Promjene mikrobiote u postmenopauzi Doc.dr.sc. Donatella Verbanac
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1 Promjene mikrobiote u postmenopauzi Doc.dr.sc. Donatella Verbanac Mihaela Perić, Hana Čipčić Paljetak, Mario Matijašić, Marina Panek, Ana Kunović, Darija Vranešić i Željko Krznarić Odjel za međustaničnu komunikaciju Centar za translacijska i klinička istraživanja Sveučilište u Zagrebu Medicinski fakultet i Klinički bolnički centar Zagreb Zagreb,
2 Mikrobiota je naš organ The international MetaHIT (Metagenomics of the Human Intestinal Tract) project has published a gene catalogue of the human gut microbiome derived from 124 healthy, overweight and obese human adults, as well as inflammatory disease patients, from Denmark and Spain. The data provide the first insights into this gene set - over 150 times larger than the human gene complement - and permit the definition of both a minimal gut metagenome and a minimal gut bacterial genome. Project Coordinator Prof. S.D. Ehrlich Nature, 2011 Mi smo zdravi kad smo sastavljeni od: 10% ljudskih stanica i 90% bakterijskih stanica
3 Simulacije probavnog trakta Manchester, Museum of Science & Industry, July, 29th,2016: Cravings does your food control you?
4 Uloga mikrobiote Zaštitna Otklanja patogene bakterije Kompeticija za hranjiva Kompeticija za receptore Lučenje antimikrobnih čimbenika Strukturna Prirodna granica Tight junctions među stanicama epitela Razvoj imunog sustava Sinteza IgA Metabolička Sinteza kratko-lančanih MK Metabolizam UH iz hrane Sinteza vitamina K, folne kiseline i biotina Apsorpcija Fe 2++ Mowat and Agace, Nat.rev. Immunol. 2014
5 Metode istraživanja mikrobiote Filogenetska analiza Sekvenciranje gena za 16S rrna Sastav, relativna zastupljenost Metagenomika Sekvenciranje genomske DNA Analiza setova gena funkcionalna metagenomika Filogenetski odnosi Metatranskriptomika Analiza cjelokupne mrna, uvid u diferencijalnu ekspresiju gena Metaproteomika Analiza ukupnih proteina različita ekspresija ovisno o uvjetima Metabolomika Profiliranje metabolizma domaćina i mikrobiote Lepage, P., Gut, 2013
6 Usvajanje mikrobiote novorođenčad Reid, Nature Rev Microbiol, 2011
7 Razvoj mikrobiote u najranijoj dobi majčino mlijeko groznica rižine pahuljice dohrana i kruta hrana amoksicilin cefdinir, kravlje mlijeko i prehrana odraslih Prestanak dojenja i dohrane Čimbenici koji moduliraju crijevnu mikrobiotu kod novorođenčadi POZITIVNI vaginalni porod terminski porod dojenje izlaganje mikroorganizmima NEGATIVNI INTERVENCIJE porod na carski rez probiotici od rođenja terapija antibioticima vaginalni brisevi dohrana prijevremeni porod Koenig PNAS 108, (2011) ; Dominguez-Bello Nature Medicine (2016)
8 Poremećaj u ravnoteži crijevne mikrobiote disbioza Kronična upala - vodi do nastanka kroničnih metaboličkih bolesti Matijašić et al, Int. J. Mol. Sci. 2016, 17, 578
9 Bolesti povezane s promjenom mikrobiote Odnos crijevo-mozak 1. Autizam 2. Raspoloženje 3. Parkinsonova bolest Astma Atopičke bolesti Hipertenzija Ishemija srca HIV Nekrotizirajući enterokolitis Karcinom debelog crijeva Celijakija Intolerancije Žučne bolesti Reumatoidni artritis Promijenjen metabolizam ksenobiotika/lijekova Bolesti perifernih žila Pretilost Metabolički sindrom Dijabetes Približno trećina malih metabolita koji cirkuliraju u našem tijelu izravni su produkti nastali pod utjecajem crijevne mikrobiote. IBD Iritabilini kolon Gastroenteritis Modificirano prema Sanders ME, J Clin Gastroenterol 45 (2011) Conlon and Bird,Nutrients 2015, 7, 17-44
