Prebiotic Effects: Metabolic and Health Benefits · 2019-07-30 · Weight management and obesity-related disorders ... might improve health status and reduce disease risk. Introduction:

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Bernd Stahl & Marcel Roberfroid

ILSI Europe Prebiotics Task Force

M. Roberfroid,

G. R. Gibson, L. G. R. Gibson, L. HoylesHoyles, A. L. McCartney, R. , A. L. McCartney, R. RastallRastall, , I.RowlandI.Rowland, D. , D. Wolvers, B. Wolvers, B. WatzlWatzl, H. , H. SzajewskaSzajewska, , B. Stahl F. F. GuarnerGuarner, F. , F. RespondekRespondek, K. Whelan, , K. Whelan,

V. V. CoxamCoxam, M, M--J. J. DaviccoDavicco, L. , L. LLééotoingotoing, Y. , Y. WittrantWittrant, N. M. , N. M. DelzenneDelzenne, , PP. D. . D. CaniCani, A. M. , A. M. NeyrinckNeyrinck, A. , A. MeheustMeheust

From Prebiotic Concept to Prebiotic Effects:

Metabolic and Health Benefits

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Which data support the hypothesisWhich data support the hypothesisof a causal relationship betweenof a causal relationship between

a a selective change in gut selective change in gut microbiotamicrobiota compositioncomposition

and and health effects/benefits? health effects/benefits?

Basic questionBasic question:

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Introduction: Introduction: PrebioticPrebiotic concept concept

& &

PrebioticPrebiotic effects on:effects on:

GutGutImmune systemImmune systemPaediatricsPaediatricsGastroGastro--intestinal disordersintestinal disordersMineral metabolismMineral metabolismWeight management and obesityWeight management and obesity--related disordersrelated disorders

Conclusions and perspectivesConclusions and perspectives

CONTENTCONTENT

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& & PrebioticPrebiotic effects effects on:on:



CONTENTCONTENT

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Gut Gut microbiotamicrobiota a key player in health and wella key player in health and well--beingbeing

A composition in which potentially A composition in which potentially health promotinghealth promoting dominant microorganismsdominant microorganisms

Elevated and/or more active Elevated and/or more active saccharolyticsaccharolytic genera/species e.g. genera/species e.g. bifidobacteriabifidobacteria) )

Reduced Reduced proteolyticproteolytic/putrefactive/putrefactive genera/species genera/species potentially harmful ones potentially harmful ones

Situation: Situation: ‘‘normobioticnormobiotic' or ' or ‘‘eubioticeubiotic’’..

Introduction: the Introduction: the prebioticprebiotic conceptconcept

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Health beneficial dominant Health beneficial dominant microbiotamicrobiota::

Genus Genus BifidobacteriumBifidobacterium plays an important roleplays an important role

Future Research different genera/species Future Research different genera/species ((egeg EubacteriumEubacterium, , FaecalibacteriumFaecalibacterium and and RoseburiaRoseburia) )

Hypothesis: Hypothesis: Increasing these genera/species in gut Increasing these genera/species in gut microbiotamicrobiota, , might improve health status and reduce disease riskmight improve health status and reduce disease risk..


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Validate and expand the original idea Validate and expand the original idea of the of the prebioticprebiotic conceptconcept as: as:

““The The selectiveselective stimulation stimulation of growth and/or of growth and/or activity(iesactivity(ies))of one or a limited number of one or a limited number

of microbial of microbial genus(eragenus(era)/species )/species in the gut in the gut microbiotamicrobiota that that confer(sconfer(s))

health benefits to the hosthealth benefits to the host””,,


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““SelectivitySelectivity””the key condition that the key condition that needs to be demonstrated, needs to be demonstrated, in vivoin vivo, , in the complex human (animal) gut in the complex human (animal) gut microbiotamicrobiota

““ActivityActivity((iesies))””a a metabolicmetabolic profile(s), profile(s), molecularmolecular signallingsignalling, , prokaryoteprokaryote--eucaryote eucaryote cellcell--cellcell interactioninteraction

““Confer(s)Confer(s)””referringreferring to one or a to one or a limitedlimited numbernumberof of selectivelyselectively stimulatedstimulated genusgenus((eraera)/)/speciesspecies


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The conceptual approach emphasizes The conceptual approach emphasizes the the LINKLINK between between

