Health Benefits of Probiotics by Impacting the Intestinal Barrier ...
Transcript of Health Benefits of Probiotics by Impacting the Intestinal Barrier ...
Health Benefits of Probiotics by
Impacting the Intestinal Barrier Function
Budapest, June 21-23, 2016
P. A. Bron1, M. Kleerebezem2, R.J. Brummer3, P.D. Cani4, A.
Mercenier5, T.T. MacDonald6, C.L. Garcia Rodenas5, J.M. Wells2
1 NIZO food research and BE-Basic Foundation, NL; 2 Wageningen University, NL; 3Örebro University, SE; 4Université catholique de Louvain, BE; 5Nestlé Research
Center, CH; 6 Queen Mary University of London, UK
IPC2016
Introduction
Background
Scope of the review
The GI barrier: a complex multilayer system designed to prevent translocation of microbes, antigens & toxins
from the lumen inside the body
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Gastro-intestinal barrier Mucosal barrier
Perrier C & Corthesy B (2011) Gut permeability and food allergies. Clin Exp Allergy 41, 20-28.
Soderholm et al. (1999) Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal
defence? Gut 44, 96-100.
Cani, P. D. et al. (2007). "Metabolic Endotoxemia Initiates Obesity and Insulin
Resistance." Diabetes 56, 1761-72.
Leaky gut barrier and disease
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Roxas JL, et al. (2010) Enterohemorrhagic E. coli alters murine intestinal epithelial tight
junction protein expression and barrier function in a Shiga toxin independent manner.
Lab Invest 90, 1152-1168
Camilleri et al. (2012) Irritable bowel syndrome: methods, mechanisms, and
pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome, Am J PhysiolGastrointest Liver Physiol 303, G775-85.
Julio-Pieper, M, et al. (2014) Review article: intestinal barrier dysfunction and
central nervous system disorders-a controversial association. Aliment.
Pharmacol. Ther 40, 1187-1201
Anand RJ et al. (2007) The role of the intestinal barrier in thepathogenesis of necrotizing
enterocolitis. Shock 27, 124-33
Heyman et al. (2012) Intestinal permeability in coeliac disease: insight into mechanisms and relevance to
pathogenesis, Gut 61, 1355-64.
LEAKY GUT
Allergy
Metabolic Syndrome
Neuro-psychiatric disorders
GI infection
IBD
NEC
IBS
Celiac Disease
Probiotics & barrier mechanisms
Colonization resistance
Antimicrobial compounds
(metabolites, bacteriocins)
Inhibition of toxin production/toxin
degradation
Mucin, antimicrobials & SIgA secretion
Epithelial integrity
Gut motility
Immunomodulation
Commensal microbiota Mucosal barrier
Sanchez, M. et al. (2014) Effect of Lactobacillus rhamnosusCGMCC1.3724 supplementation on weight loss and maintenance in obese men and women. Br J Nutr. 28;111(8):1507-19
Goldenberg J.Z. et al. (2015) Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 22;12:CD004827
Clarke G. et al. (2012) Review article: probiotics for the treatment of irritable bowel syndrome-focus on lactic acid bacteria, Aliment PharmacolTher. 35(4):403-13.
AlFaleh K., Anabrees J. (2014) Probiotics for prevention of necrotizing enterocolitis in preterm infants Cochrane Database Syst Rev. 10;4:CD005496
Ghouri Y.A. et al. (2014) Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease. Clin ExpGastroenterol. 9;7:473-87
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Metabolicsyndrome
GI infections
IBDNEC
IBS
ProbioticsPrebioticsSynbiotics
Probiotics and disease
Scope
Impact of probiotics on mucosal barrier* integrity and
commensal microbiota as mediating factors of their
beneficial effects on model disorders
* Studies on mucosal immunity not included
Results
Probiotics, barrier & management
of model disorders
Probiotics and enteric infection
“Moderate quality evidence suggests a protective effect of probiotics
in preventing AAD” Goldenberg J.Z. et al. (2015) Cochrane Database Syst Rev.
22;12:CD004827
“Moderate quality evidence suggests that probiotics are both safe
and effective for preventing Clostridium difficile-associated diarrhea”Goldenberg J.Z. et al. (2013) Cochrane Database Syst Rev. 31;5:CD006095
“There is evidence that selected strains of probiotics decrease the
duration of acute gastroenteritis” Vandenplas Y. (2016) Best Pract Res Clin
Gastroenterol. 2016 Feb;30(1):49-53
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Probiotics & pathogen challenges to the
barrier
Colonization resistance
B. longum Bar33 and L. helveticus Bar13
C. difficile, C. perfringens, E. faecium,
Campylobacter in elderly volunteers(Rampelli 2013)
Antimicrobial compounds
Reuterin (L. reuteri) inhibits enteric
pathogens (Cleusix 200 7)
Abp 118 (L. salivarius UCC118) inhibits L.
monocytogenes translocation (Corr 2007).
