1 s2.0 S2161831323000765 Main

REVIEW
Orally Ingested Probiotics, Prebiotics, and

Synbiotics as Countermeasures for Respiratory
Tract Infections in Nonelderly Adults: A Systematic
Review and Meta-Analysis
Julie L Coleman,1,2 Adrienne Hatch-McChesney,1 Stephanie D Small,1,2 Jillian T Allen,1,2 Elaine Sullo,3 Richard T Agans,4,5
Heather S Fagnant,1 Asma S Bukhari,1 and J Philip Karl1
1 US Army Research Institute of Environmental Medicine, Natick, MA, USA; 2 Oak Ride Institute of Science and Education, Belcamp, MD, USA; 3 The George
Washington University, Washington, DC, USA; 4 Naval Medical Research Unit Dayton, Dayton, OH, USA; and 5 PARSONS Government Services, San Antonio,
TX, USA
ABSTRACT
The impact of gut microbiota–targeted interventions on the incidence, duration, and severity of respiratory tract infections (RTIs) in nonelderly
adults, and factors moderating any such effects, are unclear. This systematic review and meta-analysis aimed to determine the effects of orally
ingested probiotics, prebiotics, and synbiotics compared with placebo on RTI incidence, duration, and severity in nonelderly adults, and to identify
potential sources of heterogeneity. Studies were identified by searching CENTRAL, PubMed, Scopus, and Web of Science up to December 2021.
English-language, peer-reviewed publications of randomized, placebo-controlled studies that tested an orally ingested probiotic, prebiotic, or
synbiotic intervention of any dose for ≥1 wk in adults aged 18–65 y were included. Results were synthesized using intention-to-treat and per-
protocol random-effects meta-analysis. Heterogeneity was explored by subgroup meta-analysis and meta-regression. Risk of bias was assessed
using the Cochrane risk-of-bias assessment tool for randomized trials version 2 (RoB2). Forty-two manuscripts reporting effects of probiotics (n = 38),
prebiotics (n = 2), synbiotics (n = 1) or multiple -biotic types (n = 1) were identified (n = 9179 subjects). Probiotics reduced the risk of experiencing
≥1 RTI (relative risk = 0.91; 95% CI: 0.84, 0.98; P = 0.01), and total days (rate ratio = 0.77; 95% CI: 0.71, 0.83; P < 0.001), duration (Hedges’ g = −0.23;
95% CI: −0.39, −0.08; P = 0.004), and severity (Hedges’ g = −0.16; 95% CI: −0.29, −0.03; P = 0.02) of RTIs. Effects were relatively consistent across
different strain combinations, doses, and durations, although reductions in RTI duration were larger with fermented dairy as the delivery matrix,
and beneficial effects of probiotics were not observed in physically active populations. Overall risk of bias was rated as “some concerns” for most
studies. In conclusion, orally ingested probiotics, relative to placebo, modestly reduce the incidence, duration, and severity of RTIs in nonelderly
adults. Physical activity and delivery matrix may moderate some of these effects. Whether prebiotic and synbiotic interventions confer similar
protection remains unclear due to few relevant studies. This trial was registered at https://www.crd.york.ac.uk/prospero/ as CRD42020220213. Adv
Nutr 2022;13:2277–2295.
Statement of Significance: This systematic review and meta-analysis extends previous meta-analyses relying primarily on studies of pediatric
populations by demonstrating that orally ingested probiotics also reduce the incidence, duration, and severity of respiratory tract infections
(RTIs) in nonelderly adult populations. Further, this analysis identifies physical activity level and probiotic delivery matrix as potential effect
moderators and highlights the need for research regarding effects of prebiotics and synbiotics on RTI incidence, duration, and severity in adult
populations.
Keywords: respiratory infection, respiratory illness, common cold, influenza, coronavirus, gut microbiome, fermentable fiber, dietary supplement
Introduction worldwide public health issues (1). RTI symptoms often