““selectiveselective stimulation stimulation of of growthgrowth and/or and/or activity(iesactivity(ies))

of one or a limited number of one or a limited number of specific bacteria genus/speciesof specific bacteria genus/species””

and and ““health health benefit(sbenefit(s))””

by specific food products/ingredients/supplementsby specific food products/ingredients/supplements

Introduction: Introduction: prebioticprebiotic effectseffects

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CONTENTCONTENT

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Reviewing the most recent data:Reviewing the most recent data:

GastroGastro--intestinal microbiology esp. large intestineintestinal microbiology esp. large intestine

Bacterial fermentation & physiology Bacterial fermentation & physiology incl. substrate utilisation & ferment. products (incl. substrate utilisation & ferment. products (egeg SCFAsSCFAs))

in vivo & in vitro in vivo & in vitro studies on studies on prebioticprebiotic effects;effects;

CONCLUSIONS are:CONCLUSIONS are:

PrebioticPrebiotic effects and the guteffects and the gut

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In vitro In vitro test: test: comparationcomparation, selection,, selection, identificationidentification and and quantificationquantification potential ingredients & fermentation productspotential ingredients & fermentation products

The The multimulti--stage modelsstage models are designed are designed to mimic the different segments of the intestineto mimic the different segments of the intestine

IIn vivo n vivo studies studies essentialessential to prove the to prove the prebioticprebiotic effecteffect

PrebioticPrebiotic effects and the gut: effects and the gut: Conclusions IConclusions I

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2.2. NonNon--digestible carbohydrates with digestible carbohydrates with prebioticprebiotic effects effects selectively stimulateselectively stimulate the growth of bacterial genera/species the growth of bacterial genera/species characterized exclusively, or preferably, characterized exclusively, or preferably, by by saccharolyticsaccharolytic fermentationfermentation..

3. This is well established today for 3. This is well established today for prebioticprebiotic effects effects favouringfavouring the growth of the growth of bifidobacteriabifidobacteria and and lactobacillilactobacilliEmerging genera are Emerging genera are EubacteriumEubacterium, , FaecalibacteriumFaecalibacterium and and RoseburiaRoseburiaalthough more evidence is needed on their although more evidence is needed on their physiological propertiesphysiological properties

PrebioticPrebiotic effects and the gut: effects and the gut: Conclusions IIConclusions II

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CONTENTCONTENT

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Rationale : Rationale :

That modulation of the immune system may result That modulation of the immune system may result from from prebioticprebiotic effectseffects is based on the interaction betweenis based on the interaction betweenthe the intestinal intestinal microbiotamicrobiota and the host immune systemand the host immune system..

The The microbiotamicrobiota is essential for an optimal structuralis essential for an optimal structuraland functional and functional developmentdevelopment of the immune system.of the immune system.

PrebioticPrebiotic effects and the immune systemeffects and the immune system

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Rationale : Rationale :

Interactive coInteractive co--existence of existence of immune cellsimmune cellsand and microbiotamicrobiota is strongest in GI tract: is strongest in GI tract: GALT:GALT:

optimal optimal defensedefense:: against intestinal pathogens, against intestinal pathogens, tolerancetolerance: dietary and self: dietary and self--antigens, antigens, commensalcommensal

nonnon--pathogenic pathogenic microbiotamicrobiota..

Intestinal cellsIntestinal cells key intermediateskey intermediates convey signalsconvey signalsfrom intestinal lumen to mucosal immune system andfrom intestinal lumen to mucosal immune system andare target for a are target for a prebioticprebiotic effect on immune system.effect on immune system.


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Mechanisms : Mechanisms :

PrebioticPrebiotic effects may influence the immune system effects may influence the immune system directly or indirectlydirectly or indirectly via intestinal fermentation via intestinal fermentation and selective promotion of the gut and selective promotion of the gut microbiotamicrobiota, thus, that , thus, that may change the may change the immunoimmuno--interactive profile interactive profile of the of the microbiotamicrobiota..

