Probiotic Supplementation Has a Limited Effect on Circulating Immune and Inflammatory Markers in Healthy Adults: A Systematic Review of Randomized Controlled Trials

Published:October 21, 2019DOI:https://doi.org/10.1016/j.jand.2019.08.018

      Abstract

      Background

      A main mechanism of action proposed for oral probiotic supplementation is immunomodulation, which is expected to impart health benefits in the host by influencing circulating immune and inflammatory factors. To date, the effectiveness of probiotic supplementation for immunomodulation in healthy adults without disease has not been evaluated in a systematic review.

      Objective

      The objective of this systematic review was to evaluate the effect of probiotic supplementation on circulating immune and inflammatory markers of healthy adults compared to placebo.

      Methods

      PubMed, SCOPUS, ISI Web of Science, ProQuest, and Cochrane databases were searched for English articles up to May 15, 2019. Additional papers were identified by checking references of relevant papers. Only randomized controlled trials studying the administration of probiotic supplements compared to placebo on immune and inflammatory markers in healthy adults (aged 18 to 65 years), without acute or chronic disease, and in generally good health were examined. Independent extraction of articles was conducted by two authors using predefined search terms and restrictions/filters. The methodologic quality of each study was appraised using the Academy of Nutrition and Dietetics Evidence Analysis Library Quality Rating Worksheet and the body of evidence was assessed using the Academy of Nutrition and Dietetics Grade Definitions and Conclusion Grading Table.

      Results

      Eighteen articles, including 819 subjects, met eligibility criteria and were included in the present systematic review. Five articles were rated neutral in quality and 13 were rated high in quality. Eight articles reported a significant effect on immune and/or inflammatory parameters including increases in natural killer cells, lymphocytes, and monocytes, and decreases in proinflammatory cytokine concentrations.

      Conclusions

      Based on the 18 articles extracted in this systemic review, probiotic supplementation was concluded to have a limited effect on immune and inflammatory markers in healthy adults. Overall, the evidence was heterogenous, precluding a meta-analysis, and difficult to aggregate and conclude on effect size.

      Systematic review registration number

      PROSPERO ref CRD42018110856.