Respiratory tract infections (RTIs), defined as respira- impair quality of life and productivity, and exist on a
tory illnesses that culminate in infections of the sinuses, spectrum from nuisance, such as sore throat, cough, nasal
throat, airways, and lungs, are common and present major obstruction, and headache, to potentially life-threatening
Published by Oxford University Press on behalf of the American Society for Nutrition 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US. Adv Nutr
2022;13:2277–2295; doi: https://doi.org/10.1093/advances/nmac086. 2277
complications, such as pneumonia, myocarditis, otitis media, clinical studies indicates that health benefits of these gut
and glomerulonephritis (2). RTIs are a leading cause for microbiota–targeted interventions may include modification
seeking outpatient medical care, generate a high number of local and systemic immune function (7–10). However,
of hospital admissions, increase medical costs, contribute immunomodulatory effects may vary according to the
to overwhelmed health care systems, and are responsible probiotic strains or prebiotic substrates used, have not been
for >2 million deaths annually (1, 3, 4). Despite this high observed in every population studied, and do not always
prevalence and disease burden, current therapies are limited result in observable effects on infection and illness in vivo
and often palliative rather than preventative, especially for (11).
the most common RTIs. Although vaccines are available to Interest in using prebiotics, synbiotics, and probiotics,
prevent certain types of RTIs, developing new vaccines can in particular, for reducing RTI burden (i.e., incidence,
be a lengthy and costly process that frequently results in duration, and severity) is reflected by a growing evidence
products with variable effectiveness (4, 5). Hence, identifying base summarized within several recent narrative reviews,
novel and cost-effective strategies for reducing the incidence, systematic reviews, and meta-analyses (11–21). The latter
duration, and severity of a broad-spectrum of RTIs is of have collectively reported that probiotics lower the odds
interest. or risk of experiencing RTIs by 11% to 47% (15, 16,
Interventions targeting the gut microbiota may provide 18), synbiotics reduce RTI incidence by 16% (13), and
one such strategy. This complex and dynamic community prebiotics reduce RTI incidence by 27% (12). However,
plays a critical role in several physiological functions, several knowledge gaps remain. First, the majority of studies
which includes protecting against pathogens and regulat- included in these meta-analyses involve pediatric popula-
ing host immune function (6). Approaches to modulating tions. To what extent findings are generalizable to adults
the composition and function of the gut microbiota, if and their more developed immune systems is unclear. Other
only transiently, include consumption of probiotics, pre- systematic reviews and meta-analyses have focused only on
biotics, and synbiotics. Probiotics are defined as live or- physically active and athletic populations (14, 19). Whether
ganisms that, when administered in adequate amounts, findings are applicable to less active adult populations is
confer a health benefit on the host and are found in unclear given that exercise itself modulates RTI risk (22). In
dietary supplements and some fermented food products addition, the effects of probiotics, prebiotics, and synbiotics
(7). Prebiotics are substrates that are selectively utilized on RTI risk may differ based on the product type and
by host microorganisms conferring a health benefit (8). duration of use. However, few meta-analyses have empirically
Established prebiotics include the fermentable saccharides tested those factors as potential sources of heterogeneity in
inulin, fructo-oligosaccharides, oligofructose, and galacto- study results. Finally, few meta-analyses have considered the
oligosaccharides. Other oligo- and polysaccharides are also duration and severity of RTI as outcomes, which are relevant
fermented by beneficial gut microbes. While those com- to understanding the full potential impact of probiotic,
pounds may not currently meet the definition of a prebiotic, prebiotic, and synbiotic interventions on disease burden.
microbial metabolism of those saccharides can result in This has recently been evidenced by the global experience
the production of the same health-promoting and immune- with coronavirus disease 2019 (COVID-19) wherein disease
modulating compounds produced during utilization of pre- severity ranges from no symptoms to terminal illness,
biotics (8). Synbiotics are a mixture of live microorganisms and symptom duration can last from days to months
and substrate(s) selectively utilized by host microorganisms (23).
that confer a health benefit on the host (9). Synbiotics The objective of this systematic review and meta-analysis
include combinations of probiotics and prebiotics that work was to address these gaps by determining the effects of
independently or live microbes and substrates selectively orally ingested probiotics, prebiotics, and synbiotics on the
utilized by those microbes. Evidence from preclinical and incidence, duration, and severity of RTIs in nonelderly adults.
Secondary objectives were to explore potential sources of
Supported in part by the US Army Medical Research and Development Command and heterogeneity in those effects resulting from the physical
appointment to the US Army Research Institute of Environmental Medicine administered by activity level of the population studied and dose, duration,
the Oak Ridge Institute for Science and Education (to JLC, JTA, and SDS) through an type, and form of treatment.
interagency agreement between the US Department of Energy and the US Army Medical
Research and Development Command.
Author disclosures: The authors report no conflicts of interest. The sponsor had no role in the
study design, data analysis, or interpretation of results.
The opinions or assertions contained herein are the private views of the authors and are not to Methods
be construed as official or reflecting the views of the Army or the Department of Defense. Any The systematic review protocol was registered on the
citations of commercial organizations and trade names in this report do not constitute an
official Department of the Army endorsement or approval of the products or services of these
PROSPERO International Register of Systematic Reviews
organizations. Approved for public release; distribution is unlimited. (National Institute for Health Research, University of York,
Supplemental Figures 1–7 and Supplemental Tables 1–10 are available from the UK; https://www.crd.york.ac.uk/prospero/) on 11 December
“Supplementary data” link in the online posting of the article and from the same link in the
online table of contents at https://academic.oup.com/advances/.
2020 (CRD42020220213) and was performed according to
Address correspondence to JPK (e-mail: james.p.karl.civ@health.mil). the Preferred Reporting Items for Systematic Reviews and
Abbreviations used: ITT, intention-to-treat; RoB2, Cochrane risk-of-bias assessment tool for Meta-Analyses (PRISMA).
randomized trials version 2; RTI, respiratory tract infection.
2278 Coleman et al.