Through Through patternpattern--recognition receptorsrecognition receptors ((eg.TLReg.TLR), ), both both immune cellsimmune cells and and enterocytesenterocytes interact with interact with pathogenpathogen--associated molecular patternsassociated molecular patterns ((PAMPsPAMPs), ), ((egeg. LPS, . LPS, lipoteichoiclipoteichoic acids and acids and unmethylatedunmethylated CpGCpG DNA) DNA)


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Mechanisms : Mechanisms :

These These interactionsinteractions result in a variety of result in a variety of downstreamdownstreamevents eventually leading to events eventually leading to cytokine productioncytokine production steering steering towards an appropriate immune response.towards an appropriate immune response.

SCFAsSCFAs may interact with may interact with immune cellsimmune cells and and enterocytesenterocytesand modify their activity through binding to Gand modify their activity through binding to G--protein protein coupled receptors and modulate coupled receptors and modulate chemokinechemokine expression expression in intestinal epithelial cellsin intestinal epithelial cells


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ConclusionsConclusions

Limited, yet promising, evidence that ingredients showingLimited, yet promising, evidence that ingredients showinga a prebioticprebiotic effect modulate effect modulate immune markersimmune markers in humans.in humans.

Important to know whether such an Important to know whether such an immunoimmuno--modulationmodulationresults in a results in a clinically relevant outcomeclinically relevant outcome. .

Preliminary yet promising clinical endpoint studies Preliminary yet promising clinical endpoint studies exist that integrate the exist that integrate the measurement of immune markers measurement of immune markers as possible explanation of as possible explanation of prebioticprebiotic efficacyefficacy..

PrebioticPrebiotic effects and the immune system:effects and the immune system:

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CONTENTCONTENT

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One type of oligosaccharide mixture consistingOne type of oligosaccharide mixture consistingof of galactooligosaccharidesgalactooligosaccharides and high MW and high MW inulininulin((scGOS/lcFOSscGOS/lcFOS; ratio of 9:1 ) has, so far, been extensively ; ratio of 9:1 ) has, so far, been extensively evaluated for paediatric applications.evaluated for paediatric applications.

Directive 2006/141/EC on infant and followDirective 2006/141/EC on infant and follow--on formulae on formulae specifically allows the addition of GOS/FOS in a ratio of 9/1specifically allows the addition of GOS/FOS in a ratio of 9/1and in a quantity of 0.8g/ 100 ml prepared productand in a quantity of 0.8g/ 100 ml prepared product

PrebioticPrebiotic effects in effects in PaediatricsPaediatrics

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ConclusionsConclusions

GOS/FOS increases, selectively and doseGOS/FOS increases, selectively and dose--dependependentlydently, the number of , the number of bifidobacteriabifidobacteria in faeces and in faeces and modulates stool characteristics (consistency, pH, modulates stool characteristics (consistency, pH, & & SCFAsSCFAs pattern) similarly to breast fed infants.pattern) similarly to breast fed infants.

Controlled trials show that GOS/FOS is ableControlled trials show that GOS/FOS is ableto to reduce the incidence of atopic diseasesreduce the incidence of atopic diseases, , the effect persists beyond the intervention period,the effect persists beyond the intervention period,

Reduce the risk of some infectiousReduce the risk of some infectious diseases diseases

The available data on The available data on prebioticprebiotic effects effects do NOT demonstrate adverse effectsdo NOT demonstrate adverse effects in infants in infants

PrebioticPrebiotic effects in effects in PaediatricsPaediatrics

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CONTENTCONTENT

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PrebioticPrebiotic effects and IBSeffects and IBS

To date, two published studies of adequate design To date, two published studies of adequate design report the positive effects of report the positive effects of ITF and GOS in IBSITF and GOS in IBS..

Evidence accumulated so far in wellEvidence accumulated so far in well--designed clinical designed clinical studies is limited, but suggests possible benefits studies is limited, but suggests possible benefits at moderate dosesat moderate doses

PrebioticPrebiotic effects effects and gastroand gastro--intestinal disordersintestinal disorders

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PrebioticPrebiotic effects and effects and IBDIBDThere is convincing evidence that patients with There is convincing evidence that patients with IBDIBDhave a GI have a GI dysbiosisdysbiosis characterised by lower concentrations characterised by lower concentrations of luminal and mucosal of luminal and mucosal bifidobacteriabifidobacteria and of and of SCFAsSCFAssuggesting a potential for suggesting a potential for prebioticprebiotic intervention.intervention.