Inhibition of toxin production/toxin
degradation
B breve Yakult STEC Shiga toxin in
vitro and in vivo (Asahara 2004)
S. boulardii protease degrades Toxin A
from C. difficile (Castagliuolo 2014)
Mucin expression
Adherent Lactobacillus spp mucin
expression and prevent EPEC adherence in
vitro (Mack 1999)
Inhibition of pathogen-induced disruption
of epithelial integrity
L acidophilus (Sherman 2005), L plantarum (Mangell
2002), L casei (Parassol 2005), reduce the EHEC
and EPEC increase in permeability in vitro
SIgA production
L. plantarum P8 fecal SIgA in middle-age
and elderly humans (Wang 2014).
Direct effects on pathogens Mucosal barrier modulation
Probiotics and NEC
“Enteral supplementation of probiotics prevents severe NEC and all
cause mortality in preterm infants. Our updated review of available
evidence strongly supports a change in practice.” AlFaleh K., Anabrees
J. (2014) Cochrane Database Syst Rev. 10;4:CD005496
“Supplementation with prebiotic oligosaccharides was safe and did
not result in decreased incidence of NEC” Srinivasjois R. et al. (2013) Clin
Nutr. 32(6):958-65
“In VLBW infants, probiotic (Bifidobacterium lactis) and synbiotic
(Bifidobacterium lactis plus inulin) but not prebiotic (inulin) alone
decrease NEC” Dilli D. et al. (2015) J. Pediatr. 166:545-51
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Beneficial effects
B. longum subsp. infantis (Underwood 2012), B.
lactis BB12 (Mohan 2006), S. boulardii (Costalos
2003) bifidobacteria, potential
pathogens
L. rhamnosus LGG (Manzoni 2006; Romeo 2011),
L. reuteri ATCC 55730 (Romeo 2011) and L.
reuteri DSM 17938 (Oncel 2015) prevent
Candida colonization
Inconsistent effects
No effects of LGG+BB536 (Rougé 2010)
LGG Gram + and anaerobic species diversity
in preterms under 1500 g but not in more
mature infants (Agarwal 2003)
In preterm infants
B. lactis BB12 permeability (Stratiki 2007),
fecal SIgA, fecal calprotectin (Mohan 2008)
Heat-inactivated B. breve C50/S.
thermophilus 065 fecal SIgA in partially
breast-fed infants, but not in exclusively
formula-fed (Campeotto 2011)
In animal models
permeability to small solutes,
macromolecules and endotoxin, bacterial
translocation to extraintestinal tissues
Restored expression and localization of TJ
and adherens junctions proteins
enterocyte proliferation, migration,
apoptosis
Normalized expression of TLRs, mucins
antimicrobials
Microbiota modulation Mucosal barrier modulation
Probiotics, immature barrier & NEC
Probiotics and IBD
“There is insufficient data to recommend probiotics for use in
CD. There is evidence to support the use of (some) probiotics for
induction1 and maintenance of remission in UC2 and pouchitis3.
Future quality studies are needed to confirm whether probiotics,
prebiotics, and synbiotics have a definite role in induction or
maintenance of remission in CD, UC, and pouchitis”
Ghouri Y.A. et al. (2014) Clin Exp Gastroenterol. 9;7:473-87
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1 VSL#3, 2 E. coli Nissle 1917 & L. rhamnosus GG, 3 VSL# 3
Probiotics, barrier & IBD
VSL#3 Lactobacillus, Bifidobacterium and S. salivarius in UC (Venturi 1999); total bacterial
numbers, richness and diversity of the bacterial microbiota & diversity of fungal flora (Kuhbacher
2006)
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Microbiota modulation
Mucosal barrier modulation
Increased epithelial integrity Probiotics protect against cytokine-driven epithelial barrier dysfunction (multiple in vitro studies)
P40 component of L rhamnosus GG prevents cytokine-induced hyperpermeability and
ameliorates DSS-induced colitis in mice (Yan 2011)
Soluble factor from B infantis increases ZO-1 and occludin in epithelial cell lines and improves
colitis in IL10 Ko mice (Ewaschuk 2008)
L. plantarum duodenal perfusion in healthy individuals results in structural changes in ZO-1 and
occludin, associated with reduced permeability (Karczewski 2011)
Stimulation of antimicrobial production by the mucosa B. breve NCC 22950 normalized RegIII-γ expression (not permeability) and decreased
susceptibility to DSS colitis in Nod1(-/-); Nod2(-/-) mice (Natividad 2012)
Probiotics and IBS
“Probiotics are effective treatments for IBS, although
which individual species and strains are the most
beneficial remains unclear. Further evidence is required
before the role of prebiotics or synbiotics in IBS is
known.”