Search strategy who were blinded to the other’s responses. A third reviewer
Initial searches of the electronic databases CENTRAL compared the data extraction and risk-of-bias assessments
(Cochrane Central Register of Controlled Trials), PubMed, and determined consensus.
Scopus, and Web of Science were conducted on 9 November Risk-of-bias assessment used the Cochrane risk-of-bias
2020 for all articles published up to that date. Searches assessment tool for randomized trials version 2 (RoB2)
used terms and Medical Subject Headings (MeSH) designed (24). The RoB2 assesses risk of bias resulting from the
specifically for both interventions and outcomes, and in- randomization process (domain 1), due to deviations from
cluded a validated randomized controlled trials filter for intended interventions (domain 2), due to missing outcome
each database except for CENTRAL (Supplemental Tables data (domain 3), in measurement of the outcome (domain 4),
1–4). Reference lists of other relevant systematic reviews and in selection of the reported result (domain 5). Risk of bias
were hand-searched to identify any articles not captured in for each domain was determined by answering the domain-
the initial search. All databases except for CENTRAL were specific signaling questions, recorded as “low,” “high,” or
searched again on 4 December 2021 using the same strategy “some concerns,” and used to determine overall bias (24). As
used for the initial searches. the primary aim of this review was to assess effects of assign-
ment to the intervention, signaling questions were structured
Eligibility criteria based on an intention-to-treat (ITT) effect. If needed, clinical
English-language, published, randomized-controlled trials trial registrations or other publications from the same study
examining effects of orally ingested probiotics, prebiotics, were sought to complete risk-of-bias assessments.
or synbiotics on the incidence, duration, or severity of Data extraction was completed using a modified version
RTIs in human adults were included. For the purposes of of the standard template provided within the Covidence
this review, probiotic was defined as any live population software. Descriptive information extracted from all articles
of unicellular microorganisms characterized to at least the deemed eligible for inclusion included funding source(s),
species level being studied for a health benefit. Prebiotic was study first author, year of publication, general description
defined as any nondigestible saccharide fermented by the gut of study setting and population including eligibility criteria,
microbiota, and synbiotic was defined as any combination number randomized, and number completing the study.
of probiotic(s) and prebiotic(s). Abstracts, conference pro- Information extracted for each intervention included inter-
ceedings, clinical trial registrations, and other gray literature vention type (pro-, pre-, or synbiotic), number of -biotics
were excluded. Additional exclusion criteria included the used (single or multiple), strain of probiotic, brand name
following: animal or in vitro studies; mean or median age and type of -biotic, treatment dose and duration, form of
of the study population not between 18 and 65 y; studies of intervention (capsule, powder, beverage, fermented dairy
hospitalized patients or cohorts with an immunodeficiency, product), and information on any other ingredients used
autoimmune or other immune system disorder, or taking in the intervention or placebo products. Outcome data
immune-modulating therapies; intervention periods <1 wk extracted included incidence of RTI (defined as number of
total duration; unmatched intervention and placebo, defined subjects with ≥1 RTI, total number of RTIs, or odds/risk ratio
as the intervention or placebo containing added bioactive of either outcome), RTI duration (total days of illness, days
ingredients not found in the other product; nonrandomized per event, days per person), and RTI severity as defined by the
or observational studies; and incidence, duration, or severity study authors. Although the number of missed days of school,
of RTIs not measured or reported. work, or athletic training due to RTI was also extracted, too
few studies reported those data to conduct a meta-analysis.
Selection process and data collection Attempts were made to contact corresponding authors by
Citations and corresponding abstracts identified through e-mail when relevant outcomes were not reported or not
each database search were uploaded into Covidence system- reported in sufficient detail for inclusion in the meta-analysis.
atic review software (Veritas Health Innovation) and dupli- Manual measurements were used to extract outcome data
cate entries were removed using the software’s automated presented only in figure format by digitally measuring the
system. The title and abstract of each entry were screened by location of means and error bars and converting those
2 reviewers blinded to the other’s responses. Any differences values using a height-to-unit ratio determined from digital
in voting were adjudicated by a third reviewer. Entries were measurement of the y-axis units (25).
eliminated only if 2 reviewers voted to exclude that entry.
Full texts of each entry that passed screening were retrieved Meta-analysis and publication bias
and screened by 2 reviewers blinded to the other’s responses. All analyses were completed using Comprehensive Meta
Reasons for any exclusions were noted and any differences Analysis version 3.3.070 software (Biostat). Outcomes in-
were adjudicated by a third reviewer. cluded risk ratio for the number of participants experiencing
Data extraction and risk-of-bias assessment were then ≥1 RTI during the intervention period, Hedges’ g effect size
conducted for all articles deemed eligible for inclusion. The for mean duration and mean severity of each RTI episode,
same reviewer completed both the data extraction and risk- and the rate ratio for total days of illness with an RTI. Risk
of-bias assessment for an article, and each article underwent ratios were calculated as the proportion with ≥1 RTI in the
data extraction and risk-of-bias assessment by 2 reviewers intervention group relative to the proportion with ≥1 RTI
Biotics and respiratory tract infections 2279

in the placebo group. Rate ratios were calculated using the Records identified through
incidence rate in the intervention group (total days of RTI CENTRAL, PubMed, Scopus
& Web of Science
illness/number of person-years) relative to the incidence rate (n = 20,948)
in the placebo group. Hedges’ g effect sizes were calculated
Duplicates removed:
using the means and SDs reported for each group, and (n = 3,539)
interpreted as small (0.20), medium (0.50), or large (0.80)
Records screened:
effects (26). (n = 17,409)
All outcomes were analyzed using the DerSimonian and
Excluded by title/abstract:
Laird inverse variance method for random-effects meta- (n = 17,254)
analysis and are presented as effect measure (95% CI). Risk
ratios and rate ratios were analyzed using both ITT (primary Full-text records reviewed:
(n = 155)
analysis) and per-protocol (secondary analysis) analyses. For Excluded by full text (n = 113):
• Relevant outcomes
ITT analyses, all subjects who were randomly assigned were
not reported
included in the calculation of risk or rate ratio. For per- • Not a peer-reviewed
protocol analyses, all subjects completing the study were Included in systematic review: full-text publication
• Probiotic (n = 38) • Wrong intervention
included in the risk and rate ratio calculations. Duration and • Prebiotic (n = 2) • Wrong population
severity of RTI were analyzed using per-protocol analyses • Synbiotic (n = 1) • No matched placebo
only. Heterogeneity was assessed using the I2 statistic from • Multiple intervention • Not written in English
types (n = 1) • Not a human RCT
a fixed-effects model. I2 statistics were interpreted based
on Cochrane handbook recommendations, wherein 30–60%,
50–90%, and 75–100% may suggest moderate, substantial, FIGURE 1 Flow diagram for screening and selection of studies
and considerable heterogeneity, respectively (27). Publica- assessing effects of orally ingested probiotics, prebiotics, or
tion bias was detected by visually inspecting funnel plots for synbiotics on the incidence, duration, or severity of respiratory tract
asymmetry and using Egger’s test (28). infections in nonelderly adults. RCT, randomized controlled trial.
Subgroup meta-analyses and meta-regressions were
undertaken for all outcomes to assess potential sources of reported data for different types of RTIs separately but not
heterogeneity. These analyses were largely defined a priori, combined (35, 36), which affected whether and how these
although several were developed a posteriori based on studies were included in the analyses. Any assumptions
characteristics of identified studies (use of fermented dairy or decisions made regarding treatment of these studies in
and population physical activity level). Subgroups included individual analyses are described in the table legends. Finally,
number of strains used in a probiotic intervention (single data from the 4 crossover studies identified in the search
or multi-strain), genus and species of probiotic, whether could not be included in the meta-analyses due to insufficient
the probiotic was delivered in a fermented dairy product, data (37–40).
and physical activity level of the study population. Random-
effects meta-analysis for each subgroup was conducted Results
whenever 3 or more studies were available for inclusion in Study selection and characteristics
the analysis. Random-effects meta-regression was conducted The study screening and selection process is shown in
using the DerSimonian and Laird method to compare Figure 1. Of 17,409 records screened, 39 studies reporting
effects within subgroups and to determine associations results in 42 separate manuscripts met the inclusion cri-
between study outcomes and daily dose of probiotic, teria (Tables 1 and 2). Of the studies included, 35 used
duration of intervention, and the total dose of probiotic a parallel-group design and 4 used a crossover design.
(dose × duration). Publication year ranged from 2001 to 2021. Studies were
Two studies included only 1 placebo group but multiple conducted in 16 countries, with continental percentages as
treatment groups (29, 30). Prior to calculating risk and rate follows: 53%, Europe; 17%, North America; 14%, Asia; 14%,
ratios, the number of events and number of participants Australia/Oceania; and 2%, South America. Populations
in the placebo group were divided by the number of included healthy adults (n = 19), healthy physically active
intervention groups. Prior to calculating effect sizes, the adults (n = 15), and adults with chronic illness (n = 5).
number of participants in the placebo group was divided Within the 39 studies, 39 probiotic (n = 8046 subjects),
by the number of intervention groups with no adjustments 4 prebiotic (n = 499 subjects), and 5 synbiotic (n = 634
made to the mean or SD in the placebo group. Each subjects) interventions were tested. Intervention durations
intervention group along with the reduced placebo group ranged from 3 to 52 wk. Intervention dose ranged from 40
was treated as a separate study in the meta-analysis (27). million to 100 billion CFU/d of probiotic, 2.5 to 5.6 g/d of pre-
Although this approach does not fully overcome unit-of- biotic, and for synbiotics, 5 to 10 billion CFU/d of probiotic
analysis error resulting from correlated measurements, it in addition to 2.5 to 3 g/d of prebiotic. The probiotic inter-
does allow these studies to be included in subgroup analyses. ventions were delivered as single strains of Bifidobacterium
Several studies used multiple intervention forms, doses, or (n = 7), Enterococcus (n = 2), Lactobacillus (n = 19), and
durations within a single intervention group (31–34) or Lactococcus (n = 1) or as multiple-strain products (n = 10).
2280 Coleman et al.

TABLE 1 Characteristics of included studies examining effects of probiotics on the incidence, duration, or severity of respiratory tract infections in nonelderly adults1
Study, year; country

(reference) Study design n (% Female), age,2 y Population Intervention (CFU/d); form Duration, wk
Ahrén et al., 2021; RCT, parallel group PRO: 448 (63), 41 ± 13 Healthy adults with PRO: Lactiplantibacillus plantarum HEAL9 DSM 15312 12
Sweden (41) PLA: 450 (65), 41 ± 14 reoccurring colds (1 × 109 ), Lacticaseibacillus paracasei 8700:2 DSM
13434 (1 × 109 ); powder
PLA: maltodextrin, powder
Altadill et al., 2021; RCT, parallel group PRO: 56 (70), 30 (21–58) Healthy adults PRO: Lactobacillus plantarum DR7 (1 × 109 ); powder 12
Malaysia (42); PLA: 53 (72), 28 (21–63) PLA: maltodextrin; powder
Chong et al., 2019;
Malaysia (43)
Berggren et al., 2011; RCT, parallel group PRO: 137 (66), 46 ± NR Healthy adults PRO: Lactobacillus plantarum (1 × 109 ); powder 12
Sweden (44) PLA: 135 (67), 43 ± NR PLA: maltodextrin; powder
Childs et al., 2014; RCT, crossover 44 (50), 43 ± 12 Healthy adults PRO: Bifidobacterium animalis subsp. lactis Bi-07 3
United Kingdom (1 × 109 ); powder
(40) PLA: maltodextrin; powder
Cox et al., 2010; RCT, crossover 20 (0), 27.3 ± 6.4 Highly trained PRO: Lactoacillus fermentum VRI-003 (1.2 × 1010 ); 4
Australia (39) distance runners capsule
PLA: microcrystalline cellulose; capsule
de Vrese et al., 2005 RCT, parallel group PRO: 225 (NR), 37 ± 12 Healthy adults PRO: Lactobacillus gasseri PA 16/8 (5 × 107 ), 12–22
and 2006; Germany PLA: 229 (NR), 38 ± 14 Bifidobacterium longum SP 07/3 (4 × 107 ),
(34, 45) Bifidobacterium bifidum MF 20/5 (5 × 106 ); tablet
PLA: multivitamin; tablet
Gleeson et al., 2011; RCT, parallel group PRO: 32 (NR), 32 ± 14 Healthy PRO: Lactobacillus casei Shirota (1.3 × 1010 ); fermented 16
United Kingdom PLA: 26 (NR), 25 ± 9 recreational/elite beverage
(46) endurance athletes PLA: fermented milk; beverage
Gleeson et al., 2012; RCT, parallel group PRO: 27 (NR), 25 ± 5 Healthy, highly active PRO: Lactobacillus salivarius (2 × 1010 ); powder 16
United Kingdom PLA: 27 (NR), 24 ± 4 adults PLA: maltodextrin, magnesium stearate; powder
(47)
Gleeson et al., 2016; RCT, parallel group PRO: 126 (42), 20 ± 2 Healthy, PRO: Lactobacillus casei Shirota (1.3 × 1010 ); fermented 20
United Kingdom PLA: 117 (41), 21 ± 2 endurance-trained, beverage
(48) with normal PLA: fermented milk; beverage
hematology
Guillemard et al., RCT, parallel group PRO: 478 (96), 32 ± 9 Healthy adult shift PRO: Lactobacillus casei, Streptococcus thermophiles and 12
2010; Germany (35) PLA: 484 (97), 32 ± 9 workers Lactobacillus delbrueckii (2 × 109 ); fermented
beverage
PLA: nonfermented, acidified, sweetened, flavored
dairy drink without active components; beverage
Habermann et al., RCT, parallel group PRO: 70 (NR), 47 ± 11 Confirmed medical PRO: Enterococcus faecalis group D (11.25–33.75 × 107 ); 26
2001; Germany (32) PLA: 66 (NR), 47 ± 11 history of chronic droplet
recurrent bronchitis PLA: isotonic saline with starch; liquid
(Continued)
Biotics and respiratory tract infections

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TABLE 1 (Continued)

Habermann et al., RCT, parallel group PRO: 78 (NR), 40 ± 12 Chronic recurrent PRO: Enterococcus faecalis (11.25–33.75 × 107 ); droplet 26
Coleman et al.
2002; Germany (33) PLA: 79 (NR), 42 ± 13 hypertrophic sinusitis PLA: starch suspension diluted in saline; liquid
Haywood et al., 2014; RCT, crossover 30 (0), 25 ± 4 Elite rugby athletes PRO: Lactobacillus gasseri (2.6 × 109 ), Bifidobacterium 4
New Zealand (38) bifidum (0.2 × 109 ), Bifidobacterium longum (0.2 ×
109 ); capsule
PLA: corn flour; capsule
Hor et al., 2018; RCT, parallel group PRO: 72 (51), 44 ± 15 Healthy adults PRO: Lactobacillus casei LCZ (1 × 109 ); powder 52
Malaysia (49) PLA: 65 (58), 45 ± 17 PLA: brown rice powder and maltodextrin; powder
Jespersen et al., 2015; RCT, parallel group PRO: 538 (NR), 32 ± NR Healthy adults PRO: Lactobacillus paracasei L. casei 431 (1 × 109 ); 6
Denmark (36) PLA: 528 (NR), 31 ± NR acidified beverage
PLA: acidified milk; beverage
Kalima et al., 2016; RCT, parallel group PRO: 121 (NR), NR Military PRO: Bifidobacterium animalis ssp. lactis BB12 12
Finland (50) PLA: 103 (NR), NR (16 × 109 ), Lactobacillus rhamnosus GG (4 × 1010 ); 21
PRO: 63 (NR), NR tablet
PLA: 73 (NR), NR PLA: xylitol, sorbitol, microfibrous cellulose,
magnesium stearate, and citrus flavor; tablet
Kekkonen et al., 2007; RCT, parallel group PRO: 61 (NR), 40 ± NR Healthy marathon PRO: Lactobacillus rhamnosus GG (1 to 4 × 1010 ); 12
Finland (31) PLA: 58 (NR), 40 ± NR runners beverage
PLA: milk-based fruit drink; beverage
Kumpu et al., 2015; RCT, parallel group PRO: 19 (63), 24 ± 11 Healthy adults PRO: Lactobacillus rhamnosus GG (1 × 109 ); beverage 6
United States (51); PLA: 20 (65), 22 ± 9 PLA: fruit juice; beverage
Tapiovaara et al.,
2016; Finland (52)
Langkamp-Henken et RCT, parallel group PRO1: 142 (60), 20 ± 1 Healthy university PRO1: Bifidobacterium bifidum R0071 (3 × 109 ); capsule 6
al., 2015; United PRO2: 148 (66), 20 ± 1 students under PRO2: Bifidobacterium longum ssp. infantis R0033
States (29) PRO3: 145 (62), 20 ± 1 academic stress (3 × 109 ); capsule
PLA: 147 (67), 20 ± 1 PRO3: Lactobacillus helveticus R0052 (3 × 109 ); capsule
PLA: magnesium stearate and potato starch; capsule
Meng et al., 2016; RCT, crossover 30 (63), 28 ± 1.2 Healthy adults PRO: Bifidobacterium animalis subsp. lactis BB-12 4
United States (37) (1 × 1010 ); fermented yogurt smoothie
PLA: yogurt; yogurt smoothie
Michael et al., 2020; RCT, parallel group PRO: 110 (60), 45 ± 10 Adults classified as PRO: Lactobacillus acidophilus CUL60 (NCIMB 30157), 26
Bulgaria (53) PLA: 110 (61), 47 ± 10 overweight or obese Lactobacillus acidophilus CUL21 (NCIMB 30156),
Lactobacillus plantarum CUL66 (NCIMB 30280)
Bifidobacterium bifidum CUL20 (NCIMB 30153) and
Bifidobacterium animalis subsp. lactis CUL34 (NCIMB
30172) (5 × 1010 ); capsule
PLA: microcrystalline cellulose; capsule
Michalickova et al., RCT, parallel group PRO: 20 (25), 23 ± 3 Elite athletes PRO: Lactobacillus helveticus (2 × 1010 ); capsule 14
2016; Serbia (54) PLA: 19 (26), 23 ± 3 PLA: Maltodextrin capsule
(Continued)
TABLE 1 (Continued)

Nishihira et al., 2016; RCT, parallel group PRO: 94 (83), 50 ± 13 Healthy adults PRO: Lactobacillus gasseri SBT2055 LG2055 (1 × 109 ), 16
Japan (55) PLA: 94 (82), 50 ± 12 fermented drinkable yogurt
PLA: lactic acid bacteria starter (Streptococcus
thermophiles), skim milk powder, flavoring,
polysaccharide from soybeans, pectin, sucralose;
drinkable yogurt
Pumpa et al., 2019; RCT, parallel group PRO: 9 (NR), 27 ± 3 Elite athletes PRO: Lactobacillus rhamnosus, Lactobacillus casei, 17
Australia (56) PLA: 10 (NR), 27 ± 3 Lactobacillus acidophilus, Lactobacillus plantarum,
Lactobacillus fermentum, Bifiodbacteriumlactis,
Bifidobacterium bifidum, Streptococcus thermophilus,
Saccharomyces bouladri (6 × 109 ); capsule
PLA: cellulose; capsule
Rizzardini et al., 2012; RCT, parallel group PRO: 53 (47), 29 ± 11 Healthy adults PRO: Bifidobacterium animalis ssp. lactis BB-12 6
Italy (57) PLA: 48 (56), 31 ± 11 (1 × 109 ); capsule
PRO: 56 (55), 37 ± 14 PLA: NR; capsule
PLA: 54 (65), 35 ± 14 PRO: Lactobacillus casei 431 (1 × 109 ); acidified
beverage
PLA: acidified dairy drink; beverage
Schröder et al., 2015; RCT, parallel group PRO: 79 (0), 42 ± 10 Healthy adults PRO: Lactobacillus reuteri DSM 17938 (5 × 108 ); tablet 13
Germany (58) PLA: 80 (0), 42 ± 10 involved in physically PLA: isomalt, xylitol, palm oil, lemon-lime flavoring,
active or sedentary citric acid; tablet
work
Shida et al., 2017; RCT, parallel group PRO: 50 (0), 41 ± 5 Healthy adults PRO: Lactobacillus casei Shirota YIT 9029 (1 × 1011 ); 12
Japan (59) PLA: 50 (0), 41 ± 6 working within office fermented beverage
buildings PLA: milk; 1 beverage
Smith et al., 2013; RCT, parallel group PRO: 101 (82), NR Healthy university PRO: Bifidobacterium animalis ssp. lactis BB-12 12
United States (60) PLA: 97 (72), NR students (1 × 109 ), Lactobacillus (1 × 109 ); powder
PLA: strawberry-flavored powder; powder
Strasser et al., 2016; RCT, parallel group PRO: 14 (43), 26 ± 3 Healthy, trained PRO: Bifidobacterium bifidum W23, Bifidobacterium 12
Austria (61) PLA: 15 (67), 27 ± 3 athletes lactis W51, Enterococcus faecium W54, Lactobacillus
acidophilus W22, Lactobacillus brevis W63, and
Lactococcus lactis W58 (1 × 1010 ); powder
PLA: cornstarch, maltodextrin, vegetable protein,
MgSO4 , MnSO4 , and KCl; powder
(Continued)