Numerous small Numerous small pilot human studiespilot human studies have been conducted have been conducted in in pouchitispouchitis, UC and CD indicating potential benefit , UC and CD indicating potential benefit in treating active disease.in treating active disease.

Results are Results are substancesubstance-- and studyand study--specificspecific, but do , but do not warrant a conclusion for not warrant a conclusion for prebioticprebiotic effects in general.effects in general.

No adverse effect has been reported.No adverse effect has been reported.


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PrebioticPrebiotic effects and effects and gastrogastro--intestinal infectionsintestinal infections

Experimental studiesExperimental studies in different models of IBD have in different models of IBD have demonstrated beneficial effects of ingredient demonstrated beneficial effects of ingredient with with prebioticprebiotic effectseffectsIn humansIn humans, t, the number of studies on the efficacy a he number of studies on the efficacy a prebioticprebiotic effect effect in the prevention of infectious in the prevention of infectious diseases is limited. diseases is limited. Clearly, a rationale is present but the measurement Clearly, a rationale is present but the measurement of the putative associated effect on the of the putative associated effect on the microbiotamicrobiotais not always included in these studies, is not always included in these studies, hindering any conclusions on possible underlying hindering any conclusions on possible underlying mechanisms.mechanisms.


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PrebioticPrebiotic effects and colon cancereffects and colon cancer

Experimental studiesExperimental studies, in different models of colon , in different models of colon carcinogenesis, have demonstrated beneficial effects carcinogenesis, have demonstrated beneficial effects of ingredient with of ingredient with prebioticprebiotic effects.effects.

These studies show beneficial effects on :These studies show beneficial effects on :incidence & yield of aberrant crypt foci, tumoursincidence & yield of aberrant crypt foci, tumours and and cancerscancers changes in gut changes in gut bacterial enzyme activitiesbacterial enzyme activities, , upup--regulation of regulation of apoptosis & induction of apoptosis & induction of protective enzymesprotective enzymes


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PrebioticPrebiotic effects and colon cancereffects and colon cancer

In humansIn humans, up to date, only one, up to date, only one study on the efficacy study on the efficacy a a prebioticprebiotic effect in the reduction of risk is available based effect in the reduction of risk is available based on on early or intermediate biomarkers of cancer.early or intermediate biomarkers of cancer.

Data show a Data show a reduction in DNA damagereduction in DNA damage,,cell proliferation in colon biopsies cell proliferation in colon biopsies and and genotoxicgenotoxic activity of faecal extractsactivity of faecal extracts


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CONTENTCONTENT

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Experimental studiesExperimental studies, in different models, show , in different models, show that ingredient with that ingredient with prebioticprebiotic effects increase effects increase Ca and Mg (and possibly Fe) absorption & bone min. dens.Ca and Mg (and possibly Fe) absorption & bone min. dens.

A possible mechanism is A possible mechanism is extensionextension of the site of of the site of mineral absorption (through the tight junctions) mineral absorption (through the tight junctions) towards the large intestinetowards the large intestine..

Clearly, a rationale is present to consider that Clearly, a rationale is present to consider that compounds showing compounds showing prebioticprebiotic effects as a source effects as a source for putative innovative dietary health intervention for putative innovative dietary health intervention for improvement of mineral retention.for improvement of mineral retention.

PrebioticPrebiotic effects effects and mineral metabolismand mineral metabolism

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In humansIn humans

Enhanced calcium absorptionEnhanced calcium absorption, depending of , depending of age (age (egeg adolescents) or physiological status adolescents) or physiological status (no effect in early postmenopausal women).(no effect in early postmenopausal women).

In adolescents, the In adolescents, the long term benefitslong term benefits translate into translate into benefits to bone health, especially enhancement of benefits to bone health, especially enhancement of calcium accretion in bones, but also bone calcium accretion in bones, but also bone mineral densitymineral density

PrebioticPrebiotic effects effects and mineral metabolismand mineral metabolism

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CONTENTCONTENT

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Regulation of food intake, fat mass and bodyRegulation of food intake, fat mass and body weightweight

In In experimental studiesexperimental studiesregulate regulate food intake, fat mass and weight gainfood intake, fat mass and weight gain, , (possibly via a modulation of GI peptides production) (possibly via a modulation of GI peptides production) modulate modulate metabolic disordersmetabolic disorders assoc. with obesity, assoc. with obesity, egeg. liver . liver steatosissteatosis, , dyslipidemiadyslipidemia, diabetes, hypertension. , diabetes, hypertension.