      Keywords

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      References

        • Clarke T.
        • Black L.
        • Stussman B.
        • et al.
        Trends in the use of complementary health approaches among adults: United States, 2002-2012.
        Natl Health Stat Report. 2015; : 1-16
        • Market Research Engine
        Probiotics Market By Ingredient Analysis (Bacteria, Yeast); by Application Analysis (Food & Beverages, Dietary Supplements, Animal Feed); by End User Analysis (Human Probiotics, Animal Probiotics) and by Regional Analysis—Global Forecast by 2018- 2024. Market Research Engine website.
        (Published November 2018. Accessed January 12, 2019)
        • Hill C.
        • Guarner F.
        • Reid G.
        • et al.
        Expert consensus document: The international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic.
        Nat Rev Gastroenterol Hepatol. 2014; 11: 506-514
        • Sanders M.E.
        • Merenstein D.
        • Merrifield C.A.
        • et al.
        Probiotics for human use.
        Nutr Bull. 2018; 43: 212-225
        • Di Cerbo A.
        • Palmieri B.
        Review: The market of probiotics.
        Pak J Pharm Sci. 2015; 28: 2199-2206
        • Markowiak P.
        • Ślizewska K.
        Effects of probiotics, prebiotics, and synbiotics on human health.
        Nutrients. 2017; 9
        • Khalesi S.
        • Bellissimo N.
        • Vandelanotte C.
        • et al.
        A review of probiotic supplementation in healthy adults: Helpful or hype?.
        Eur J Clin Nutr. 2019; 73: 24-37
        • Kristensen N.B.
        • Bryrup T.
        • Allin K.H.
        • et al.
        Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: A systematic review of randomized controlled trials.
        Genome Med. 2016; 8: 52
        • Shreiner A.B.
        • Kao J.Y.
        • Young V.B.
        The gut microbiome in health and in disease.
        Curr Opin Gastroenterol. 2015; 31: 69-75
        • Lebeer S.
        • Vanderleyden J.
        • De Keersmaecker S.C.
        Host interactions of probiotic bacterial surface molecules: Comparison with commensals and pathogens.
        Nat Rev Microbiol. 2010; 8: 171-184
        • Ouwehand A.C.
        • Salminen S.
        • Isolauri E.
        Probiotics: An overview of beneficial effects.
        Antonie van Leeuwenhoek. 2002; 82: 279-289
        • Oelschlaeger T.A.
        Mechanisms of probiotic actions—A review.
        Int J Med Microbiol. 2010; 300: 57-62
        • Elmadfa I.
        • Klein P.
        • Meyer A.L.
        Immune-stimulating effects of lactic acid bacteria in vivo and in vitro.
        Proc Nutr Soc. 2010; 69: 416-420
        • Douglas L.C.
        • Sanders M.E.
        Probiotics and prebiotics in dietetics practice.
        J Am Diet Assoc. 2008; 108: 510-521
        • Bermudez-Brito M.
        • Plaza-Díaz J.
        • Muñoz-Quezada S.
        • et al.
        Probiotic mechanisms of action.
        Ann Nutr Metab. 2012; 61: 160-174
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • et al.
        Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
        BMJ. 2009; 339: b2535
        • 103rd Congress
        Dietary Supplement Health and Education Act of 1994; Public Law 103-417. National Institutes of Health, Office of Dietary Supplements website.
        (Approved October 25, 1994. Accessed November 15, 2018)
        • US Food and Drug Administration
        Dietary Supplements Guidance Documents & Regulatory Information. Food and Drug Administration website.
        (Published 2018. Accessed December 3, 2018)
        • Plaza-Díaz J.
        • Gomez-Llorente C.
        • Fontana L.
        • et al.
        Modulation of immunity and inflammatory gene expression in the gut, in inflammatory diseases of the gut and in the liver by probiotics.
        World J Gastroenterol. 2014; 20: 15632-15649
        • Smolinska S.
        • Groeger D.
        • O’Mahony L.
        Biology of the microbiome 1: Interactions with the host immune response.
        Gastroenterol Clin North Am. 2017; 46: 19-35
        • La Fata G.
        • Weber P.
        • Mohajeri M.H.
        Probiotics and the gut immune system: Indirect Regulation.
        Probiotics Antimicrob Proteins. 2018; 10: 11-21
        • Academy of Nutrition and Dietetics
        Evidence Analysis Manual. Academy of Nutrition and Dietetics website.
        (Published April 2016. Accessed January 1, 2019)
        • Handu D.
        • Moloney L.
        • Wolfram T.
        • et al.
        Academy of Nutrition and Dietetics methodology for conducting systematic reviews for the Evidence Analysis Library.
        J Acad Nutr Diet. 2016; 116: 311-318
        • Wang R.
        • Lagakos S.W.
        • Ware J.H.
        • et al.
        Statistics in medicine—Reporting of subgroup analyses in clinical trials.
        N Engl J Med. 2007; 357: 2189-2194
        • Cox A.J.
        • West N.P.
        • Horn P.L.
        • et al.
        Effects of probiotic supplementation over 5 months on routine haematology and clinical chemistry measures in healthy active adults.
        Eur J Clin Nutr. 2014; 68: 1255-1257
        • West N.P.
        • Horn P.L.
        • Barrett S.
        • et al.
        Supplementation with a single and double strain probiotic on the innate immune system for respiratory illness.
        ESPEN J. 2014; 9: e178-e184
        • Ibrahim N.S.
        • Muhamad A.S.
        • Ooi F.K.
        • et al.