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Coleman et al.
TABLE 1 (Continued)

Sugimura et al., 2015; RCT, parallel group PRO: 106 (58), 45 ± 8 Healthy adults PRO: Lactococcus lactis JCM5805 (1 × 1011 ); fermented 10
Japan (62) PLA: 107 (56), 45 ± 8 yogurt beverage
PLA: milk, powdered skim milk, milk peptide,
granulated sugar, pectin, lactic acid, flavoring agent
and water; yogurt beverage
Tiollier et al., 2007; RCT, parallel group PRO: 24 (0), 21 ± 1 Military cadets PRO: Lactobacillus casei DN-114 001 (NR); fermented 3.5
France (63) PLA: 23 (0), 21 ± 2 beverage
PLA: nonfermented milk; beverage
Turner et al., 2017; RCT, parallel group PRO: 58 (67), 22 ± 6 Healthy adults PRO: Bifidobacterium animalis (2 × 109 ); powder 4.5
United States (64) PLA: 57 (57), 23 ± 7 susceptible to PLA: sucrose; powder
rhinovirus type 39
Vaisberg et al., 2019; RCT, parallel group PRO: 20 (0), 40 ± 9 Amateur marathon PRO: Lactobacillus casei strain Shirota (40 × 109 ); 4
Brazil (65) PLA: 22 (0), 40 ± 10 runners fermented beverage
PLA: unfermented milk; beverage
West et al., 2011; RCT, parallel group PRO: 18 (100), 36 ± 9 Female cyclists and PRO: Lactobacillus fermentum (1 × 109 ); capsule 11
Australia (66) PLA: 17 (100), 36 ± 10 triathletes PLA: microcrystalline cellulose; capsule
PRO: 29 (0), 35 ± 10 Male cyclists and
PLA 33 (0), 36 ± 9 triathletes
West et al., 2014; RCT, parallel group PRO1: 161 (50); 36 ± 12 Healthy active adults PRO1: Bifidobacterium animalis subsp. lactis Bl-04 21.5
Australia (30) PRO2: 155 (46); 36 ± 11 (2 × 10 (2 × 109 ); powder
PLA: 149 (48); 37 ± 11 PRO2: Lactobacillus acidophilus NCFM and
Bifidobacterium animalis subsp. lactis Bi-07
(1 × 1010 ); powder
PLA: sucrose; powder
Zhang et al., 2018; RCT, parallel group PRO: 67 (51), 34 ± 6 Healthy adults with PRO: Lactobacillus paracasei (4.5 × 109 ), Lactobacillus 12
China (67) PLA: 67 (51) 33 ± 6 ≥4 RTIs per year casei 431 (4.5 × 109 ), Lactobacillus fermentium PCC
(4.5 × 108 ); fermented beverage
PLA: starter culture and milk; beverage
1
NR, not reported; PLA, placebo; PRO, probiotic; RCT, randomized controlled trial.
2
Values are means ± SDs or means (range).
TABLE 2 Characteristics of included studies examining effects of prebiotics and synbiotics on the incidence, duration, or severity of respiratory tract infections in nonelderly adults1