In In humanshumans,,promote promote satietysatiety and to reduce hungerand to reduce hunger ,,(possibly via a modulation of GLP(possibly via a modulation of GLP--1, PYY or 1, PYY or GhrelinGhrelin) ) to help to help maintaining an appropriate BMI and fat massmaintaining an appropriate BMI and fat massin in non obesenon obese adolescentsadolescentsto decrease food intake, body weight gain to decrease food intake, body weight gain and fat mass development in and fat mass development in obeseobese subjectssubjects ..

PrebioticPrebiotic effects in weight management effects in weight management and obesityand obesity--related disordersrelated disorders

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Glucose homeostasisGlucose homeostasis

In In humanshumans

to to decrease basal hepatic glucose production, decrease basal hepatic glucose production, but had no detectable effect on insulinbut had no detectable effect on insulin--stimulated stimulated glucose metabolismglucose metabolismto lower blood lipids in to lower blood lipids in normonormo-- and moderately and moderately hyperlipidemichyperlipidemic subjects but both positive and negative subjects but both positive and negative data have been obtained data have been obtained


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ObesityObesity--associated inflammationassociated inflammation

Hypothesis: obesity and insulin resistanceHypothesis: obesity and insulin resistanceare associated with a are associated with a low grade inflammationlow grade inflammation due to due to circulating bacterial LPS as triggering factor.circulating bacterial LPS as triggering factor.That situation is known as That situation is known as ““metabolic metabolic endotoxemiaendotoxemia”” and is and is likely to be due to change in gut likely to be due to change in gut microbiotamicrobiota composition composition (especially decrease in (especially decrease in bifidobacteriabifidobacteria). ).

In In micemice, an , an inverse relationshipinverse relationship has been established has been established between the level of between the level of faecalfaecal bifidobacteriabifidobacteria and some and some features of the metabolic alterations linked to obesity features of the metabolic alterations linked to obesity ((endotoxemiaendotoxemia, fat mass, glucose intolerance) , fat mass, glucose intolerance)


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CONTENTCONTENT

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As a result of the research activity that followed the publication of the prebiotic concept 15 years ago, it has become clear that specific food products/ingredients/supplements that cause a selective modification in the gut microbiota’s composition and/or activity(ies) and thus strengthens normobiosis could either inducebeneficial physiological effects in the colon and also in extra-intestinal compartments or contribute towards reducing the risk of dysbiosis and associated intestinal and systemic pathologies.


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GutGut

Immune systemImmune system

PaediatricsPaediatrics

GastroGastro--intestinal disordersintestinal disorders

Mineral metabolismMineral metabolism

Weight management & obesityWeight management & obesity--related disordersrelated disorders


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Which of the physiological and/or pathophysiological well-being and health benefits are causally linked with a particular composition of the gut microbiota or (a) selective change(s) therein?

Which observed benefits, is (are) not linked to a particular composition of the gut microbiota or (a) selective change(s) therein but is (are) the consequence(s) of other mechanism(s) of the product claimed to have a prebiotic effect?

Which protocol(s)/markers are validated to demonstrate change(s) in microbiota composition

Key questions I

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Which protocol(s), methodologies and markers are available and validated to demonstrate links between a particular composition of the gut microbiota or a selective change therein and a particular physiological and/or pathophysiological well-being and health benefit?

Key questions II

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Increased intestinal levels of bifidobacteria in majority of human studies

Often associated with improvement in accepted markers of health.

Strongly associates prebiotic effects with GI and systemic health benefits.

Consideration of results on PRObiotic bifidobacteria:

Compelling evidence: Relationship between intestinal microbiota (esp. bifidobacteria) and health might well be causal.


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Danke

Merci

Hvala

Gracias

Grazie

Děkuji

Ačiu

ΕυχαριστωDank

Tak

ありがとう

Tack

Obrigado

Спасиб

о

Tesekkurler

谢谢

감사

Kiitos

Mulţumesc

Köszönöm

شكرا

Thank you for your attention

Documents

Prebiotic Effects: Metabolic and Health Benefits · 2019-07-30 · Weight management and obesity-related disorders ... might improve health status and reduce disease risk. Introduction: