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La Medic ina nel l ’era del Microbiota
Come le recenti conoscenze sul microbiota sconvolgono i concetti
della medicina e della nutrizione.
Paolo Mainardi
Funzioni fisiologiche, es.:
• Pressione sanguigna (Yang T, Zubcevic J. Gut-Brain Axis in Regulation of Blood Pressure.
Front Physiol. 2017 Oct 25;8:845).
• Colesterolemia (Gérard P. Metabolism of cholesterol and bile acids by the gut microbiota.
Pathogens. 2013 Dec 30;3(1):14-24.)
• Funzioni cardiache (Luedde M, Winkler T, Heinsen FA, Rühlemann MC, Spehlmann ME,
Bajrovic A, Lieb W, Franke A, Ott SJ, Frey N. Heart failure is associated with depletion of
coreintestinal microbiota. ESC Heart Fail. 2017 Aug;4(3):282-290)
• Funzioni renali (Jiang S, Xie S, Lv D, Wang P, He H, Zhang T, Zhou Y, Lin Q, Zhou H, Jiang J,Nie
J, Hou F, Chen Y. Alteration of the gut microbiota in Chinese population with chronic kidney disease.
Sci Rep. 2017 Jun 6;7(1):287)0
• Sistema Neuroendocrino (Farzi A, Fröhlich EE, Holzer P. Gut Microbiota and the
Neuroendocrine System. Neurotherapeutics. 2018 Jan;15(1):5-22)
• …
Allo stesso modo con cui noi teniamo pulita e efficiente la nostra casa
Microbiota intestinale:
Ago della bilancia tra salute e malattia.
Feng Q, Chen W-D and Wang Y-D (2018) Gut Microbiota: An Integral Moderator in Health and Disease. Front. Microbiol. 9:151
2018: 4573 articles on pubmed
Paolo Mainardi
Taste receptors to produce anticipatory response to foods or pathogens.
• They recognize food
• Memorized it
• To produce fast response
✓ The main role of digestive system is to
protect gut ecosystem
✓ By the food we can talk with microbiota
✓ Food information goes beyond thenutritional aspect
Let the food to be the medicine and the medicine to be the food.
Hippocrates
La loro scoperta rivoluziona i concetti della nutrizione.
When are stimulated by bitter compounds, such as
nicotine or quinine, the cilia waved back and forth
vigorously, helping to clear the airways of irritating
compounds
Taste receptors response to bitter-tasting compunds in airway
Bitter receptors are also found on cilia on
human airway epithelium cells
“they stop breathing,
they cough and sneeze,”
This response is to stop the irritant from being inhaled deep into the lungs
Microbiota alters taste receptors
• Germ-free mice had altered TRs for fat on tongues and on intestine.(Duca FA et al. 2012 Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota. PLoS ONE 7:
e39748)
• Germ-free mice preferred more sweets, have more sweet TRs in gut vs normal
mice.(Swartz T et al. 2012 Up-regulation of intestinal type 1 taste receptor 3 and sodium glucose luminal transporter-1 expression and
increased sucrose intake on mice lacking microbiota. Br J Nutr 107:621)
Microbiota alters taste receptors
• Germ-free mice had altered TRs for fat on tongues and on intestine.(Duca FA et al. 2012 Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota. PLoS ONE 7:
e39748)
• Germ-free mice preferred more sweets, have more sweet TRs in gut vs normal
mice.(Swartz T et al. 2012 Up-regulation of intestinal type 1 taste receptor 3 and sodium glucose luminal transporter-1 expression and
increased sucrose intake on mice lacking microbiota. Br J Nutr 107:621)
• Gastric bypass surgery modifies TR, change microbiota and alters satiety and
food preferences.(Miras AD, Ie Roux CW. 2013 Mechanisms underlying weight loss after bariatic surgery. Nat Rev Gastroenterol Hepatol 10:)575-84
Microbes could influence food preferences by altering receptor expression or transduction
Microbiota alters taste receptors
• Germ-free mice had altered TRs for fat on tongues and on intestine.(Duca FA et al. 2012 Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota. PLoS ONE 7:
e39748)
• Germ-free mice preferred more sweets, have more sweet TRs in gut vs normal
mice.(Swartz T et al. 2012 Up-regulation of intestinal type 1 taste receptor 3 and sodium glucose luminal transporter-1 expression and
increased sucrose intake on mice lacking microbiota. Br J Nutr 107:621)
• Gastric bypass surgery modifies TR, change microbiota and alters satiety and
food preferences.(Miras AD, Ie Roux CW. 2013 Mechanisms underlying weight loss after bariatic surgery. Nat Rev Gastroenterol Hepatol 10:)575-84
Microbes could influence food preferences by altering receptor expression or transduction
Allergie/Intolleranze= reazioni paradosso dei recettori del gusto
NON DIPENDONO DAL CIBO MA DA UNA RISPOSTA SBAGLIATA
Influenza selettiva del microbiota sulla dieta:
Wu GD, Chen J, Hoffmann C, et al. Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes. Science (New York, N.y). 2011;334(6052):105-108. doi:10.1126/science.1208344.
CarboidratiPrevotella
FibreBifidobacteria
Alcuni grassiBacteroidetes
Topi privati dei TLR5 diventano obesi anche se a dieta standard.
Paolo Mainardi
Un’insalata, per favore
Per noi cheeseburger
e patatine
Controllano la trasformazione del cibo in energia
Queipo-Ortuño MI, Seoane LM, Murri M, et al. Gut Microbiota Composition in Male Rat Models under Different NutritionalStatus and Physical Activity and Its Association with Serum Leptin and Ghrelin Levels. Sanz Y, ed. PLoS ONE. 2013;8(5):e65465.
Gut Microbiota modifies Serum Leptin and Ghrelin Levels
Wu GD, Chen J, Hoffmann C, et al. Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes. Science (New York, N.y). 2011;334(6052):105-108. doi:10.1126/science.1208344.
Attraverso i recettori del gusto:
Taste receptors response to carbohydrates and proteins
T1R3 receptors secrete ghrelin, encouraging eating
when important nutrients are available .
The sweet receptor on L cells produce the gastrointestinal
incretin hormone GLP-1, which stimulates insulin
production and sends a satiety signal to the brain
Jang,H.J.etal.Proc.NatlAcad.Sci.USA104, 15069–15074 (2007).
Margolskee, R. F. et al. Proc. Natl Acad. Sci. USA 104, 15075–15080 (2007).
Ci incoraggiano a mangiare se c’è cibo “buono” (Proteine e carboidrati),
ma se ingeriamo carboidrati indigeribili, questi, poi, ci danno senso di sazietà.
Taste receptors response bitter-tasting compunds
Initially, T1R3 receptors secrete ghrelin,
encouraging eating when important nutrients are
available .
This curbs the appetite by prolonging the sense of fullness
and satiety — perhaps to prevent the ingestion of toxic food.
Margolskee, R. F. et al. Proc. Natl Acad. Sci. USA 104, 15075–15080 (2007).
But after 30 minutes, food intake decreased, as
did gastric emptying, keeping the food in the
stomach
The Romans drank wine infused with bitter herbs to prime the appetite and preventover-eating.
Taste receptors response bitter-tasting compunds
Initially, T1R3 receptors secrete ghrelin,
encouraging eating when important nutrients are
available .
This curbs the appetite by prolonging the sense of fullness
and satiety — perhaps to prevent the ingestion of toxic food.
Margolskee, R. F. et al. Proc. Natl Acad. Sci. USA 104, 15075–15080 (2007).
But after 30 minutes, food intake decreased,
as did gastric emptying, keeping the food in
the stomach
The Romans drank wine infused with bitter herbs to prime the appetite and preventover-eating.
Ippocrate consigliava a chi proprio non aveva voglia di
mangiare un medicinale di sua invenzione, il vinum
ippocraticum, vino bianco dolce, speziato con macerati di
dittamo, assenzio e ruta.
Un vino che i romani, per migliorarne il sapore amarognolo,
mischiarono con rosmarino e salvia. E che chiamarono,
pertanto, vinum absinthiatum.
