2016 11-30 prez inde

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 , PhDDepartment of Life Sciences - Clinical Studies & BiometryNutribiotic & Microbes for Health TeamCentre de Recherche Daniel Carasso, Palaiseau

GUT-BRAIN AXIS & PROBIOTICS

© Reproduction, even partial, is not authorized I R.MORIEZ

Gut-Brain Axis is more than an emerging concept

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GUT-BRAIN AXIS| R. MORIEZ

To have in mind before 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


• 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’s TALK


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


• 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

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


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


Differents approaches to demonstrate Gut-Brain axis interactionPreclinical Research

Cryan & Dinan, Nature Neurosci Rev (2012)


• 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 interactionPreclinical Research


HPA axis response is influence by gut microbiota composition

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

*

Preclinical Research


The body of Evidence of Gut-Brain axis interaction in GF models

Luczynski P et al., Int J.of Neuropsychopharmacology (2016)

Preclinical Research


Can we transpose preclinical data to humans ?

? Þ Experimentally, Technically & Ethically difficult to investigate Gut brain mechanism and its components [microbiota, GIT & brain biopsy….]

Þ 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







❷ gut microbiota

❶ brain

Gut-Brain Axis in Human – IBS as model of evidence







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)







❷ gut microbiota

❶ brain

The other Troubles & Pathologies where Gut-Brain is altered

Stress

StressStress Stress

Stress

Autism

Autism

AutismAutism

Autism

Autism

Autism

mood disorders

psychiatric diseases

metabolic disordersObesity T2DM

Obesity T2DM

Obesity T2DM

Obesity T2DM

Obesity T2DM

Obesity T2DM

GI diseasesIBD

IBD

IBD

IBD

IBD IBD







❷ gut microbiota

❶ brain

Gut-Brain Interaction - Impact on Health ?

Stress

StressStress 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

GutBrain

Gut Brain

vicious circle

Chicken or egg ?

stress, ATBdiet & life style…

HEALTHY Behavior changesSyndromes Pathologies


Clinical studies with probiotics in 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)


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 arm11 in the CONTROL arm13 in the NO INTERVENTION (NO IN) arm

Inclusion criteria:Healthy womenAge 18-55No chronic painNo gastrointestinal symptomsNo psychiatric illnessRight handed

Tillisch K, Gastroenterology (2013)



Assessment of regional cerebral activity at resting state and following a negative emotional attention task

EmotionalMatching

ShapeMatching

EmotionalLabelling

GenderLabelling

ConditionsEmotionalMatching

ShapeMatching

EmotionalLabelling

GenderLabelling

ConditionsMatched Emotion (ME)

Matched Forms (MF)

ID Emotion (IDE)

ID Gender (IDG)

Conditions1) 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



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

EmotionalMatching

ShapeMatching

EmotionalLabelling

GenderLabelling


ShapeMatching

EmotionalLabelling

GenderLabelling


Matched Forms (MF)

ID Emotion (IDE)

ID Gender (IDG)

Conditions

(PAG)




EmotionalMatching

ShapeMatching

EmotionalLabelling

GenderLabelling


ShapeMatching

EmotionalLabelling

GenderLabelling


Matched Forms (MF)

ID Emotion (IDE)

ID Gender (IDG)

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




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



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 arm70 in the LcS arm


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


How does it work ? Possible mechanisms.

B. longum strains on anxiety=> vagus nerves, brain BDNF pathways

L. rhamnosus strains on anxiety & depressionÞ GABA upregulation in brain

L. helveticus strains on anxietyÞ ↘ neuroinflammation, ↘ serotonin metabolism

B. Animalis strains propertiesÞ Inhibitor of Monoamine oxidase (allow serotonin, dopamine..to remain inSynaptic 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).


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


“Let food be thy medicine and medicine be thy food.” Hippocrates (c. 460 BC – c. 370 BC)


2016 11-30 prez inde

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