PREBIOTIC AND ALLERGY

NIA KURNIATI
DEPT. OF CHILD HEALTH
CIPTO MANGUNKUSUMO HOSPITAL, JAKARTA
OUTLINE

¡ Definition and type of fiber

¡ Theoretical mechanisms of fiber in influencing immunity and allergy
¡ Latest study on fiber and allergy
 ENVIRONMENT AND ALLERGY

Aitoro et al. Nutrients 2017;9:672

DEFINITION

¡ Dietary fiber consists of non-digestible carbohydrates sourced from plant

polysaccharides and plant or human milk-derived oligosaccharides.
¡ They are resistant to enzymatic and chemical digestion until they reach the large
intestine, where they are fermented to short-chain fatty acids (SCFAs) and other
metabolites by gut bacteria
¡ Mammals, including humans, are deficient in the enzymes required to degrade the
bulk of polysaccharides and resistant oligosaccharides
Folkerts, et al.
Front Immunol
2018;9:1067
SPECIFIC DIETARY FIBER: PREBIOTIC

¡ International Scientific Association of Probiotics and Prebiotics (ISAPP), prebiotic is

“substrates selectively used by micro-organisms of the host conferring benefits for his
health”.
¡ Prebiotics must meet three criteria:
¡ 1: Be resistant to digestion in the stomach and upper intestine
¡ 2: Be fermentable by the gut microbiota
¡ 3: Specifically stimulate the growth and/or activity of intestinal bacteria beneficial to our health

¡ Gibson et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus
statement on the definition and scope of prebiotics. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 491–502.
Gibbson et al. Nat Rev Gastroenterol Hepatol 2017;14:491-502
HUMAN MILK OLIGOSACCHARIDES (HMO)

¡ Prebiotics are naturally present in human milk; contains at least 200 human milk oligosaccharides
(HMO); which explains the increase of gut bifidobacteria observed in breastfed infants compared with
standard formula-fed (SF)
¡ Human milk oligosaccharides may represent an excellent meal for beneficial species and prevent the
adhesion of pathogens, contributing to the shift of the infant gut microbiota, influencing the immune
system and infants health.
¡ The molecular structure differs in size and sequence among women, being influenced by certain
factors (lactation period, secretor status, maternal Lewis Blood Group, etc.), and giving the infant a
different degree of protection.
SYNTHETIC PREBIOTIC-FOOD INDUSTRY

Single, combination mixture

PREBIOTIC INFLUENCE THE HOST HEALTH-
INVITRO AND ANIMAL STUDY
MAST
CELLS
AND
DIETARY
FIBER

Folkerts, et al.
Front Immunol
2018;9:1067
 INDIRECT EFFECT

Non-starch
polysaccharides
Resistant Analogous
oligosaccharides carbohydrate
Short Chain
Fatty Acid

Effect

Brosseau, et al. Nutrients 2019;11:1841

SCFA-INTESTINE CELLS ACTIVATION

Brosseau C, Selle A, Palmer DJ, Prescott SA, Barbarot S, Bodini A. Nutrients 2019;11:1841
INTRAEPITHELIAL CELLS

¡ Wu et al. in an in vitro study investigated the application of prebiotics

onto immortalized gut-derived epithelial cell lines and human intestinal
organoids. Prebiotics directly promoted barrier integrity to prevent
pathogen-induced barrier disruptions involving the induction of select
tight junction proteins through a protein kinase C (PKC)-dependent
mechanism.
¡ Réquilé et al. confirmed the effects of prebiotics on the tight junction
gene expression thus maintaining gut homeostasis to protect the host
against challenge by enteric pathogens or allergens.

Wu, R.Y. et al. Protein kinase C δ signaling is required for dietary prebiotic-induced strengthening of intestinal epithelial barrier function. Sci. Rep. 2017, 7, 1–10
Réquilé, et al. Use of a combination of in vitro models to investigate the impact of chlorpyrifos and inulin on the intestinal microbiota and the permeability of the
intestinal mucosa. Environ. Sci. Pollut. Res. 2018, 25, 1–12.
SCFA-BLOODSTREAM

Brosseau C, Selle A, Palmer DJ, Prescott SA, Barbarot S, Bodini A. Nutrients 2019;11:1841
DIRECT EFFECT