10 Probiotici Živi mikroorganizmi s pozitivnim utjecajem na ravnotežu u crijevu Lactobacillus, Bifidobacterium, Bacillus Mijenjaju metabolizam: Lipida, ugljikohidrata, kolesterola, makro i mikro nutrijenata, te reguliraju tjelesnu masu
11 Nerazgradive sastavnice hrane - potiču rast i/ili aktivnost povoljnih crijevnih bakterija Polioli ksilitol, sorbitol, manitol Disaharidi laktuloza, laktitol Oligosaharidi rafinoza iz soje, oligofruktoze, galakto-oligosaharidi, Ostali nerazgradivi poli- i oligosaharidi palatinoza, laktosaharoza Namirnice/jela: kuhani krumpir; svježi voćni sokovi iz bobičastog voća Polisaharidi inulin, škrob otporan na glikolitičke enzime Oligosaharidi majčinog mlijeka Sinbiotici sinergističke mješavine probiotika i prebiotika Prebiotici de Vrese, Menopause Int Mar;15(1):35-4
12 Novije istraživanja SPOLNI HORMONI I MENOPAUZA SPECIFIČNI ASPEKTI MIKROBIOTE
13 Naš metabolizam pod utjecajem je središnjeg živčanog sustava, ali i
14 Promjena sastava mikrobiote u pretilosti i posljedičnim bolestima Istraživanja su pokazala da se udio bakterija u crijevu mijenja promjenom životnog stila: Povećanje Bacteroidetes i smanjenje Firmicutes mršavljenjem (Nadal, 2008) Kod pretile djece više Firmicutes (Kalliomaki 2008) Smanjenje Firmicutes nakon barijatričke kirurgije i mršavljenja (Zhang, 2009), te povećanje Bacteroides/Prevotella (Furet, 2010) Mikrobiom posjeduje nižu raznolikost, primjeri Pretilost (Greenblum, 2012) Upalne bolesti crijeva (Ananthakrishnan, 2015) Hipertenzija (Yang, 2015) Omjer Firmicutes vs. Bacteroidetes (F/B ratio) Potencijalni biomarker patoloških promjena (Sanz, 2014) Bacteroidetes Debljanje Bacteroidetes Druge bakterije Firmicutes Mršavljenje Druge bakterije Firmicutes Tsukumo, 2009
15 Estradiol i prehrana vs. mikrobiota crijeva u OVX mišica 16 OVX mišica C57BL6 8 OVX (50 ug 17 estardiol) 8 OVX (uljna otopina - kontrola) Ex Uravnotežena dijeta Dijeta bogata mastima Dan 0 Dan 10 Dan 35 Praćena tjelesna masa i skupljani su uzorci fecesa Rezultat: 8 OVX (uljna otopina - kontrola) Tjelesna masa uvećana 30% Firmicutes : Bacterioidetes 8 OVX (50 ug 17 estardiol) Tjelesna masa održana Firmicutes: Bacterioidetes STABILAN Ram et al., Endocrine Reviews, Vol. 36, 2, 2015
16 Prva studija te vrste provedena na na ljudima Suplementacije hrane s hormonski djelujućim tvarima (izoflavonima) i funkcionalnom hranom Promjene u različitosti i sastavu dominantnih bakterija u crijevima. J. Nutr. 135: , 2005.
17 Izoflavoni soje Elisabetta Poluzzi et al., Phytoestrogens in Postmenopause: Current Medicinal Chemistry, 2014
18 Međuodnos mikrobiote crijeva i Endogeni i egzogeni estrogeni i njima slični spojevi bivaju metabolizirani podu utjecajem crijevnih bakterija estrogena glycitin daidzein genistein Nastali metaboliti djeluju pozitivno na metabolizam domaćina i smanjuju rizik obolijevanja od pojedinih bolesti Mikrobiota crijeva kao potencijalni biomerker pri vrednovanju i/ili u prevenciji bolesti izazvanih estrogenima equol desmethylangolensin Chen and Madak-Erdogan; Trends in Endocrinology & Metabolism, Nov 2016
19 Promjene u vaginalnoj sluznici u različitim fazama u životu žene Microbiota zastupljena s Lactobacilus sp. - visoke razine estorogena Održavanje lagano kiselog ph sluznice - metabolizam glikogena - glukoze - laktata Petrova et al, FEMS Microbiol Rev 37 (2013)
20 Pregledni rad