When are stimulated by bitter compounds,
such as nicotine or quinine, the cilia waved back and
forth vigorously, helping to clear the airways of
irritating compounds
Taste receptors response to bitter-tasting compunds in airway
Bitter receptors are also found on cilia on
human airway epithelium cells
“they stop breathing,
they cough and sneeze,”
This response is to stop the irritant from being inhaled deep into the lungs
Urinary metabolites in Chocolate indifferent and Chocolate desidering
Rezzi S, et al. Human metabolic phenotypes link directly to specific dietary preferences in healthy individuals. J Proteome Res. 2007 Nov;6(11):4469-77.
Microbiota dei golosi diverso da quello dei non golosi
Oggi non ha più senso:
- Parlare di calorie
- Dividere il cibo in grassi, carboidrati, e proteine.
• Quali grassi?
• Quali Proteine?
• Quali carboidrati?
Pasquaretta, C.; Gómez-Moracho, T.; Heeb, P.; Lihoreau, M. Exploring Interactions between the Gut Microbiota and Social Behaviorthrough Nutrition. Genes 2018, 9, 534.
- Comportamento alimentare
- Comportamento sociale
- Comportamento sessuale
Processi infiammatori per riparare i tessuti
Paolo Mainardi
Il microbiota controlla ANCHE la risposta infiammatoria
Andreasen AS, Krabbe KS, Krogh-Madsen R, Taudorf S, Pedersen BK, Møller K. Human Endotoxemia as a model of systemicinflammation. Curr Med Chem. 2008;15(17):1697-705.
CASCATA INFIAMMATORIA:
• Le pro-infiammatorie producono necrosi
• Le anti-infiammatorie ricostruiscono i tessuti
Nel sistema nervoso centrale:
• Le pro-infiammatorie inibiscono i processi di sinaptogenesi e neurogenesi,
• Le anti-infiammatorie attivano i processi di sinaptogenesi e neuogenesi
Microbiota intestinale e Neurosviluppo Fondazione Domus Angelorum - Onlus
Paolo Mainardi
Danno Tissutale
Vasta demolizione
Ricostruzione
Paolo Mainardi
Risposta infiammatoria acuta o cronica
Demoliscono Abili aricostruire
Inabili aricostruire
Hang Ch et al, Intestinal mucosa structure after TBI. World J Gastroenterol 2003,9 (12) 2776-2781
Prima trauma cranico
3 giorni dopo trauma cranico
3 giorni dopo Trauma Cranico collassa la membrana intestinale
Brain
GutIntestinal mucosa
Paolo Mainardi
IL-6 elevation in the brain is involved in the mediation of autism-like behaviors through impairments of neuroanatomical
structures and neuronal plasticity
Wei H, Alberts I, Li X. Brain IL-6 and autism. Neuroscience. 2013 Nov 12;252:320-5.
Brain
Gut
Paolo Mainardi
• Danni neuroanatomici strutturali
• Riduce la neuroplasticità
23
Paolo Mainardi
24
• Le citochine INABILI non consentono una
corretta rigenerazione cellulare.
(degenerazione)
Paolo Mainardi
25
• Le citochine INABILI non consentono una
corretta rigenerazione cellulare.
(degenerazione)
Paolo Mainardi
Patologie autoimmuni: (sistema immunitario impazzito?)
Linfociti T: prodotti casualmente, eliminati il 97% per apoptosi
Linfociti B: le citochine controllano la tolleranza.
Autoanticorpi= cacciatori nella caccia di selezione nei parchi naturali
26
• Le citochine INABILI non consentono una
corretta rigenerazione cellulare.
(degenerazione)
Paolo Mainardi
- Cytokines participate in neuronal development in brain functioning. Inappropriate activity can produce
different neurological symptomsGoines PE, Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol Teratol.
2013 Mar-Apr;36:67-81.
• Citochine partecipano al neurosviluppo
Metabolic changes during pregnancy:
- Same nutritional intake
- Increased energy extraction by foods:
• the microbiota undergoes profound changes in T3 vs T1
• It is not due to nourish the fetus, but to realize his tissues by anti-
inflammatory citokines
No-problems
Houston, we have a problem!
Stig Bengmark, Acute and ‘‘chronic’’ phase reaction - a mother of disease. Clinical Nutrition (2004) 23, 1256–1266
• Poi, nei primi 1000 giorni di vita, il microbiota si evolve aumenta la biodiversità dei
ceppi
• Nei primi giorni di vita fetale è stato campionato una piccola quantità di ceppi
batterici (simbionti permanenti)
Paolo Mainardi
Insediamento del microbiota, verso un aumento della biodiversità dei ceppi.
???
Jeremy E. Koenig et al. Succession of microbial consortia in the developing infant gut microbiome Proceedings of the National Academy ofSciences Mar 2011, 108 (Supplement 1) 4578-4585;
Febbre
RisoAntibiotic
o
Antibiotico
Antibioticocefalosporina
adulto
Più FORTE
Più DEBOLE
adulto anziano
Invecchiando si torna bambini.
“Fragilità dell’anziano”
Invecchiando si torna bambini.
Vu l n e ra b i l i tà F r a g i l i t à
?
Ridotta diversità ceppi:
• Ridotta capacità di riparare i danni
• Ridotta capacità a rigenerare i tessuti
• Ridotta capacità a scremare linfociti T
• Ridotta capacità a controllare organi
…
Tu questa la chiami vita?
Lo scopo principale del sistema digerente è mantenere ambiente confortevole ai
batteri residenti nel colon, non è quello di nutrirci!!!!!!
Nel corpo umano vivono 100 trilioni di forme di vita microbiche
Pat.
H+Mucin
Mucus
pH=7.0
pH=8.2
“good” Bacteria
“Bad” Bacteria
Gastric Juices, biliary salts
SCFAs:The nutrients of the cells of digestive systemof all mammals
First of all: Nourish
the cells of digestive
system
Protonic pumps
L’intestinonon
nasceimparato
Il distacco del neonato dalla mamma non avviene al taglio del cordone ombelicale.
Il colostro si va a sostituire nella duplice funzione di PROTEGGERE e nutrire
Inoltra INSEGNA al neonato a prodursi gli anticorpi e i fattori di crescita.
• Alla nascita è completamente permeabile e sterile• Prima maturazione con il colostro• Maggiore maturazione con lo svezzamento
L’intestinonon
nasceimparato
Azioni intestinali dell’alfa-lattoalbumina
• gastrite cronica• atrofia gastrica• …
Stomaco
Corpus AntrumDuodeno
Digiuno
Ileo
Colon
gel sol
pH 7pH 5-6
pH 1.2pH 5- 7 pH 1.2
pH 2
pH 7
H+
HCO3-
H2O + CO2
Demolisce cibo eAgenti patogeni
Pompa protonica
muco
Il pH controlla il rapporto tra i ceppi batterici.
Alpha-lactalbumin protects in a
dose-dependent manner from
gastric ulcers induced by alcool or
stress
Hung CR, Cheng JT, Shih CS. Gastric mucosal damage induced by arecoline seizure in rats. Life Sci. 2000 May 5; 66 (24): 2337-49.
- The amount of gastric ulcers depend in a
dose-dependent manner on the amount of
epileptogenic agent injected i.c.v.
Alpha-lactalbumin protects in a
dose-dependent manner from gastric
ulcers induced by alcool or stress
Alpha-lactalbumin increases IL-1ra/IL-1 ratio:
OFF
Reparativeprocesses
ON
Reparativeprocesses
It becomes REALLY INTERESTING to correlate the ability to act on intestinal
inflammation with to control epileptic seizures.
Alpha-lactalbumin increases IL-1ra/IL-1 ratio:
OFF
Reparativeprocesses
ON
Reparativeprocesses
• brings out chronic inflammation,
• Restore endogenous riparative processes
• MORE POWERFUL THAN ANY DRUGS
It becomes REALLY INTERESTING to correlate the ability to act on intestinal
inflammation with to control epileptic seizures.
➢ Bovine milk-derived α-lactalbumin inhibits colon inflammation andcarcinogenesis in azoxymethane and dextran sodium sulfate-treated mice. Yamaguchi M, Takai S, Hosono A, Seki T.. Biosci Biotechnol Biochem.
2014;78(4):672-9.
➢ Anti-inflammatory mechanisms of bioactive milk proteins in theintestine of newborns Chatterton DE, Nguyen DN, Bering SB, Sangild PT.. Int J
Biochem Cell Biol. 2013 Aug;45(8):1730-47.