Brosseau C, Selle A, Palmer DJ, Prescott SA,

Barbarot S, Bodini A. Nutrients 2019;11:1841
SKIN CELLS
¡ In an AD mouse model: skin inflammatory cell
infiltrations (i.e skin Th2-related cytokines, TSLP and
IL-4) were significantly reduced by treatments with
FOS.
¡ CD4+ Foxp3+ Treg cells were significantly increased
in skin lymph nodes.
¡ Supplementation with prebiotics (Konjac
glucomannan) inhibits a scratching behavior and skin
inflammatory immune responses by preventing
germline class-switching and IgE production.
¡ Prebiotic dietary supplementation significantly
suppressed eczematous skin lesions, dermal
mastocytosis and eosinophilia.
¡ Concomitantly, cutaneous overproductions of
substance P, IL-10, IL-4, and TNF-alfa were all
inhibited.
¡ In humans (RCT study on adult healthy subjects
received GOS oral supplementation for 12 weeks).
GOS supplementation was beneficial to the skin
(better corneometer values and reduced
transepidermal water loss (TEWL)).
¡ Total and percentage of wrinkle areas between the
two groups were statistically significant.
¡ GOS prevent keratin depletion caused by phenolic
compounds.
¡ In another trial involving patients with skin damage
due to diabetes, 4 weeks of daily application of
emollient containing prebiotics improved biophysical
parameters of the epidermis.
Hong, K.B et al Int. J. Food Sci. Nutr. 2015, 66, 923–30
Suzuki, H et al. Int. Arch. Allergy Immunol. 2010, 152, 122–30.
Onishi, N et al. Biosci. Biotechnol. Biochem. 2007, 71, 2551–6
Hong, Y.H et al. Asia Pac. J. Clin. Nutr. 2017, 26, 613–8
LUNG CELLS (IN VITRO)
¡ Treatment with prebiotics (Mannan Derived from Saccharomyces cerevisiae)
stimulated cell spreading and facilitates wound repair in human bronchial epithelium,
involving mannose receptors (direct effect).
¡ Prebiotics also increased the expression and activation of Krüppel-like factors (KLFs)
4 and 5, key transcription factors for epithelial cell differentiation, survival, and
proliferation.

¡ Michael, C.F.; Waters, C.M.; LeMessurier, K.S.; Samarasinghe, A.E.; Song, C.Y.; Malik, K.U.; Lew, D.B. Airway Epithelial Repair
by a Prebiotic Mannan Derived from Saccharomyces cerevisiae. J. Immunol. Res. 2017, 2017, 1–7.
IMMUNE SYSTEM
¡ Prebiotics can be absorbed through the intestinal barrier and may thus be in direct contact with circulating
immune cells.
¡ Inulin and FOS induce the secretion of IL-10, IL-1 and TNF-⍶ by blood monocytes, but not T-lymphocytes. This
secretion is due to the activation of the NF-KB pathway by the binding of the TLR4.
¡ Possible direct effects: to entail ligation of pathogen recognition receptors (PRRs) on the surface of intestine
DCs. These PRRs involved in prebiotics signaling include TLRs, C-type lectin receptors (CLRs), NOD-like
receptors (NLRs), and galectins.
¡ On DC derived from human blood monocytes, GOS and FOS induce IL-10 secretion stimulated by TLR4 binding.
Increased secretion of IL-10 by DC leads to the induction of regulatory Foxp3+ T cells.
¡ Perdijk et al. have shown that HMOs (60-SL and 20-FL) and GOS do not alter DC differentiation or maturation
(in vitro differentiated DC types).
¡ It was also shown that prebiotics supplementation in rats acted at the level of GALT enhancing the production of
IL-10 and IFN- by CD4+ T lymphocytes in Peyer’s patches as well as the production of IgA in the caecum
Perdijk, O, et al. The oligosaccharides 6 -sialyllactose, 2 -fucosyllactose or galactooligosaccharides do not directly modulate human
dendritic cell differentiation or maturation. PLoS One 2018, 13, 1–15
Folkerts, et al.
Front Immunol
2018;9:1067
CLINICAL APPLICATION: ALLERGY PREVENTION
IDEAL STUDY

¡ Cohort
¡ Clear definition of allergic asthma, not other cause of wheez
¡ Clear definition of conjungtivities and/or allergic rhinitis
¡ Type of prebiotic (and/or dosage)---geographic and cultural wise
¡ Ratio of each intended prebiotic
 Cumulative
incidence of
allergic
SUPPORTIVE manifestations

Infants, 2 week of age on formula feeding, 6 month intervention

Prevalence of allergic
manifestation at 5
year

Arslanoglu et al. J Biol Regulator Hoemostatic Agents. 2012;26:49-59

SUPPORTIVE: 12 MONTH PREBIOTIC

¡ Term infants at low atopy risk due to no family history of allergic diseases
¡ Intervention (n = 414) CM formula with added GOS: FOS (0.8 g/100 mL) and pAOS (0.12 g/100 mL)
¡ Control (n = 416) CM formula.
¡ At 12 months of age, fewer infants had AD in GOS: FOS: pAOS group (5.7%) than the control group
(9.7%; p = 0.04) and AD was less severe among the infants affected in the supplemented group (n = 8;
median SCORAD score, 8; range, 3–25) than in the control group (n = 16; median SCORAD score,
12; range, 2–59; p = 0.08).

