryan & Dinan, Nature Neurosci Rev (2012) GUT-BRAIN AXIS| R. MORIEZ
  10. 10. • Research using GF mice has arguably provided the most convincing evidence for a role of microbiota in gut-brain signaling • One of the main advantages of the GF model is that identical strains of bacteria can be introduced and GF mice can be « humanized » by transplanting fecal microbiota from human patients with different diseases. Differents approaches to demonstrate Gut-Brain axis interaction PreclinicalResearch GUT-BRAIN AXIS| R. MORIEZ
  11. 11. HPA axis responseis influence bygut microbiotacomposition Germ Free [GF] Specific Pathogen Free [SPF] Germ Free [GF] Germ Free [GF] B. infantis EPEC Mutant EPEC Tir [SPF] GERM FREE vs. SPECIFIC PATHOGEN FREE MONOASSOCIATED FLORA FECAL TRANSPLANTATION vs. Acute Restraint Stress [1h] => measure of plasmatic corticosterone Sudo et al., J Physiol (2004) *Tir (translocated intimin receptor) is an essential component in the adherence of E.coli * PreclinicalResearch GUT-BRAIN AXIS| R. MORIEZ
  12. 12. The body of Evidence of Gut-Brain axis interaction in GF models Luczynski P et al., Int J.of Neuropsychopharmacology (2016) PreclinicalResearch GUT-BRAIN AXIS| R. MORIEZ
  13. 13. Can we transposepreclinical data to humans? ?  Experimentally, Technically & Ethically difficult to investigate Gut brain mechanism and its components [microbiota, GIT & brain biopsy….]  Brain structure, microbiota composition is different in humans compared to animal models… No direct evidence of a gut-brain- microbiota interaction in human [How it works], but a robust and coherent level of indirect evidence GUT-BRAIN AXIS| R. MORIEZ
  14. 14. ❸ neuroanatomical pathway of gut-brain axis ❹ neuroendocrine HPA axis pathway ❺gut immune system & neuroimmune pathways ❻ gut microbiota & metabolism system ❼ intestinal barrier & blood brain barrier ❷ gut microbiota ❶ brain Gut-Brain Axis in Human– IBS as model of evidence GUT-BRAIN AXIS| R. MORIEZ
  15. 15. ❸ neuroanatomical pathway of gut-brain axis ❹ neuroendocrine HPA axis pathway ❺gut immune system & neuroimmune pathways ❻ gut microbiota & metabolism system ❼ intestinal barrier & blood brain barrier ❷ gut microbiota ❶ brain Gut-Brain Axis in Human– IBS as model of evidence Enck P et al., Nature Reviews I Disease Primers (2016) GUT-BRAIN AXIS| R. MORIEZ
  16. 16. ❸ neuroanatomical pathway of gut-brain axis ❹ neuroendocrine HPA axis pathway ❺gut immune system & neuroimmune pathways ❻ gut microbiota & metabolism system ❼ intestinal barrier & blood brain barrier ❷ gut microbiota ❶ brain The other Troubles & Pathologies where Gut-Brain is altered Stress Stress Stress Stress Stress Autism Autism Autism Autism Autism Autism Autism mood disorders psychiatric diseases metabolic disorders Obesity T2DM Obesity T2DM Obesity T2DM Obesity T2DM Obesity T2DM Obesity T2DM GI diseases IBD IBD IBD IBD IBD IBD GUT-BRAIN AXIS| R. MORIEZ
  17. 17. ❸ neuroanatomical pathway of gut-brain axis ❹ neuroendocrine HPA axis pathway ❺gut immune system & neuroimmune pathways ❻ gut microbiota & metabolism system ❼ intestinal barrier & blood brain barrier ❷ gut microbiota ❶ brain Gut-Brain Interaction - Impact on Health ? Stress Stress Stress Stress Stress Autism Autism Autism Autism Autism Autism mood disorders Class of pathologies psychiatric diseases metabolic disorders Obesity T2DM Obesity T2DM Obesity T2DM Obesity T2DM Obesity T2DM GI diseases IBD IBD IBD IBD IBD Gut Brain Gut Brain vicious circle Chicken or egg ? stress, ATB diet & life style… HEALTHY Behavior changes Syndromes Pathologies GUT-BRAIN AXIS| R. MORIEZ
  18. 18. Clinical studies with probioticsin the Gut-Brain Axis • A growing wave of striking clinical studies mainly focused on response to emotional attention tasks, mood disorders, stress, anxiety & depression. • In order to evaluate levels of stress, brain activity and psychological symptoms in clinical studies, several tools have been applied, including biomarkers (i.e. salivary cortisol), brain MRI and validated psychological scales typically used for the evaluation of anxiolytic drugs. Pirbaglou M et al., Nutrition Research (2016) GUT-BRAIN AXIS| R. MORIEZ
  19. 19. The evidence of a gut-brain interaction using FMRI* *FMRI. Functional Magnetic Resonance Imaging Objective: To assess the effect of a 4-week consumption of Fermented Milk Product (FMP: 5 strains of probiotics including B. animalis lactis DN 173 010B) (2x125g/day) on brain intrinsic connectivity and responses to emotional attention task in healthy women. Sample size: 36 subjects (ITT = Intention To Treat; 45 randomized) 12 in the FMP arm 11 in the CONTROL arm 13 in the NO INTERVENTION (NO IN) arm Inclusion criteria: Healthy women Age 18-55 No chronic pain No gastrointestinal symptoms No psychiatric illness Right handed Tillisch K, Gastroenterology (2013) GUT-BRAIN AXIS| R. MORIEZ
  20. 20. The evidence of a gut-brain interaction using FMRI* Tillisch K, Gastroenterology (2013) GUT-BRAIN AXIS| R. MORIEZ