        The effects of combined probiotic ingestion and circuit training on muscular strength and power and cytokine responses in young males.
        Appl Physiol Nutr Metab. 2018; 43: 180-186
        • Ibrahim N.S.
        • Ooi F.K.
        • Chen C.K.
        • et al.
        Effects of probiotics supplementation and circuit training on immune responses among sedentary young males.
        J Sports Med Phys Fitness. 2018; 58: 1102-1109
        • Boesmans L.
        • Valles-Colomer M.
        • Wang J.
        • et al.
        Butyrate producers as potential next-generation probiotics: Safety assessment of the administration of Butyricicoccus pullicaecorum to healthy volunteers.
        mSystems. 2018; 3
        • Mäkeläinen H.
        • Tahvonen R.
        • Salminen S.
        • et al.
        In vivo safety assessment of two Bifidobacterium longum strains.
        Microbiol Immunol. 2003; 47: 911-914
        • Christensen H.R.
        • Larsen C.N.
        • Kaestel P.
        • et al.
        Immunomodulating potential of supplementation with probiotics: A dose-response study in healthy young adults.
        FEMS Immunol Med Microbiol. 2006; 47: 380-390
        • Kim H.S.
        • Park H.
        • Cho I.Y.
        • et al.
        Dietary Supplementation of probiotic Bacillus polyfermenticus, bispan strain, modulates natural killer cell and T cell subset populations and immunoglobulin G levels in human subjects.
        J Med Food. 2006; 9: 321-327
        • Lee Y.J.
        • Lee A.
        • Yoo H.J.
        • Kim M.
        • Noh G.M.
        • Lee J.H.
        Supplementation with the probiotic strain Weissella cibaria JW15 enhances natural killer cell activity in nondiabetic subjects.
        J Funct Foods. 2018; 48: 153-158
        • Wind R.D.
        • Tolboom H.
        • Klare I.
        • et al.
        Tolerance and safety of the potentially probiotic strain Lactobacillus rhamnosus PRSF-L477: A randomised, double-blind placebo-controlled trial in healthy volunteers.
        Br J Nutr. 2010; 104: 1806-1816
        • Sierra S.
        • Lara-Villoslada F.
        • Sempere L.
        • et al.
        Intestinal and immunological effects of daily oral administration of Lactobacillus salivarius CECT5713 to healthy adults.
        Anaerobe. 2010; 16: 195-200
        • Burton J.P.
        • Cowley S.
        • Simon R.R.
        • et al.
        Evaluation of safety and human tolerance of the oral probiotic Streptococcus salivarius K12: A randomized, placebo-controlled, double-blind study.
        Food Chem Toxicol. 2011; 49: 2356-2364
        • Childs C.E.
        • Röytiö H.
        • Alhoniemi E.
        • et al.
        Xylo-oligosaccharides alone or in synbiotic combination with Bifidobacterium animalis subsp. lactis induce bifidogenesis and modulate markers of immune function in healthy adults: A double-blind, placebo-controlled, randomised, factorial cross-over study.
        Br J Nutr. 2014; 111: 1945-1956
        • Mangalat N.
        • Liu Y.
        • Fatheree N.Y.
        • et al.
        Safety and tolerability of Lactobacillus reuteri DSM 17938 and effects on biomarkers in healthy adults: Results from a randomized masked trial.
        PLoS One. 2012; 7e43910
        • Marcial G.E.
        • Ford A.L.
        • Haller M.J.
        • et al.
        Lactobacillus johnsonii N6.2 modulates the host immune responses: A double-blind, randomized trial in healthy adults.
        Front Immunol. 2017; 8: 655
        • Rajkumar H.
        • Mahmood N.
        • Kumar M.
        • et al.
        Effect of probiotic (VSL#3) and omega-3 on lipid profile, insulin sensitivity, inflammatory markers, and gut colonization in overweight adults: A randomized, controlled trial.
        Mediators Inflamm. 2014; 2014348959
        • Rajkumar H.
        • Kumar M.
        • Das N.
        • et al.
        Effect of probiotic Lactobacillus salivarius UBL S22 and prebiotic fructo-oligosaccharide on serum lipids, inflammatory markers, insulin sensitivity, and gut bacteria in healthy young volunteers: A randomized controlled single-blind pilot study.
        J Cardiovasc Pharmacol Ther. 2015; 20: 289-298
        • Kelly J.R.
        • Allen A.P.
        • Temko A.
        • et al.
        Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects.
        Brain Behav Immun. 2017; 61: 50-59
        • McHugh M.L.
        Interrater reliability: The kappa statistic.
        Biochem Medica (Zagreb). 2012; 22: 276-282
        • Kang E.J.
        • Kim S.Y.
        • Hwang I.H.
        • et al.
        The effect of probiotics on prevention of common cold: A meta-analysis of randomized controlled trial studies.
        Korean J Fam Med. 2013; 34: 2-10
        • King S.
        • Glanville J.
        • Sanders M.E.
        • et al.
        Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions: A systematic review and meta-analysis.
        Br J Nutr. 2014; 112: 41-54
        • Miller L.E.
        • Lehtoranta L.
        • Lehtinen M.J.
        The effect of Bifidobacterium animalis ssp. lactis HN019 on cellular immune function in healthy elderly subjects: Systematic review and meta-analysis.
        Nutrients. 2017; 9
        • McFarland L.V.
        • Evans C.T.
        • Goldstein E.J.C.
        Strain-specificity and disease-specificity of probiotic efficacy: A systematic review and meta-analysis.
        Front Med. 2018; 5: 124
        • Shane A.L.
        • Cabana M.D.
        • Vidry S.
        • et al.
