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 הקישורים הבאים הינם למחקרים שנעשו באוניברסיטאות מובילות בעולם ובבתי חולים וכתבות מקצועיות באתרי הבריאות המקצועיים המובילים בעולם ועוד.

https://www.ynet.co.il

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tasmc.org.il/Be-Well

psych.ox.ac.uk/news

www.hayadan.org.il

ramsayhealth.co.uk

huffpost.com/entry/gut

cbsnews.com/news

webmd.com

sciencedaily.com/releases/2020

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getthegloss.com/news

pnas.org/content/109/4

ncbi.nlm.nih.gov/pubmed

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taltech.ee/a-recent-study

pubmed.ncbi.nlm.nih.gov/289

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bmj.com/content/348

pubmed.ncbi.nlm.nih.gov/2113

weizmann.ac.il/online/askexpert

weizmann.ac.il/online/sciencepanorama

washingtonpost.com/lifestyle

pubmed.ncbi.nlm.nih.govid=28491964

https://europepmc.org/article/med/28491964

europepmc.org/article/med/28491964

livescience.com/46502-probiotics

practicaldermatology.com/articles/2019

nature.com/nature/journal/vaap/ncurrent

weizmann.ac.il/online/sciencenew

davidson.weizmann.ac.il/online

tevalife.com/article

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researchgate.net/publication

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https://www.nature.com/articles/nature18309

ncbi.nlm.nih.gov/20801

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sciencedaily.com/03120514

health.gov.il/Dementia

tnuva.co.il/Child_Nutrition/1/

tnuva.co.il/Child_Nutrition2

tnuva.co.il/Child_Nutrition3

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ynet.co.il/articles/0,7340l

www.hayadan.org.il/naama

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academic.oup.com/jn/article/138

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1. Chicory root fibers: Prebiotic properties

Prebiotics are non-digestible or partially digestible food ingredients that beneficially affect the host (consumer) by selectively stimulating the growth and/or activity of one or more of a limited number of bacteria in the colon and thus improve host health. Chicory root fibers are among the very few ingredients scientifically proven to be prebiotics. Numerous studies in infants, young children and adults have been carried out to investigate and confirm the prebiotic effect of chicory root fibers. Selective changes in the microbiota’s composition, especially a significant increase in bifidobacteria have been convincingly demonstrated after chicory root fiber consumption. The activities of the gut microbiota, and notably the saccharolytic fermentation further contribute to colonic function by generating short-chain fatty acids (SCFA), decreasing the production of potentially harmful nitrogen-containing compounds and modulating toxic enzymatic activities in the colon.

Chicory root fibers contribute accordingly to a healthy state of microbiota structure called normobiosis, as opposed to dysbiosis in which one or more potentially harmful bacterial species are dominant. The effect of increased bifidobacteria levels due to intake of chicory root fibers has been confirmed by numerous studies. Research of more than 20 years proved this benefit independent of intake conditions and target groups including age, sex, ethnicity or health status,

Key references (human studies) of effect on the microbiota composition:

In healthy and diabetic adult subjects

Bouhnik Y, Raskine L, Champion K, Andrieux C, Penven S, Jacobs H, Simoneau G (2007) Prolonged administration of low-dose inulin stiumulates the growth of bifidobacteria in humans. Nutr Res 27:187–193. http://www.sciencedirect.com/science/article/pii/S0271531707000358

Clarke ST, Green-Johnson JM, Brooks SPJ, Ramdath DD, Bercik P, Avila C, Inglis GD, Green J, Yanke LJ, Selinger LB, Kalmokoff M (2016) ß2-1 Fructan supplementation alters host immune responses in a manner consistent with increased exposure to microbial components: results from a double-blinded, randomised, cross-over study in healthy adults. Br J Nutr 2016 // 115(10):1748–1759. http://www.ncbi.nlm.nih.gov/pubmed/26987626

Gibson GR, Beatty ER, Wang X, Cummings JH (1995) Selective Stimulation of Bifidobacteria in the Human Colon by Oligofructose and Inulin. Gastroenterology 108:975–982. http://www.gastrojournal.org/article/0016-5085(95)90192-2/pdf