  21. 21. The evidence of a gut-brain interaction using FMRI* Assessment of regional cerebral activity at resting state and following a negative emotional attention task Emotional Matching Emotional Matching Matched Emotion (ME) Emotional Matching Emotion Labellin Emotional Matching Emotion Labellin Matched Emotion (ME) ID Emo (IDE) Co 1) Resting state: eyes closed for a 5 minutes functional scan; no stimulation 2) Negative emotional attention task: – Validated task probing attention to negative context (Lieberman, 2007) – Assess the brain response while viewing human negative emotional faces (angry or fearful expressions) and matching shapes as a control Tillisch K, Gastroenterology (2013) GUT-BRAIN AXIS| R. MORIEZ
  22. 22. The evidence of a gut-brain interaction using FMRI* Study Results: Emotional attention task - 1/2 • 4 week FMP consumption decreases reactivity to a negative emotional attention task of a brain network receiving afferent signals from the gut: – FMP group: decreased reactivity of a widely distributed brain network (insula, somatosensory cortex, PAG) to the task (p<0.0001) – Control group: no change in the reactivity of the brain network to the task – No IN group: increased reactivity of the brain network to the task No IN FMPP Emotional Matching Sha Matc Emotional Labelling Conditions Emotional Matching Sha Matc Emotional Labelling Conditions Matched Emotion (ME) Matc Form ID Emotion (IDE) nal ng Shape Matching Emotional Labelling Conditions nal ng Shape Matching Emotional Labelling Conditions d n (ME) Matched Forms (MF) ID Emotion (IDE) Conditions (PAG) Tillisch K, Gastroenterology (2013) GUT-BRAIN AXIS| R. MORIEZ
  23. 23. The evidence of a gut-brain interaction using FMRI* Emotional Matching Sha Matc Emotional Labelling Conditions Emotional Matching Sha Matc Emotional Labelling Conditions Matched Emotion (ME) Matc Form ID Emotion (IDE) nal ng Shape Matching Emotional Labelling Conditions nal ng Shape Matching Emotional Labelling Conditions d n (ME) Matched Forms (MF) ID Emotion (IDE) Conditions Study Results: Emotional attention task - 2/2 • Individual analyses of the regions from the identified network support previous network results for the 3 groups • 4 week FMP consumption decreases reactivity of interoceptive (mid-insula) and somatosensory regions to a negative emotional attention task, compared to NO IN (p<0.004; p<0.005) and CONTROL (p<0.03; p<0.02) No IN > FMPP Control > FMPP Tillisch K, Gastroenterology (2013) GUT-BRAIN AXIS| R. MORIEZ
  24. 24. The evidence of a gut-brain interaction using FMRI* CONCLUSION. • To our knowledge, this is the first demonstration in humans that chronic intake of a fermented milk product with probiotic can modulate brain activity • The findings suggest that regular intake of a fermented milk product with probiotic can (i) affect brain regions concerned with the central processing of afferent signals from the gut, and (ii) reduce the impact of the brain regions involved in emotional arousal on the central processing of gut afferent signals • Moreover, 4 week FMP consumption induced a shift away from an emotional arousal- based resting state network towards a rationalization network Tillisch K, Gastroenterology (2013) GUT-BRAIN AXIS| R. MORIEZ
  25. 25. The evidence of a gut-brain interaction using BIOMARKER Takada M, Neurogastroenterology & Motility (2016) Objective: Three double-blind, placebo-controlled trials were conducted to examine the effects of of a 8-week consumption of Lactobacillus casei strain Shirota (once daily) on psychological and physiological (BIOMARKER Cortisol) stress responses in healthy medical students under academic examination stress. Sample size: 140 subjects 70 in the placebo arm 70 in the LcS arm GUT-BRAIN AXIS| R. MORIEZ
  26. 26. The evidence of a gut-brain interaction using BIOMARKER Takada M, Neurogastroenterology & Motility (2016) Study Results: Ingestion of LcS suppressed stress-induced increases in glucocorticoids in an academic stress model in healthy medical students GUT-BRAIN AXIS| R. MORIEZ
  27. 27. How does it work ? Possible mechanisms. B. longum strains on anxiety => vagus nerves, brain BDNF pathways L. rhamnosus strains on anxiety & depression  GABA upregulation in brain L. helveticus strains on anxiety  ↘ neuroinflammation, ↘ serotonin metabolism B. Animalis strains properties  Inhibitor of Monoamine oxidase (allow serotonin, dopamine..to remain in Synaptic cleft ?) / scavenged free radicals Exact mechanism of action of probiotics on Gut-Brain still remains to be established but combining intrinsic properties of strains and the Preclinical & Clinical data we can speculate that probiotics impact all the component of Gut-Brain axis (microbiota, barrier, immune system, enteric nervous system, vagus nerves, brain). GUT-BRAIN AXIS| R. MORIEZ
  28. 28. Conclusion • A growing list of disorders – IBS, depression and autism spectrum disorders - recently recognized as brain-gut disorders • Potential for novel therapeutic interventions at the microbiome or at the gut level • Probiotics have potential as agents to manage these syndromes/pathologies associated with Gut-Brain axis dysfunction GUT-BRAIN AXIS| R. MORIEZ
  29. 29. “Let food be thy medicine and medicine be thy food.” Hippocrates (c. 460 BC – c. 370 BC) GUT-BRAIN AXIS| R. MORIEZ

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