Grüber, C.; et al. Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. J. Allergy Clin.
Immunol. 2010, 126, 791–797.
PREBIOTIC DOES NOT PREVENT ATOPIC DERMATITIS

¡ term infants at risk of atopy due to parental history of allergic diseases.

¡ Intervention (n = 375) PHF formula with added GOS:FOS:pAOS (0.8 g/100 mL)
for 6 month
¡ Control (n = 383) CM formula.
¡ At 12 months of age: There was no difference in the incidence of AD between
the PHF GOS: FOS: pAOS intervention group (28.7%) and the CM formula
control group (28.7%; p = 0.90).

Boyle, R.J.,et al. Prebiotic-supplemented partially hydrolysed cow’s milk formula for the prevention of eczema in high-risk
infants: A randomized controlled trial. Allergy Eur. J. Allergy Clin. Immunol. 2016, 71, 701–10
OTHER FINDINGS
¡ Infants supplemented with FOS/GOS have fecal microbial composition, metabolites, and pH closer to
that of breast-fed infants
¡ Infants with eczema by 18 months showed discordant development of bacterial genera of
Enterobacteriaceae and Parabacteroides species in the first 26 weeks, as well as decreased acquisition of
Eubacterium and Anaerostipes species, supported by increased lactate and decreased butyrate levels.
¡ The cumulative number of infants with at least 1 episode of AD was not statistically different between
infants supplemented or not with GOS/PDX at 36 weeks, 48 weeks and 96 weeks.
¡ The number of respiratory infection episodes until 48 weeks were lower in infants supplemented with
GOS/PDX than in infants fed with standard formula (p = 0.023) but no longer detected at 96 weeks.
¡ Bifidobacteria and Clostridium cluster I colonization increased over time in the supplemented group but
decreased in the control groups.
Wopereis, H, et al. Intestinal microbiota in infants at high risk for allergy: Effects of prebiotics and role in eczema development. J. Allergy Clin. Immunol. 2018, 141, 1334–
42.
Ranucci, G. et al. Galacto-oligosaccharide/polidextrose enriched formula protects against respiratory infections in infants at high risk of atopy: A randomized clinical
trial. Nutrients 2018, 10, 286.
INFANT OR MATERNAL SUPPLEMENTATION?
MATERNAL DIETARY FIBER DURING LATE PREGNANCY
• Soluble fiber (fermentable fiber or prebiotic fiber) –
which dissolves in water – is generally fermented
in the colon into gases and physiologically
active by-products, such as SCFA. Examples
are beta-glucans (in oats, barley, and mushrooms)
and raw guar gum.
• Psyllium – a soluble, viscous, nonfermented fiber
– is a bulking fiber that retains water as it moves
through the TGI, easing defecation.
• Soluble fiber is generally viscous and delays
gastric emptying.
• Inulin (in chicory root), wheat dextrin,
oligosaccharides, and resistant starches (in
legumes and bananas), are soluble non-viscous
fibers.

Pretorius et al. Nutrients 2019;11:1767

MATERNAL DIETARY FIBER DURING LATE PREGNANCY

Maternal dietary At 12 month

Late pregnancy

Pretorius et al. Nutrients 2019;11:1767

¡ Higher maternal resistant starch intakes was associated with lower risk of doctor diagnosed
wheeze, (aOR) 0.68 (95% CI 0.49, 0.95, p = 0.02))
¡ Higher maternal intakes of resistant starch were associated with higher risk of parent
reported eczema (aOR 1.27 (95% CI 1.09, 1.49, p < 0.01)) and doctor diagnosed eczema
(aOR 1.19 (95% CI 1.01, 1.41, p = 0.04)).
¡ Higher maternal resistant starch intakes in late pregnancy were identified to be specifically
associated with infant doctor diagnosed eczema without allergen sensitization (aOR 1.29
(95% CI 1.06, 1.57, p = 0.01)).
¡ Higher maternal intakes of fiber from green vegetables were also associated with higher risk
of infant doctor diagnosed eczema (aOR 1.32 (95% CI 1.06, 1.64, p = 0.01)), specifically
associated with eczematous infants without allergen sensitization (aOR 1.36 (95% CI 1.04,
1.79, p = 0.03)).

Pretorius et al. Nutrients 2019;11:1767

SUMMARY

¡ Dietary fiber (e.c prebiotic) supplementation has future potential for allergy prevention
through modulation the three major systems that are dysfunctional in allergic disease
development: the microbiota, the IS and the epithelial barriers.
¡ Preclinical models have shown the efficacy of prebiotic supplementation to overcome skin,
food and respiratory allergic symptoms.
¡ Infant supplementation with prebiotics still showed limited effects.
¡ Maternal prebiotic supplementation during pregnancy seems to be the best window of
opportunity to modulate biological systems.
¡ EAACI, WAO: prebiotic supplementation for the prevention of allergy is conditional and
based on very low certainty of the evidence.
THANK YOU