Migrene og mikroflora. Linda Mulder, MSc. Vårseminaret 2014
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1 Migrene og mikroflora Linda Mulder, MSc. Vårseminaret 2014
2 Contents Introduction to migraine Introduction to intestinal barrier The role of the intestine & microbiota in migraine Finding the best probiotic Results clinical (pilot) trial PAGE 2
3 Introduction to migraine Migraine is a chronic disorder, affecting more than 10% of the population worldwide Symptoms: - Recurrent headache at one side - Often associated with nausea, vomiting, increased sensitivity to light and/or sound - Duration 4-72 hours Associated with gastrointestinal diseases PAGE 3
4 Introduction to migraine The cause of migraine is not clear Most problably caused by a neurogenic inflammation of tissues surrounding the brains However, anti-inflammatory medicins do not always help, and can cause side-effects Literature suggests association between migraine and inflammatory diseases like: allergy, cealiac disease, obesity, metabolic syndrome, IBS and IBD PAGE 4
5 Migraine and the intestine Literature search revealed: People that often suffer from intestinal complaints, have more frequent headaches People with IBS often suffer from migraine Children with migraine had more often colic at young age Patients with cealiac disease have more often migraine Patients with chronic inflammatory bowel diseases have more often migraine PAGE 5
6 Barrier function of the gut Intestinal barrier (level 2): Defence to prevent infection and inflammation Consisting of: Mucous layer Antimicrobial peptides siga Epithelial junctional adhesion complexes Prevent from leaky gut PAGE 6
7 Link between leaky gut / inflammation / migraine gut permeability / leaky gut stress diet effects other factors PAGE 7
8 Disruption of the epithelial barrier high fat diet Heredity PAGE 8
9 LPS LPS = lipopolysaccharides = endotoxin Outer cell membrane of gram-negative bacteria Very pro-inflammatory compounds Normal physiological process that LPS enter the body Under certain conditions increased uptake of LPS, leading to chronic inflammatory diseases in susceptible people PAGE 9
10 Link between leaky gut / inflammation / migraine gut permeability / leaky gut stress diet effects other factors +intake NSAIDs LPS in blood circulation migraine release proinflammatory cytokines NSAIDs=non-steroidal anti-inflammatory drugs PAGE 10
11 Disruption of the epithelial barrier Increased permeability is associated with different diseases - Inflammatory bowel diseases (IBD) - Irritable bowel syndrome (IBS) - Chronic low-grade inflammation (including autism, migraine & metabolic syndrome) Probiotic bacteria have the potential to improve barrier function PAGE 11
12 Link between leaky gut / inflammation / migraine probiotics gut permeability/ leaky gut intake NSAIDs stress diet effects other factors LPS in blood circulation migraine release proinflammatory cytokines PAGE 12
13 Disruption of the epithelial barrier Increased permeability is associated with different diseases - Inflammatory bowel diseases - Irritable bowel syndrome - Chronic low-grade inflammation (including autism, migraine & metabolic syndrome) Probiotic bacteria have the potential to improve barrier function And have an indirect positive effect on migraine? Effects are strain-specific! PAGE 13
14 Selecting strains for probiotic Direct effects of probiotics: TEER assay (trans-epithelial electrical resistance) PAGE 14
15 TEER assay Addition of bacteria Ω Measuring resistance Addition of stressor (TNFα, IL- 1β) Measuring the permeability (resistance) of the epithelial cells Caco-2 trans-well system Epithelial layer stressed with cytokines PAGE 15
16 TEER strain specific results controle stressor W64-Bac. coagulans W53-B. animalis W23-B. bifidum W28-B. bifidum W119-B. bifidum W25-B. breve W125-B. infantis W51-B. lactis W52-B. lactis W108-B. longum W54-E. faecium W74-L. acidophilus W22-L. acidophilus W37-L. acidophilus W55-L. acidophilus W70-L. acidophilus W63-L. brevis W78-L. brevis W20-L. casei W56-L. casei W79-L. casei W129-L. fermentum W21-L. plantarum W62-L. plantarum W71-L. rhamnosus W24-L. salivarius W57-L. salivarius W19-Lc. lactis W58-Lc. lactis W122-S. salivarius Stressor + strain PAGE 16 % TEER
17 Selecting strains for probiotic Direct effects of probiotics: TEER assay (trans-epithelial electrical resistance) Indirect effects of probiotics: Mast cell activation PAGE 17
18 Indirect effects mast cells Mast cells Present in all layers of the GI tract, predominantly in the lamina propria Respond to different stimuli (antigens, toxins, neurotransmitters) Release a wide variety of bioactive mediators which are able to influence the gut barrier PAGE 18