Harmsen H, Raangs GC, Franks AH, Wildeboer-Veloo AC, Welling GW (2002) The effect of the prebiotic inulin and the probiotic bifidobacterium longum on the fecal microflora of healthy volunteers

measured by FISH and DGGE. Microb Ecol Health Dis 14:211–219. http://www.tandfonline.com/doi/pdf/10.1080/08910600310002091

Kolida S, Meyer D, Gibson GR (2007) A double-blind placebo-controlled study to establish the bifidogenic dose of inulin in healthy humans. Eur J Clin Nutr 61(10):1189–1195. http://www.ncbi.nlm.nih.gov/pubmed/17268410

Ramirez-Farias C, Slezak K, Fuller Z, Duncan A, Holtrop G, Louis P (2009) Effect of inulin on the human gut microbiota: stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii. Br J Nutr 101(4):541–550. http://www.ncbi.nlm.nih.gov/pubmed/18590586

Rao AV (2001) The prebiotic properties of oligofructose at low intake levels. Nutr Res 21:843–848. http://www.sciencedirect.com/science/article/pii/S0271531701002846

Salazar N, Dewulf EM, Neyrinck AM, Bindels LB, Cani PD, Mahillon J, de Vos, Willem M, Thissen J, Gueimonde M, de Los Reyes-Gavilán, Clara G, Delzenne NM (2015) Inulin-type fructans modulate intestinal Bifidobacterium species populations and decrease fecal short-chain fatty acids in obese women. Clin Nutr 34(3):501–507. http://www.ncbi.nlm.nih.gov/pubmed/24969566

Vandeputte D, Falony G, Vieira-Silva S, Wang J, Sailer M, Theis S, Verbeke K, Raes J (2017) Prebiotic inulin-type fructans induce specific changes in the human gut microbiota. Gut 66(11):1968–1974. http://gut.bmj.com/content/gutjnl/66/11/1968.full.pdf

Review articles:

Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, Scott K, Stanton C, Swanson KS, Cani PD, Verbeke K, Reid G (2017) 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 14(8):491–502. http://www.nature.com/articles/nrgastro.2017.75

So D, Whelan K, Rossi M, Morrison M, Holtmann G, Kelly JT, Shanahan ER, Staudacher HM, Campbell KL (2018) Dietary fiber intervention on gut microbiota composition in healthy adults: A systematic review and meta-analysis. Am J Clin Nutr 107(6):965–983. https://www.ncbi.nlm.nih.gov/pubmed/29757343

 

2. Chicory root fibers: Effects on bowel regularity

 

The fermentation of chicory root fibers by the colonic microbiota result in an increased bacterial cell mass and SCFA. Due to the high water content of intestinal bacteria, the moisture content of feces is increased after chicory root fibers supplementation. As a consequence, stools become softer and

excretion is facilitated. Inulin and oligofructose intake facilitate fecal excretion, which results in an increase in frequency of bowel movements and/or in stool weight which is shown in several human interventions.

Those are included in the key references below:

In adults and elderly

Buddington R, Kapadia C, Neumer F, Theis S (2017) Oligofructose Provides Laxation for Irregularity Associated with Low Fiber Intake. Nutrients 9(12):1372. http://www.mdpi.com/2072-6643/9/12/1372/pdf

Dahl WJ, Wright AR, Specht GJ, Christman M, Mathews A, Meyer D, Boileau T, Willis HJ, Langkamp-Henken B (2014) Consuming foods with added oligofructose improves stool frequency: a randomised trial in healthy young adults. J Nutr Sci 3(e7):1–8. http://www.ncbi.nlm.nih.gov/pubmed/25191615

den Hond E, Geypens B, Ghoos Y (2000) Effect of high performance chicory inulin on constipation. Nutr Res Vol. 20, No. 5:731–736. http://www.sciencedirect.com/science/article/pii/S0271531700001627

Gibson GR, Beatty ER, Wang X, Cummings JH (1995) Selective Stimulation of Bifidobacteria in the Human Colon by Oligofructose and Inulin. Gastroenterology 108:975–982. http://www.gastrojournal.org/article/0016-5085(95)90192-2/pdf