Ford AC. et al. (2014) Am J Gastroenterol. 2014 Oct;109(10):1547-61
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Probiotics, barrier & IBS
Multispecies probiotic: Microbiota stabilization (Kajander 2008); increased Clostridia and
Enterococcus (Lyra 2010)
Multispecies probiotic: no effect (Brigidi 2001)
B. animalis subsp. lactis CNCM I-2494 reduced B. wadsworthia and increased the butyrate-
producing potential of the commensal microbiota (Veiga 2014)
Microbiota modulation
Mucosal barrier modulation
Increased epithelial integrity Lactibiane Tolerance® occludin expression, prevented hyperpermeability and visceral
hypersensitivity induced by LPS, stress or IBS luminal metabolites (Nebot-Vivinus 2014)
B. longum HB55020 and L. acidophilus HB56003 claudin-1 and occludin expression,
reduced inflammatory markers and prevented hypersensitivity in a model of PI-IBS (Wang 2014)
B. lactis CNCM I-2494 prevented hyperpermeability and endotoxemia induced by stress and
restored occludin and JAM-A expression (Agostini 2012)
Mucus layer L. farciminis prevented stress-mediated alterations in mucin O-glycosylation and mucus
physical properties. It also prevented hyperpermeability and hypersensitivity (Da Silva 2014)
Probiotics and metabolic disease
Probiotics
L. gasseri SBT2055 reduced fat-mass gain, body weight and waist-to-hip ratio in
overweight subjects (Kadooka Y et al. (2013). Br J Nutr. 14;110(9):1696-703)
VSL#3 improved insulin sensitivity and reduced total cholesterol, triglyceride,
LDL, and VLDL and increased HDL in overweight adults (Rajkumar, H. et al. (2014)
Mediators Inflamm. 2014, 8)
L. rhamnosus CGMCC1.3724 helped to reduce body weight in overweight
women but not in men (Sanchez, M. et al. (2014) Br J Nutr. 28;111(8):1507-19)
Pre- and Synbiotics
Enhanced weight loss and improved glucose regulation in obese adults with FOS
supplements (Parnell J.A. & Reimer, R.A. (2009) Am. J. Clin. Nutr. 89:1751-9)
Reduced endotoxemia, insulin resistance, steatosis and metabolic inflammatory
markers by B longum + FOS in NASH patients (Malaguarnera M. et al. (2012) Dig.
Dis. Sci. 57:545-53)
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Probiotics, barrier & metabolic disease
L. salivarius Ls-33 ATCC SD5208: Bacteroides-Prevotella-
Porphyromonas/Firmicutes ratio in obese adolescents (Larsen 2013), but no effects
on metabolic outcomes
VSL#3: total aerobes, total anaerobes, Lactobacillus, Bifidobacterium,
Streptococcus in overweight adults (Rajkumar,2014)
Microbiota modulation
Mucosal barrier modulation
L. casei Shirota insulin resistance and endotoxemia in diet-induced obese mice (Naito 2011)
B. longum endotoxemia, fat mass, insulin resistance, blood pressure in diet-
induced obese rat (Chen 2011)
B. animalis subsp. lactis 420 supressed bacteremia and reduced insulin resistance
and inflammation in high fat diet-fed mice (Amar et al. 2011)
Conclusions & Gaps
Conclusions & Gaps
(Some) Probiotics have the potential to prevent and/or treat
multiple disorders. Evidence ranges from good/fair (AGE,
NEC, UC, pouchitis, IBS) to emerging (metabolic disease)
(Some) Probiotics positively modulate microbiota composition
and barrier integrity, which possibly explains their impact on
health and disease (at least partially)
? Good quality, clinical trials in well-defined populations
comparing the effect of different doses and/or strains on both
clinical and barrier outcomes are required
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VCt CCt VLr CLr
Bifidobacterium abundance
VCtCCt VLrCLr
Phylogenetic similarity
VCt CCtVLrCLr
2 weeks 4 months
V=vaginal, C=C-section; Ct=control formula; Lr=L. reuteri formula