19 Mast cells affects gut permeability De Winter et al PAGE 19
20 Effects of bacterial strains on mast-cell activation PAGE 20
21 Selecting strains for probiotic Direct effects of probiotics: TEER assay (trans-epithelial electrical resistance) Indirect effects of probiotics: Mast cell activation Promotion IL-10 PAGE 21
22 Stimulation IL-10 production Interleukin-10 is an anti-inflammatory protein IL-10 has a positive influence on the gut barrier function PAGE 22
23 Production of IL-10 by PBMCs PAGE 23
24 Selecting strains for probiotic Direct effects of probiotics: TEER assay (trans-epithelial electrical resistance) Indirect effects of probiotics: Mast cell activation Promotion IL-10 Breakdown LPS PAGE 24
25 Breakdown LPS PAGE 25
26 Breakdown LPS Alkaline phosphatase (AP) Bacteria have similar enzymes Activity can be measured in vitro PAGE 26
27 Strain variation in AP activity W19 Lc lactis W20 L. casei W21 L. plantarum W22 L. acidophilus W23 B. bifidum W24 L. salivarius W25 B. breve W28 B. bifidum W29 B. breve W36 L. acidophilus W37 L. acidophilus W51 B. lactis W51 B. lactis W52 B. infantis W53 B. animalis W54 E. faecium W55 L. acidophilus W56 L. casei W57 L. salivarius W58 Lc lactis units afos per 2E+9 cfu W59 L. plantarum W60 L. helveticus W62 L. plantarum W63 L. brevis W65 L. rhamnosus W70 L. acidophilus W71 L. rhamnosus W71 L. rhamnosus W72/20 L. paracasei W74 L. acidophilus PAGE 27
28 Selecting strains for probiotic Strains Ecologic Barrier TEER Mast cell activation IL-10 stimulation alkaline phos. activity Bifidobacterium bifidum W23 X X X X Bifidobacterium lactis W52 X X X Lactobacillus acidophilus W37 X X Lactobacillus brevis W63 X Lactobacillus casei W56 X X Lactobacillus salivarius W24 X X Lactococcus lactis W19 X Lactococcus lactis W58 X PAGE 28
29 Clinical trial Probiotics & Migraine Cooperation between Winclove and Hospital De Gelderse Vallei in Ede, the Netherlands Pilot study; open label (n=27) What is the effect of the daily intake of a multispecies probiotic product (Ecologic Barrier): - on the frequency of migraine attacks - on intensity of migraine attacks PAGE 29
30 Clinical trial Probiotics & Migraine Inclusion criteria: 4 migraine days per month Stable pattern of attacks Exclusion criteria: Chronic headache Medicine dependent headache Use of antibiotics Use of (other) probiotics PAGE 30
31 Clinical trial Probiotics & Migraine Intake of the multi-species probiotic product; daily during 12 weeks Visit at the hospital every 4 weeks Questionnaire at time T=0 and T=12 weeks Headache diaries PAGE 31
32 Positive effect on migraine days Results can not be shared due to the submission of the publication PAGE 32
33 Positive effect on pain intensity Results can not be shared due to the submission of the publication PAGE 33
34 Use of medication (pain killers) Results can not be shared due to the submission of the publication PAGE 34
35 Intestinal complaints Stool problems? Stomach ache? Bloating? Diarhea? Obstipation? Results can not be shared due to the submission of the publication PAGE 35
36 Follow up study Measuring gut permeability in migraine patients and healthy volunteers (currently ongoing) Placebo controlled trial with 80 people plan to start soon Measuring intestinal permeability, calprotectin, zonulin, questionaire migraine complaints The pilot study has been submitted for publication by Saskia van Hemert, et al; Migraine and the gut: linked by increased intestinal permeability? Review of the literature Ecologic Barrier is distributed by EU Bio Tek as NDS Probiotic Barrier PAGE 36
37 Other study probiotics & migraine Probiotic product containing: L.acidophilus, L.bulgaricus, E.faecium, B.bifidum, and several vitamins, minerals and herbal ingredients 40 migraine patients were included Quality of life - (Medical Outcomes Trust Migraine Specific Quality of Life (MSQ) Questionnaire). MQS at start: 38 MQS after 90 days of probiotic intake: 76 >50% free of migraine attacks Sensenig J, Johnson M, Staverosky T. Treatment of migraine with targeted nutrition focused on improved assimilation and elimination. Altern Med Rev. 2001;6: PAGE 37
38 Summary Migraine seems to be related to gut permeability Gut permeability increases LPS leakage, which causes inflammation Inflammation causes migraine and medication increases gut permeability Probiotics may increase barrier funtion and break the circle Two pilot studies have shown promising results for probiotics in migraine More research is needed. PAGE 38
39 TAKK OG FARVEL! EU Bio Tek is Norwegian distribitor for Ecologic Barrier
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