Grasten S, Liukkonen K, Chrevatidis A, El-Nezami H, Poutanen K, Mykkanen H (2003) Effects of wheat pentosan and inulin on the metabolic activity of fecal microbiota and on bowel function in healthy humans. Nutr Res 23(11):1503–1514. http://www.nrjournal.com/article/S0271-5317(03)00164-7/abstract

Kleessen B, Sykura B, Zunft HJ, Blaut M (1997) Effects of inulin and lactose on fecal microflora, microbial activity, and bowel habit in elderly constipated persons. Am J Clin Nutr 65(5):1397–1402. http://www.ncbi.nlm.nih.gov/pubmed/9129468

Micka A, Siepelmeyer A, Holz A, Theis S, Schön C, Schon C (2017) Effect of consumption of chicory inulin on bowel function in healthy subjects with constipation: A randomized, double-blind, placebo-controlled trial. Int J Food Sci Nutr Feb 68 (1):82–89. http://www.tandfonline.com/doi/pdf/10.1080/09637486.2016.1212819?needAccess=true&

Scholtens PA, Alles MS, Willemsen LE, van den BC, Bindels JG, Boehm G, Govers MJ (2006) Dietary fructo-oligosaccharides in healthy adults do not negatively affect faecal cytotoxicity: a randomised, double-blind, placebo-controlled crossover trial. Br J Nutr 95(6):1143–1149. http://www.ncbi.nlm.nih.gov/pubmed/16768837

Review articles:

EFSA Panel on Dietetic Products, Nutrition and Allergies (2015) Scientific Opinion on the substantiation of a health claim related to “native chicory inulin” and maintenance of normal defecation by increasing stool frequency pursuant to Article 13.5 of Regulation (EC) No 1924/20061. EFSA Journal 13 (1) 3951. http://www.efsa.europa.eu/sites/default/files/scientific_output/files/main_documents/3951.pdf

Collado Yurrita L, San Mauro Martin I, Ciudad-Cabanas MJ, Calle-Puron ME, Hernandez Cabria M (2014) Effectiveness of inulin intake on indicators of chronic constipation; a meta-analysis of controlled randomized clinical trials. Nutr Hosp 30 (2)(1699-5198):244–252. http://www.aulamedica.es/nh/pdf/7565.pdf

 

3. The role of chicory root fibers in weight management

 

Chicory root fibers help you to eat less, naturally. This is important for weight loss, for keeping a healthy weight and for keeping weight after weight loss – in other words, it is relevant for everyone. Research with chicory root fibers is available related to the topics of appetite/satiety influence, hormonal influences (GLP-1, PYY), influence on the caloric intake (energy intake), in particular for mid-term and long-term durations and for weight loss. The most reliable data are related to energy intake as these type of study designs are taking care of next meal or next day compensation in caloric intake and thus provide reliable information. In the case of chicory root fibers, and more specifically Orafti® Synergy1 and Orafti©P95 oligofructose, a number of human intervention studies are available, in healthy, overweight and obese volunteers, that demonstrate a particular role for Orafti® Synergy1 and oligofructose in promoting a moderate negative energy balance in humans consuming an ad libitum diet.

References related to these studies are:

Cani PD, Joly E, Horsmans Y, Delzenne NM (2006) Oligofructose promotes satiety in healthy human: a pilot study. Eur J Clin Nutr 60(5):567–572. http://www.nature.com/ejcn/journal/v60/n5/pdf/1602350a.pdf

Daud NM, Ismail NA, Thomas EL, Fitzpatrick JA, Bell JD, Swann JR, Costabile A, Childs CE, Pedersen C, Goldstone AP, Frost GS (2014) The impact of oligofructose on stimulation of gut hormones, appetite regulation, and adiposity. Obesity 22(6):1430–1438. http://www.ncbi.nlm.nih.gov/pubmed/24715424

Guess ND, Dornhorst A, Oliver N, Frost GS (2016) A Randomised Crossover Trial: The Effect of Inulin on Glucose Homeostasis in Subtypes of Prediabetes. Ann Nutr Metab 68(1):26–34. http://www.ncbi.nlm.nih.gov/pubmed/26571012