L’alfa-lattoalbumina esplica azioni SPECIFICHE nel digerente dell’uomo,
in quanto selezionata dalla Natura ad attivarlo dopo la nascita
46
Favale E, Rubino V, Mainardi P, Lunardi G, Albano C. Anticonvulsant effect of fluoxetine in humans. Neurology. 1995Oct;45(10):1926-7.
Lunardi G, Mainardi P, Rubino V, Fracassi M, Pioli F, Cultrera S, Albano C. Tryptophan and epilepsy. Adv Exp Med Biol.1996;398:101-2.
Albano C, Cupello A, Mainardi P, Scarrone S, Favale E. Successful treatment of epilepsy with serotonin reuptake inhibitors:proposed mechanism. Neurochem Res. 2006 Apr;31(4):509-14.
Mainardi P, Leonardi A, Albano C. Potentiation of brain serotonin activity may inhibit seizures, especially in drug-resistantepilepsy. Med Hypotheses. 2008;70(4):876-9.
Mainardi P, Albano C. Is the antiepileptic effect of the ketogenic diet due to ketones? Med Hypotheses. 2008;70(3):536-9.
Striano P, D'Amato E, Pezzella M, Mainardi P, Zara F, Striano S. Sudden death in Unverricht-Lundborg patients: is serotoninthe key? Neurol Sci. 2010 Feb;31(1):115-6.
Citraro R, Scicchitano F, De Fazio S, Raggio R, Mainardi P, Perucca E, De Sarro G, Russo E. Preclinical activity profile of α-lactoalbumin, a whey protein rich in tryptophan, in rodent models of seizures and epilepsy. Epilepsy Res. 2011 Jun;95(1-2):60-9.
Errichiello L, Pezzella M, Santulli L, Striano S, Zara F, Minetti C, Mainardi P, Striano P. A proof-of-concept trial of the wheyprotein alfa-lactalbumin in chronic cortical myoclonus. Mov Disord. 2011 Dec;26(14):2573-5.
Russo E, Scicchitano F, Citraro R, Aiello R, Camastra C, Mainardi P, Chimirri S, Perucca E, Donato G, De Sarro G. Protectiveactivity of α-lactoalbumin (ALAC), a whey protein rich in tryptophan, in rodent models of epileptogenesis. Neuroscience.2012 Dec 13;226:282-8.
Dal ruolo della serotonina cerebrale, allo studio del sistema digerente…
47
Favale E, Rubino V, Mainardi P, Lunardi G, Albano C. Anticonvulsant effect of fluoxetine in humans. Neurology. 1995Oct;45(10):1926-7.
Lunardi G, Mainardi P, Rubino V, Fracassi M, Pioli F, Cultrera S, Albano C. Tryptophan and epilepsy. Adv Exp Med Biol.1996;398:101-2.
Albano C, Cupello A, Mainardi P, Scarrone S, Favale E. Successful treatment of epilepsy with serotonin reuptake inhibitors:proposed mechanism. Neurochem Res. 2006 Apr;31(4):509-14.
Mainardi P, Leonardi A, Albano C. Potentiation of brain serotonin activity may inhibit seizures, especially in drug-resistantepilepsy. Med Hypotheses. 2008;70(4):876-9.
Mainardi P, Albano C. Is the antiepileptic effect of the ketogenic diet due to ketones? Med Hypotheses. 2008;70(3):536-9.
Striano P, D'Amato E, Pezzella M, Mainardi P, Zara F, Striano S. Sudden death in Unverricht-Lundborg patients: is serotoninthe key? Neurol Sci. 2010 Feb;31(1):115-6.
Citraro R, Scicchitano F, De Fazio S, Raggio R, Mainardi P, Perucca E, De Sarro G, Russo E. Preclinical activity profile of α-lactoalbumin, a whey protein rich in tryptophan, in rodent models of seizures and epilepsy. Epilepsy Res. 2011 Jun;95(1-2):60-9.
Errichiello L, Pezzella M, Santulli L, Striano S, Zara F, Minetti C, Mainardi P, Striano P. A proof-of-concept trial of the wheyprotein alfa-lactalbumin in chronic cortical myoclonus. Mov Disord. 2011 Dec;26(14):2573-5.