21 Kliničke studije koje ukazuju na korist od uzimanja probiotika Probiotik Način korištenja Učinak L. rhamnosus, B. animalis Oralni probiotik/1x, 256 trudnica, 1 tromj. Smanjenje gastacijskog dijabetesa L. rhamnosus Oralni dodatak probiotika, 6-mjesečne bebe B. longum, B. animalis, L. acidophillus Oralni probiotik, trudnice/dojilje/dojenčad1-2 mj. prije i 6 mj. nakon poroda Povećanje otpornosti na perturbacije mikrobiote i prerastanje patogena, sprječavanje alergijskih bolesti Smanjena učestalost ekcema kod novorođenčadi L. rhamnosus, L. reuteri 5 dana/1x/vaginalete Veća uspješnost izlječenja bakterijske vaginoze nego s metronidazolom Reid Nature Rev Microbiol 2011
22 Intervencija probioticima- Intervencija primjer probioticima hipertenzija - primjer hipertenzija Meta-analiza d 9 randomiziranih studija koje su pratile utjecaj intervencije probioticima na krvni tlak Značajno smanjenje sistoličkog krvnog tlaka uočeno je u pacijenata koji su unosili dnevno 10 9 CFU probiotika Mogući mehanizmi djelovanja Modulacija lipidograma (Gou, 2011) Djelovanje na renin angiotensin; inhibicija angiotenzin konvertirajućeg enzima preko tripeptida VPP i/ili IPP (Ong, 2008) Apsorpcija bioloških tvari i fitoestrogena iz s vazodilatacijskim svojstvima (Lye, 2009) Modulacija metabolizma glukoze, smanjenje pretilosti i upale općenito (Valentini, 2014) Hypertension, 2014
23 Journal of Bone and Mineral Research, Vol. 27, No. 6, June 2012, pp Trends Endocrinol Metab Feb;26(2):69-74.
24 Mogući mehanizam djelovanja Mikrobiota crijeva (MC) jedan je od predloženih regulatora koštane mase Nedavna istraživanja na germfree miševima to potvrđuju Međuodnos je posredovan imunološkim sustavom odgovornim za regulaciju osteoklastogeneze Dodatno se istražuje metabolizam kalcija i setotonina sintetiziranog u crijevima Prehrana i okolišni čimbenici utječu na sastav MC. Intervencijska istraživanja autora pokazala su da antibiotici, probiotici i prebiotic koji mijenjaju MC, reguliraju i metabolizam kosti Autori zagovaraju istraživanja MC novi pristup u iznalaženju terapijskih opcija za osteoporozu Claes Ohlsson i Klara Sjögren (2015)
25 Projektni tim MINUTE for IBD Assessment of Microbiota, Inflammatory Markers, Nutritional and Endocrinological Status in IBD Patients - HRZZ Medicinski fakultet SuZ- Mihaela Perić, Mario Matijašić, Hana Čipčić Paljetak, Marina Panek, Vera Kufner, Donatella Verbanac Imperial College London, UK - Anja Barešić KBC Zagreb - Željko Krznarić, Silvija Čuković Čavka, Darija Vranešić Bender, Marko Brinar, Mirjana Kalauz, Dora Grgić, Nikša Turk, Ivana Kraljević, Dunja Rogić, Dina Ljubas Kelečić, Ana Kunović KB Dubrava - Marija Crnčević Urek, Marko Banić Poliklinika Dr. Zora Profozić Tomislav Meštrović Fidelta d.o.o. - Karmen Brajša Xellia Pharmaceuticals - Gabrijela Ergović
26 HVALA NA PAŽNJI
27
28 TRANSLACIJSKA ISTRAŽIVANJA DOI: /HYPERTENSIONAHA životinjski modeli pacijenti Mikrobiota crijeva u Wistar Kyoto (WKY) štakora i u spontano hipertenzivnih životinja (SHRs). Smanjenje raznolikosti mikrobiote u pacijenata s hipertenzijom (n=7) u odnosu na kontrolnu skupinu (n=10)
29 Intervencija antibiotikom - primjer hipertenzija Minociklin smanjuje angiotenzinom II izazvanu hipertenziju Sastav mikrobiote fecesa razlikovao se nakon tretmana s antibiotikom Yang, 2015
30 Prehrana općenito modulira metabolizam Međudjelovanje prehrane i mikrobiote utječe na metabolizam domaćina Kovatcheva-Datchary, 2013
31 Astronautski programi Manchester, Museum of Science & Industry, July, 29th,2016: Cravings does your food control you?
32 Intervencije u sastav mikrobiote Fekalna transplantacija Manchester, Museum of Science & Industry, July, 29th,2016: Cravings does your food control you?
33 2014. Značajni projekti
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