Guess ND, Dornhorst A, Oliver N, Bell JD, Thomas EL, Frost GS (2015) A randomized controlled trial: the effect of inulin on weight management and ectopic fat in subjects with prediabetes. Nutr Metab (Lond) 12:36. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619305/

McCann MT, Livingstone MB, Wallace JMW, Gallagher AM, Welch RW (2011) Oligofructose-enriched inulin supplementation decreases energy intake in overweight and obese men and women. Obesity reviews 12(S1):63–279. http://onlinelibrary.wiley.com/doi/10.1111/j.1467-789X.2011.00889.x/pdf

Parnell JA, Reimer RA (2009) Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am J Clin Nutr 89(6):1751–1759. http://ajcn.nutrition.org/content/89/6/1751.full.pdf

Reimer RA, Willis HJ, Tunnicliffe JM, Park H, Madsen KL, Soto-Vaca A (2017) Inulin-type fructans and whey protein both modulate appetite but only fructans alter gut microbiota in adults with overweight/obesity: A randomized controlled trial. Mol Nutr Food Res 61(11):1-12.

https://www.ncbi.nlm.nih.gov/pubmed/28730743

The beneficial effects of chicory root fibers for weight management have also been studied in children and young adolescents. The references for this age group are:

Abrams SA, Griffin IJ, Hawthorne KM, Ellis KJ (2007) Effect of Prebiotic Supplementation and Calcium Intake on Body Mass Index. J Pediatr 151:293–298. http://www.ncbi.nlm.nih.gov/pubmed/17719942

Hume MP, Nicolucci AC, Reimer, Raylene A. (2017) Prebiotic supplementation improves appetite control in children with overweight and obesity: a randomized controlled trial: A randomized controlled trial. Am J Clin Nutr 105(4):790–799. https://www.ncbi.nlm.nih.gov/pubmed/28228425

Liber A, Szajewska H (2014) Effect of oligofructose supplementation on body weight in overweight and obese children: a randomised, double-blind, placebo-controlled trial. Br J Nutr 112(12):2068–2074. http://www.ncbi.nlm.nih.gov/pubmed/25327394

Nicolucci AC, Hume MP, Martínez I, Mayengbam S, Walter J, Reimer, Raylene A., Martinez I (2017) Prebiotic Reduces Body Fat and Alters Intestinal Microbiota in Children With Overweight or Obesity. Gastroenterology 153(3):711–722. http://www.gastrojournal.org/article/S0016-5085(17)35698-6/pdf.

 

4. Chicory root fibers and blood sugar management

 

Since inulin and oligofructose are non-digestible carbohydrates they do not contribute to post-prandial glycemia. Replacing digestible and glycemic carbohydrates partially or completely with inulin or oligofructose on a weight-by-weight basis in a food product reduces the amount of available carbohydrates and consequently the postprandial blood glucose response of the food. Human studies show significant reductions in the postprandial glycemic response for different foods in which sugars have been replaced by oligofructose at levels of 20% or more. A linear relationship between the extent of sugar replacement and a reduction in the resulting blood glucose response shows that higher fructan levels will result in greater effects, respectively. Also the corresponding insulin levels have been measured and confirmed to be lower as well.

References related to postprandial blood glucose response:

Lightowler H, Thondre S, Holz A, Theis S (2017) Replacement of glycaemic carbohydrates by inulin-type fructans from chicory (oligofructose, inulin) reduces the postprandial blood glucose and insulin response to foods: Report of two double-blind, randomized, controlled trials. Eur J Nutr. https://rd.springer.com/article/10.1007%2Fs00394-017-1409-z

Tarini J, Wolever TM (2010) The fermentable fibre inulin increases postprandial serum short-chain fatty acids and reduces free-fatty acids and ghrelin in healthy subjects. Appl Physiol Nutr Metab 35(1):9–16. http://www.ncbi.nlm.nih.gov/pubmed/20130660

A positive European Food Safety Authority (EFSA) opinion and approved health claim have been granted as a result of these data:

EFSA Panel on Dietetic Products, Nutrition and Allergies (2014) Scientific Opinion on the substantiation of health claims related to non-digestible carbohydrates and a reduction of post-prandial glycaemic responses pursuant to Article 13 (5) of Regulation (EC) No. 1924/2006. EFSA Journal 12(1):3513. http://www.efsa.europa.eu/sites/default/files/scientific_output/files/main_documents/3513.pdf