Russo E, Scicchitano F, Citraro R, Aiello R, Camastra C, Mainardi P, Chimirri S, Perucca E, Donato G, De Sarro G. Protectiveactivity of α-lactoalbumin (ALAC), a whey protein rich in tryptophan, in rodent models of epileptogenesis. Neuroscience.2012 Dec 13;226:282-8.
…alla rivalutazione delle diete del passato…
Mainardi P, Albano C.Is the antiepileptic effect of the ketogenic diet due to ketones?Med Hypotheses. 2008;70(3):536-9.
Dear Paolo,
I actually read your article a few weeks ago and agree. We have one of our researchers, dr
Adam Hartman, investiging KD in a mouse model and he agrees (as do I in my clinical
research) that ketosis is probably over-rates.
Erick Kossoff
L’efficacia della dieta chetogenica non è dovuta alla chetosi
ERICK KOSSOFF
49
La conoscenza del microbiota ci aiuta ad individuare una corretta dieta per la salute
Paolo MainardiCHIMICO
Pasquale StrianoNeurologo-Pediatra
Paolo CartaBIOLOGO
NUTRIZIONISTAEmilio RussoFarmacologo
La ricerca scientifica si basa sulla falsificabilità dei risultati. Karl Popper (1902-1994)
Prof.Emilio Perucca past prresident ILAE Prof. De SarroRettore Magna Grecia Catanzaro
Thanks to these results, ALAC entered in the NIH new drug program screening
Serplus is reported in a Thesis of Master of Nutrition on the
basis of results on autism.
With Dr Tosatto we are planning a clinical study at Dubai
Serplus in autism
The gut brain connection in pediatric migraine: an open label trial.M. Carotenuto et al.
52
Mainardi P, Carta P, Montinari M, Striano P et al. From the Ancient Diets to the RecentAcquisitions on the Role of Brain Inflammation in Epilepsy, Are there Any Links? J NeurolNeurophysiol 2015, 6:3
P.Mainardi, P.Carta, P.Striano. How Knowledge on Microbiota may be Helpful to Establishan Optimal Diet for Health Maintenance. Int J Nutrition, 2018..
Dalle antiche diete al ruolo dell’infiammazione
La conoscenza del microbiota ci aiuta ad individuare una corretta dieta per la salute
Intestinal inflammation is linked to anticonvulsant activity in a mouse model of epilepsy
Prof. Emilio Russo ([email protected]) (University of Catanzaro)
Contributing AuthorsProf. Carmen De Caro , Dr. Antonio Leo , Miss Valentina Nesci , Prof. Carla Ghelardini , Dr.Lorenzo Di Cesare Mannelli , Prof. Pasquale Striano , Dr. Carmen Avagliano , Antonio
Calignano , Dr. Paolo Mainardi , Dr. Rita Citraro , Prof. Giovambattista De Sarro
Nel 2018 a Vienna
Per la prima volta ben 2 sessioni su Gut Brain Axis al congresso europeo dell’ILAE
DSSDSS-ALAC
DSS-BuNa
DSS-VPA
CTR
DSS-MSZ
Intestinal inflammation is linked to anticonvulsant activity in a mouse model
E.Russo, P.Striano, P.Mainardi,…, submitted to Scientific Report (Nature)
FUTURO PROSSIMO:
Studi clinici su:
• Disturbi del sonno (Franzoni, presidente SINP)
• Disturbi del comportamento alimentare (Prof.Franzoni, Bologna, presidente SINP)
• S. Tourette –pandas (Dott. Pavone, Catania)
• Autismo (Dott. Viri, Novara)
• Epilessia (dott. Viri, Novara, Prof .Franzoni, Bologna, Prof. Striano, Genova)
• Cefalee (prof.Carotenuto, Napoli)
• Pre termine (prof.ssa Suppiej, Ferrara)
Verso una nuova medicina:
• Più potente di qualsiasi farmaco
Take – home message:
Cura il microbiota per consentirgli di prendersi cura di te.
• Capace di rispristinare i potenti meccanismi
endogeni di riparazione e di controllo.
2015
www.unamedicina.itwww.protocollorestart.it