Transcription
Dr. Malav Trivedi
Farmacology: Food-derived opioidpeptides in AutismMALAV S. TRIVEDI, PHDNOVA SOUTHEASTERN UNIVERSITYCOI: FINANCIAL INTEREST IN A2MC .
Farm PharmWheatMilk
Similar to its name as a SPECTRUM disorder, there are a SPECTRUM of treatmentapproaches employed by parents and support groups.Treatment does involve replenishing the redox status via supplements like:Problem:- GSH (Chapman, 2006),- B12 vitamin,- Secretin,- Folic Acid,However, one of the frequently suggested treatment is a dietary intervention;- Glutenfree/ Casein free (GF/CF)
ASD support groups and patients propagate the importance of GFCF diet,with supporting anecdotal evidenceAround 6 clinical trials are conducted andmixed results are reported in absence of amechanistic explanation of the use ofthese peptides.
Whey in milk: Natural source of Cysteine; Precursor forGlutathione productionWhey proteinDigestedAbsorbed* 2 molecules of cysteine linked togetherCystine*GutCarried in blood to cells as cystine, oferrin: Rich in Cys
Inter-organ transport of cysteine through EAAT3
CysteineinBrainVit B12Vit B6
This is about WheyWhat about the Curds? Casein Variants?
Casein is the most prominent protein in milkComposition of Beta-CaseinComposition of MilkWhey5%kappa13%Lactose37%Caseins21%Fat31%beta (A2, A1,B, C, A3)39%alpha48%
A2 is the original beta-casein protein
Casein-derived Opioid peptidesProvides kink to the structureof bBCM-7MorphineA1-derived BCM-7
Gluten and Casein Derived peptides
pH 1GLUTEN / CASEINEnzymesGliadinomorphin-7 (GM-7)Beta casomorphin- 7(BCM7)pH 7Secretin stimulates the pancreasto release bicarbonate intothe small intestine, causingthe pH to rise to about 7,inhibiting pepsin activity andstopping further BCM7 formation;Terminal ileum site of cysteine uptake by EAAT3 as well asVitamin B12 absorption; a common location for GI inflammation,which can interfere with both.
Cell culture Studies
SH-SY5YNeuronalCaco2 cells14MobBhBGMSAM / SAH Ratio1210*8******64**20Control0.54.024T ime (Hours)GM-7 and BCM7 inhibits cysteine uptake decreasesantioxidant status inTrivedi, M.S et al (2014, J Nutri Bioch)brain cells and in gut epithelial cells.
Beta Casein Variants and Glutathione Production
BCM-7 induces epigenetic changes in genesresponsible for inflammatory signaling
Pre-Clinical Studies
Pre-clinical studiesA1- dietBreeding with same dietexposed animalsAnd MeasuredF1generation1. Redox status2. Epigenetic status20 wk 10 wk1.Liver,2. Brain3. Gut tissuesF0generationAt each of these timepoints, we Isolated20 wk 10 wkNOD mice (Males Females; N 6 atleast in each group)A1- dietA2-dietBreeding with same dietexposed animalsA1- dietTrivedi et. al; PlosOne, Under Review
Mice Data: GSH Levels in Gut TissueGlutathione Levels in Gut tissueF0 and F1 generationN 6F0 generation40F1 generation35p 0.001p 0.05p 0.05p 0.0530GSH/GSSG ratiosGSH/GSSG ratios2520151050A1A2A110 weeksA220 weeksMalesA1A2A110 weeksA220 weeksFemalesA110 weeksA2A1A220 weeksMalesA110 weeksA2A1FemalesA220 weeks
Mice Data: GSH Levels in Brain TissueGlutathione Levels in Brain tissueF0 and F1 generationN 10F0 generation150F1 generation150p 0.01p 0.01p 0.001p 0.01p 0.01100100GSH/GSSG ratios125GSH/GSSG ratios1257550p 0.01p 0.00120 weeks10 weeks75502525010 weeks20 weeksMales10 weeks20 weeksFemales010 weeksMales20 weeksFemales
ConclusionMice Data: GSH LevelsA2 beta-casein containing diet elevates the GSH levels as compared to A1.And it promotes GSH homeostasis all across the body in different brain regionsIt might be a transgenerational phenomenon- involvement of epigenetics – still underinvestigation
Clinical Study
Human Clinical Trial Study DesignClinicaltrials.gov: NCT02406469
A2 beta casein from dairy maximizes GSH6Median GSH Levels(nmol/mL)Median GSH Levels(nmol/mL)6543210BLA2Phase 1BLwoA1/A2Phase 2543210BLA1/A2A2Phase 1BLA2A1/A2BLBLwowo Phase 2SequenceNA1/A2A1/A2BLBLA2A2PhasePhase1 1wowoPhasePhase2 2WilcoxonExpectedStandardrank sumunder H0deviationMean scoreBLA1/A2Phase 1BLwo PhP-valueunder ross-over0.00580.81341Nutrition Journal, Under Review
Conclusions: A1-beta casein derived BCM-7 interferes withcysteine uptake, GI, Brain. Altered glutathione homeostasis through outthe body including neuronal and gut tissues. And in subset of individuals can contributetowards elevated oxidative stress withepigenetic consequences.Cysteineµ-opioid receptorEAAT3 Similarly GM7 derived from wheat can inducesimilar changes as well .CysteineCellSignaling Seeking funding to conduct pre clinical andclinical studies for GM-7DNARepairGSHCelldivisionNeuronal orGut Epithelial hesisGlutenderivedGM-7
Summary:GF/CF dietary intervention
Acknowledgements Northeastern University Dr. Deth Dr. David Janero Dr. Joelle Carlo- Mt. Sinai- Dr. Akhbarian- Wakeforest University- Dr. Stephen Walker- Harvard School of Public Health- Dr. Andrea Baccarelli- SPRIM Research group- Charlie- JiayiEx-Lab Members Jayni Shah Dr. Nate HodgsonYiting ZhangStephanie TranSara Al MughairyVineeth NairDr. Christina MuratoreDr. Girish ChopdaJorge Benzecry Funding agencies NIH NIDA Autism Research Institute The A2 Milk Company
Thank you for your attention!
Subtle Cognitive Impairment Test- Faster response time is better
Dr. Deth Dr. David Janero Dr. Joelle Carlo Ex-Lab Members Jayni Shah Dr. Nate Hodgson Yiting Zhang Stephanie Tran Sara Al Mughairy Vineeth Nair Dr. Christina Muratore Dr. Girish Chopda Jorge Benzecry Funding agencies NIH NIDA Autism Research Institute The A2 Milk Company - Mt. Sinai - Dr. Akhbarian - Wakeforest University