Kellow NJ, Coughlan MT, Reid CM (2014) Metabolic benefits of dietary prebiotics in human subjects: a systematic review of randomised controlled trials. Br J Nutr 111(7):1147–1161. http://journals.cambridge.org/article_S0007114513003607

References of human studies related to long-term blood glucose control:

Dewulf EM, Cani PD, Claus SP, Fuentes S, Puylaert PG, Neyrinck AM, Bindels LB, Vos WM de, Gibson GR, Thissen JP, Delzenne NM (2013) Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 62(8):1112–1121. http://www.ncbi.nlm.nih.gov/pubmed/23135760

Jackson KG, Taylor GR, Clohessy AM, Williams CM (1999) The effect of the daily intake of inulin on fasting lipid, insulin and glucose concentrations in middle-aged men and women. Br J Nutr 82(1):23–30. https://www.ncbi.nlm.nih.gov/pubmed/10655953

Parnell JA, Reimer RA (2009) Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am J Clin Nutr 89(6):1751–1759. http://ajcn.nutrition.org/content/89/6/1751.full.pdf

Russo F, Riezzo G, Chiloiro M, Michele G de, Chimienti G, Marconi E, D’Attoma B, Linsalata M, Clemente C (2010) Metabolic effects of a diet with inulin-enriched pasta in healthy young volunteers. Curr Pharm Des 16(7):825–831. http://www.ncbi.nlm.nih.gov/pubmed/20388093

Liu F, Prabhakar M, Ju J, Long H, Zhou H-W (2017) Effect of inulin-type fructans on blood lipid profile and glucose level: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr 71(1):9–20. kp://onlinelibrary.wiley.com/doi/10.1359/JBMR.050114/epdf

Coudray C, Bellanger J, Castiglia-Delavaud C, Rémésy C, Vermorel M, Rayssignuier Y (1997) Effect of soluble or partly soluble dietary fibres supplementation on absorption and balance of calcium,

magnesium, iron and zinc in healthy young men. Eur J Clin Nutr 51:375–380. http://www.ncbi.nlm.nih.gov/pubmed/9192195

Griffin IJ, Hicks PMD, Heany RP, Abrams SA (2003) Enriched chicory inulin increases calcium absorption mainly in girls with lower calcium absorption. Nutr Res 23:901–909. http://www.sciencedirect.com/science/article/pii/S027153170300085X

Griffin IJ, Davila PM, Abrams SA (2002) Non-digestible oligosaccharides and calcium absorption in girls with adequate calcium intakes. Br J Nutr 87(S2):S187-S191. http://www.ncbi.nlm.nih.gov/pubmed/12088517

Holloway L, Moynihan S, Abrams SA, Kent K, Hsu AR, Friedlander AL (2007) Effects of oligofructose-enriched inulin on intestinal absorption of calcium and magnesium and bone turnover markers in postmenopausal women. Br J Nutr 97(2):365–372. http://www.ncbi.nlm.nih.gov/pubmed/17298707

 

6. Inulin and oligofructose as bioactive substances (prebiotics) in infants, small children and kindergarten age children

 

The development of the gut microbiota is a critical and essential process early in life as it impacts later health outcomes. Inulin and oligofructose can safely be used in milks for infants 0-6 years of age, showing effects on the composition of the microbiota (prebiotic properties) towards a human milk-type composition and improvements in stool consistency. In addition, studies show that prebiotics from the chicory root influence immunity positively.