(reference) Study design n (% female), age,2 y Population Intervention; form Duration, wk
Prebiotic
Childs et al., 2014; RCT, crossover 44 (50), 43 ± 12 Healthy adults PRE: xylo-oligosaccharide (8 g/d); powder 3
United Kingdom (40) PLA: maltodextrin; powder
Hughes et al., 2011; RCT, parallel group PRE1: 140 (50), 20 ± 1 Healthy university PRE1: GOS (2.5 g/d); powder 8
United States (68) PRE2:139 (51), students under PRE2: GOS (5 g/d); powder
20 ± 1 academic stress and PLA: sucrose, silicone dioxide; NR
PLA: 140 (51), ≥1 cold in past year
20 ± 1.2
Nieman et al., 2008; RCT, parallel group PRE: 19 (0), 22 ± 4 Healthy active cyclists PRE: B-glucan (5.6 g); beverage 2.5
United States (69) PLA: 17 (0), PLA: cornstarch, sports drink; beverage
25 ± 9
Synbiotic
Childs et al., 2014; RCT, crossover 44 (50), 43 ± 12 Healthy adults SYN: Bifidobacterium animalis subsp. lactis Bi-07 (1 × 109 3
United Kingdom (40) CFU/d) and xylo-oligosaccharide (8 g/d); powder
PLA: maltodextrin, powder
Pregliasco et al., RCT, parallel group SYN: 114 (NR), 39 ± 16 Healthy adults SYN: Lactobacillus plantarum probial LP 02-LMG P-21020 12
2008; Italy (70) PLA: 105 (NR), 35 ± 20 (10 × 109 CFU/d), Lactobacillus rhamnosus probial LR
SYN: 74 (NR), 38 ± 19 04-DSM 16605 (10 × 109 CFU/d), Bifidobacterium lactis
PLA: 68 (NR), probial BS 01-LMG P-21384 (10 × 109 CFU/d), FOS
38 ± 19 (3 g/d); powder
SYN1: 76 (NR), 42 ± 15 PLA: glucose, maltodextrin; powder
SYN2: 78 (NR), 45 ± 16 SYN: Lactobacillus plantarum probial LP 02-LMG P-21020
PLA: 75 (NR), (10 × 109 CFU/d), Lactobacillus rhamnosus probial LR
42 ± 19 04-DSM 16605 (10 × 109 CFU/d), Bifidobacterium lactis
probial BS 01-LMG P-21384 (10 × 109 CFU/d), FOS
(3 g/d); powder
PLA: glucose, maltodextrin; powder
SYN1: Lactobacillus plantarum probial LP 01-LMG P-21021
(5 × 109 CFU/d), Lactobacillus plantarum probial LP
02-LMG P-21020 (5 × 109 CFU/d), Lactobacillus
rhamnosus probial LR 04-DSM 16605 (5 × 109 CFU)
Lactobacillus rhamnosus probial LR 05-DSM 19739
(5 × 109 CFU/d), Bifidobacterium lactis probial BS
01-LMG P-21384 (5 × 109 CFU/d), GOS (2.5 g/d); powder
SYN2: Lactobacillus plantarum probial LP 01-LMG P-21021
(5 × 109 CFU/d), Lactobacillus plantarum probial LP
02-LMG P-21020 (5 × 109 CFU/d), Lactobacillus
rhamnosus probial LR 04-DSM 16605 (5 × 109 CFU/d),
Lactobacillus rhamnosus probial LR 05-DSM 19739
(5 × 109 CFU/d), Bifidobacturium lactis probial BS
01-LMG P-21384 (5 × 109 CFU/d), FOS (3 g/d); powder
PLA: glucose, maltodextrin; powder
1
FOS, fructo-oligosaccharide; GOS, galacto-oligosaccharide; NR, not reported; PLA, placebo; PRE, prebiotic; RCT, randomized controlled trial; SYN, synbiotic.

2
Values are means ± SDs or means (range).
2285
Study Name Statistics for each study RTI/Total Risk ratio and 95% CI
Risk Lower Upper Z- p-
Probiotic Placebo
Ratio limit limit Value Value
Ahrén 2021 (51) 0.95 0.81 1.11 -0.62 0.53 178 / 448 188 / 450
Altadill 2021 (52) 1.03 0.72 1.48 0.18 0.86 31 / 62 30 / 62
Berggren 2011 (54) 0.84 0.68 1.03 -1.67 0.09 76 / 159 91 / 159
de Vrese 2005 (34) 1.05 0.92 1.19 0.67 0.51 158 / 238 153 / 241
Gleeson 2011 (56) 0.90 0.60 1.35 -0.50 0.62 21 / 42 23 / 42
Gleeson 2012 (57) 1.00 0.58 1.72 0.00 1.00 15 / 33 15 / 33
Gleeson 2016 (58) 1.18 0.88 1.57 1.10 0.27 60 / 137 49 / 131
Guillemard 2010 (35) 0.89 0.76 1.06 -1.32 0.19 169 / 500 189 / 500
Habermann 2001 (32) 0.57 0.28 1.15 -1.57 0.12 12 / 500 21 / 500
Habermann 2002 (33) 0.61 0.35 1.06 -1.75 0.08 15 / 78 25 / 79
Jespersen 2015 (36) 1.01 0.91 1.12 0.17 0.87 315 / 548 314 / 551
Kekkonen 2007 (31) 1.25 0.84 1.86 1.09 0.28 32 / 70 26 / 71
Kumpu 2015 (61) 0.78 0.56 1.07 -1.53 0.13 14 / 20 18 / 20
Langkamp-Henken 2015 [R0052] (29) 0.80 0.51 1.25 -0.97 0.33 43 / 146 18 / 49
Michalickova 2016 (64) 1.09 0.64 1.86 0.32 0.75 12 / 20 11 / 20
Nishishira 2016 (65) 1.00 0.21 4.84 0.00 1.00 3 / 100 3 / 100
Pumpa 2019 (66) 0.14 0.01 2.45 -1.34 0.18 0 / 10 3 / 10
Rizzardini 2012 [BB12] (67) 0.19 0.01 3.92 -1.07 0.28 0 / 54 2 / 52
Rizzardini 2012 [431] (67) 0.32 0.03 2.95 -1.01 0.31 1 / 59 3 / 56
Schroder 2015 (68) 1.07 0.83 1.39 0.51 0.61 61 / 121 57 / 121
Smith 2013 (70) 1.11 0.87 1.43 0.86 0.39 63 / 114 58 / 117
Strasser 2016 (71) 0.43 0.19 0.96 -2.06 0.04 5 / 17 11 / 16
Sugimura 2015 (72) 0.50 0.21 1.20 -1.55 0.12 7 / 106 14 / 107
Tiollier 2007 (73) 0.81 0.46 1.42 -0.73 0.47 11 / 24 13 / 23
Turner 2017 (74) 0.93 0.72 1.19 -0.58 0.56 51 / 95 55 / 95
Vaisberg 2019 (75) 0.25 0.03 2.10 -1.28 0.20 1 / 28 4 / 28
West 2014 [Bl-04] (30) 0.82 0.59 1.14 -1.18 0.24 59 / 161 33 / 74
West 2014 [NCFM, Bi-07] (30) 0.77 0.56 1.07 -1.55 0.12 55 / 155 34 / 74
Zhang 2018 (77) 0.44 0.27 0.72 -3.29 0.00 16 / 68 36 / 68
0.91 0.84 0.98 -2.56 0.01
0.1 0.2 0.5 1 2 5 10