        Guide to designing, conducting, publishing and communicating results of clinical studies involving probiotic applications in human participants.
        Gut Microbes. 2010; 1: 243-253
        • Guarner F.
        • Khan A.G.
        • Garisch J.
        • et al.
        World gastroenterology organisation global guidelines: Probiotics and prebiotics October 2011.
        J Clin Gastroenterol. 2012; 46: 468-481
        • Azad M.A.K.
        • Sarker M.
        • Wan D.
        Immunomodulatory effects of probiotics on cytokine profiles.
        Biomed Res Int. 2018; 2018: 8063647
        • Vinolo M.A.
        • Rodrigues H.G.
        • Nachbar R.T.
        • et al.
        Regulation of inflammation by short chain fatty acids.
        Nutrients. 2011; 3: 858-876
        • Schlee M.
        • Harder J.
        • Köten B.
        • et al.
        Probiotic lactobacilli and VSL#3 induce enterocyte beta-defensin 2.
        Clin Exp Immunol. 2008; 151: 528-535
        • Thomas C.M.
        • Versalovic J.
        Probiotics-host communication modulation of signaling pathways in the intestine.
        Gut Microbes. 2010; 1: 148-163
        • Djaldetti M.
        • Bessler H.
        Probiotic strains modulate cytokine production and the immune interplay between human peripheral blood mononucear cells and colon cancer cells.
        FEMS Microbiol Lett. 2017; 364: fnx014
        • Arango Duque G.
        • Descoteaux A.
        Macrophage cytokines: Involvement in immunity and infectious diseases.
        Front Immunol. 2014; 5: 491
        • Alberts B.
        • Johnson A.
        • Lewis J.
        • et al.
        Lymphocytes and the cellular basis of adaptive immunity.
        Mol Biol Cell. 2002; 4552: 4-8
        • David L.A.
        • Maurice C.F.
        • Carmody R.N.
        • et al.
        Diet rapidly and reproducibly alters the human gut microbiome.
        Nature. 2014; 505: 559-563
        • Kim D.H.
        Gut microbiota-mediated drug-antibiotic interactions.
        Drug Metab Dispos. 2015; 43: 1581-1589
        • Buford T.W.
        • Carter C.S.
        • VanDerPol W.J.
        • et al.
        Composition and richness of the serum microbiome differ by age and link to systemic inflammation.
        GeroScience. 2018; 40: 257-268
        • Segata N.
        Gut Microbiome: Westernization and the disappearance of intestinal diversity.
        Curr Biol. 2015; 25 (R611-613)
        • Gupta V.K.
        • Paul S.
        • Dutta C.
        Geography, ethnicity or subsistence-specific variations in human microbiome composition and diversity.
        Front Microbiol. 2017; 8: 1162
        • Deschasaux M.
        • Bouter K.E.
        • Prodan A.
        • et al.
        Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography.
        Nat Med. 2018; 24: 1526-1531
        • Walsh N.P.
        • Gleeson M.
        • Pyne D.B.
        • et al.
        Position statement part two: Maintaining immune health.
        Exerc Immunol Rev. 2011; 17: 64-103
        • Allen J.
        • Sun Y.
        • Woods J.A.
        Exercise and the regulation of inflammatory responses.
        Prog Mol Biol Transl Sci. 2015; 135: 337-354
        • West N.P.
        • Cripps A.W.
        Are vaccination models suitable to determine whether probiotics have beneficial health effects in the general population?.
        Hum Vaccin Immunother. 2013; 9: 621-624
        • Yeh T.L.
        • Shih P.C.
        • Liu S.J.
        • et al.
        The influence of prebiotic or probiotic supplementation on antibody titers after influenza vaccination: A systematic review and meta-analysis of randomized controlled trials.
        Drug Des Devel Ther. 2018; 12: 217-230
        • Lei W.T.
        • Shih P.C.
        • Liu S.J.
        • et al.
        Effect of probiotics and prebiotics on immune response to influenza vaccination in adults: A systematic review and meta-analysis of randomized controlled trials.
        Nutrients. 2017; 9
        • Zimmermann P.
        • Curtis N.
        The influence of probiotics on vaccine responses—A systematic review.
        Vaccine. 2018; 36: 207-213
        • Nieman D.C.
        • Henson D.A.
        • Austin M.D.
        • et al.
        Upper respiratory tract infection is reduced in physically fit and active adults.
        Br J Sports Med. 2011; 45: 987-992
        • Walsh N.P.
        • Gleeson M.
        • Shephard R.J.
        • et al.
        Position statement part one: Immune function and exercise.
        Exerc Immunol Rev. 2011; 17: 6-63
        • Gleeson M.
        • Bishop N.C.
        URI in athletes: Are mucosal immunity and cytokine responses key risk factors?.
        Exerc Sport Sci Rev. 2013; 41: 148-153

      Biography

      A. E. Mohr is a PhD student, College of Health Solutions, Arizona State University, Phoenix, and a research and development scientist, Isagenix International LLC, Gilbert, AZ.

      Biography

      A. J. Basile is PhD student, School of Life Sciences, Arizona State University, Tempe, AZ.

      Biography

      M. S. Crawford is PhD student, School of Life Sciences, Arizona State University, Tempe, AZ.

      Biography

      K. L. Sweazea is an associate professor, College of Health Solutions, Arizona State University, Phoenix, and an associate professor, School of Life Sciences, Arizona State University, Tempe, AZ.

      Biography

      K. C. Carpenter is senior scientific content specialist, Isagenix International LLC, Gilbert, AZ.