References for infant and small children studies:

Brunser O, Gotteland M, Cruchet S, Figueroa G, Garrido D, Steenhout P (2006) Effect of a milk formula with prebiotics on the intestinal microbiota of infants after an antibiotic treatment. Pediatr Res 59(3):451–456. http://www.ncbi.nlm.nih.gov/pubmed/16492988

Closa-Monasterolo R, Gispert-Llaurado M, Luque V, Ferre N, Rubio-Torrents C, Zaragoza-Jordana M, Escribano J (2013) Safety and efficacy of inulin and oligofructose supplementation in infant formula: results from a randomized clinical trial. Clin Nutr 32(6):918–927. http://www.ncbi.nlm.nih.gov/pubmed/23498848

Lohner S, Jakobik V, Mihályi K, Soldi S, Vasileiadis S, Theis S, Sailer M, Sieland C, Berényi K, Boehm G, Decsi T (2018) Inulin-type fructan supplementation of 3 to 6 year-old children is associated with higher fecal bifidobacterium concentrations and fewer Febrile Episodes Requiring Medical Attention. J Nutr 102(Suppl 2):261. https://academic.oup.com/jn/advance-article/doi/10.1093/jn/nxy120/5048772

Soldi S, Vasileiadis S, Lohner S, Uggeri F, Puglisi E, Molinari P, Donner E, Sieland C, Decsi T, Sailer M, Theis S (2019) Prebiotic supplementation over a cold season and during antibiotic treatment specifically modulates the gut microbiota composition of 3-6 year-old children. Benef Microbes 19; 10 (3):253–263. https://www.wageningenacademic.com/doi/pdf/10.3920/BM2018.0116

Veereman-Wauters G, Staelens S, van de Broek H, Plaskie K, Wesling F, Roger L, McCartney A, Assam P (2011) Physiological and bifidogenic effects of prebiotic supplements in infant formulae. J Pediatr Gastroenterol Nutr 52(6):763–771. http://journals.lww.com/jpgn/Fulltext/2011/06000/Physiological_and_Bifidogenic_Effects_of_Prebiotic.20.aspx

Wernimont S, Northington R, Kullen MJ, Yao M, Bettler J (2015) Effect of an α-lactalbumin-enriched infant formula supplemented with oligofructose on fecal microbiota, stool characteristics, and hydration status: a randomized, double-blind, controlled trial. Clin Pediatr (Phila) 54(4):359–370. http://www.ncbi.nlm.nih.gov/pubmed/25297064

Yao M, Lien EL, Capeding, Maria R Z, Fitzgerald M, Ramanujam K, Yuhas R, Northington R, Lebumfacil J, Wang L, DeRusso PA, Capeding MR (2014) Effects of term infant formulas containing high sn-2 palmitate with and without oligofructose on stool composition, stool characteristics, and bifidogenicity. J. Pediatr. Gastroenterol. Nutr. 59(4):440–448. http://www.ncbi.nlm.nih.gov/pubmed/24840511

Closa-Monasterolo R, Ferré N, Castillejo-DeVillasante G, Luque V, Gispert-Llaurado M, Zaragoza-Jordana M, Theis S, Escribano J (2017) The use of inulin-type fructans improves stool consistency in constipated children. A randomised clinical trial: Pilot study. Int J Food Sci Nutr 68(5):587–594. http://www.tandfonline.com/doi/pdf/10.1080/09637486.2016.1263605?needAccess=true

Moore N, Chao C, Yang LP, Storm H, Oliva-Hemker M, Saavedra JM (2003) Effects of fructo-oligosaccharide-supplemented infant cereal: a double-blind, randomized trial. Br J Nutr 90(3):581–587. http://www.ncbi.nlm.nih.gov/pubmed/13129464

Nowacki J, Lee HC, Lien R, Cheng SW, Li ST, Yao M, Northington R, Jan I, Mutungi G (2014) Stool fatty acid soaps, stool consistency and gastrointestinal tolerance in term infants fed infant formulas containing high sn-2 palmitate with or without oligofructose: a double-blind, randomized clinical trial. Nutr J 13:105. http://www.ncbi.nlm.nih.gov/pubmed/25373935

Review articles:

Lohner S, Kullenberg D, Antes G, Decsi T, Meerpohl JJ (2014) Prebiotics in healthy infants and children for prevention of acute infectious diseases: a systematic review and meta-analysis. Nutr Rev 72(8):523–531. http://www.ncbi.nlm.nih.gov/pubmed/24903007

Skórka A, Pieścik-Lech M, Kołodziej M, Szajewska H (2018) Infant formulae supplemented with prebiotics: Are they better than unsupplemented formulae? An updated systematic review. Br J Nutr:1–16. https://www.ncbi.nlm.nih.gov/pubmed/29457570

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