Favors Probiotic Favors Placebo
FIGURE 2 Forest plot for the effects of orally ingested probiotics versus placebo on the risk of experiencing 1 or more respiratory tract
infections in nonelderly adults. Intention-to-treat random effects meta-analysis using DerSimonian and Laird inverse variance method.
Data extracted for Jespersen et al. (36) and Guillemard et al. (35) reflect the incidence of upper respiratory tract infections. Lower and
upper limits are 95% CIs. Individual study effect estimates (squares; sized by study weight) and pooled effects (diamond) are plotted.
Heterogeneity from the fixed-effects model: I2 = 33.4, P = 0.04. RTI, number of individuals experiencing ≥1 respiratory tract infection;
Total, number randomized.
Prebiotic interventions consisted of galacto-oligosaccharides Effects of orally ingested probiotics on incidence,

(n = 1), oat β-glucan (n = 1), and xylo-oligosaccharides duration, and severity of RTI
(n = 1). The synbiotics used multi- or single-strain for- Twenty-seven studies providing data on 31 probiotic versus
mulations containing Bifidobacterium and/or Lactobacil- placebo comparisons were included in meta-analyses deter-
lus, and galacto-oligosaccharides, fructo-oligosaccharides, mining the effects of probiotics on RTI incidence. Overall,
or xylo-oligosaccharides. Interventions were provided in oral ingestion of probiotics reduced the risk of experiencing
the forms of capsules, tablets, and powder, or delivered in 1 or more RTI by 9% (risk ratio = 0.91; 95% CI: 0.84,
fermented dairy (n = 10) and nonfermented foods and 0.98; P = 0.01: ITT analysis; Figure 2). Heterogeneity in
beverages. the fixed-effects model was moderate (I2 = 33.4, P = 0.04).
2286 Coleman et al.

Subgroup analyses revealed a statistically significant risk reduction in duration amounted to 1.0 day/RTI episode
reduction for single-strain Bifidobacterium interventions, but (95% CI: 0.2, 1.7; P = 0.02). Subgroup analyses were sta-
this reduction was not statistically different from single- tistically significant for multiple-strain interventions, single-
strain Lactobacillus interventions in the meta-regression strain Lactobacillus interventions, and for populations not
(ITT analysis; Figure 3 and Supplemental Table 5). Sub- considered physically active (Figure 3 and Supplemental
group analyses also revealed a risk reduction for popula- Table 9). Meta-regression indicated a greater reduction in
tions not classified as physically active, although the risk effect size for interventions delivered in fermented dairy
reduction did not differ from that in physically active products compared with other forms of delivery, but no
populations in the meta-regression (Figure 3). Heterogeneity differences in effect size between single- and multi-strain
within the subgroup fixed-effects models varied, ranging interventions or based on population physical activity level
from none to substantial (I2 = 0–63.4, P = 0.01–0.61; (Figure 3 and Supplemental Table 9). Heterogeneity within
Supplemental Table 5). The overall risk reduction was slightly the subgroup fixed-effects models ranged from moderate
greater in the per-protocol analysis (risk ratio = 0.90; to considerable across all subgroups analyzed (I2 = 49.6–
95% CI: 0.84, 0.96; P = 0.002; Supplemental Figure 1) 91.8, P ≤ 0.06; Supplemental Table 9). Neither the funnel
and analyses were statistically significant for several sub- plot (Supplemental Figure 5) nor Egger’s test (P = 0.10)
groups including both single- and multi-strain interven- suggested publication bias.
tions, single-strain Bifidobacterium and B. animalis subsp. Thirteen studies providing data on 15 probiotic versus
lactis interventions, and both fermented dairy and other placebo comparisons were included in meta-analyses deter-
intervention delivery forms (Figure 3 and Supplemental mining the effects of probiotics on RTI severity. Overall,
Table 6). However, no significant differences based on oral ingestion of probiotics reduced RTI severity (Hedges’
these subgroups were observed in the per-protocol meta- g: –0.16; 95% CI: –0.29, –0.03; P = 0.02; Figure 6). Hetero-
regression analyses (Figure 3 and Supplemental Table 6). geneity in the fixed-effects model was substantial (I2 = 65.1,
Both the funnel plot (Supplemental Figure 2) and Egger’s P < 0.001). Subgroup analyses were statistically significant
test (P < 0.001) provided evidence of publication bias (ITT only for populations not considered physically active, but
analysis). the reduction in effect size was not statistically different
Eighteen studies providing data on 21 probiotic versus from physically active populations in the meta-regression
placebo comparisons were included in meta-analyses deter- (Figure 3 and Supplemental Table 10). Heterogeneity within
mining the effects of probiotics on total days of illness due the subgroup fixed-effects models ranged from none to
to RTI. Overall, oral ingestion of probiotics reduced the rate considerable across all subgroups analyzed (I2 = 0–80.8,
ratio by 23% (rate ratio: 0.77; 95% CI: 0.71, 0.83; P = 0.001; P = 0.0001–0.88; Supplemental Table 10). Neither the funnel
ITT analysis; Figure 4). Heterogeneity in the fixed-effects plot (Supplemental Figure 6) nor Egger’s test (P = 0.09)
model was considerable (I2 = 91.4, P < 0.001). Reductions suggested publication bias.
in the rate ratio were significant across all subgroups except Three crossover studies were identified by the systematic
in physically active populations (ITT analysis; Figure 3 review but did not provide sufficient data to be included in
and Supplemental Table 7). Meta-regression indicated that the meta-analyses. These studies did not find any effects of
delivering probiotics in the form of fermented dairy lowered orally ingested probiotics on the incidence of RTIs (37, 39,
the rate ratio to a greater extent than other forms of 40), but 2 did report that the probiotic used reduced the
delivery and that the rate reduction in populations not duration of RTIs (37, 39). Oral ingestion of probiotics was
considered physically active was greater than that in phys- reported to have either no effect on RTI severity (37) or
ically active populations (Figure 3 and Supplemental Table demonstrated a tendency to lower severity (39).
7). Heterogeneity within the subgroup fixed-effects models
was considerable for most subgroups analyzed (I2 ≥ 89.8,
P < 0.001; Supplemental Table 7). Per-protocol analyses Effects of orally ingested prebiotics on incidence,
were largely consistent with the ITT analyses (overall rate duration, and severity of RTIs
ratio = 0.74; 95% CI: 0.68, 0.81; P < 0.001; Supplemental Only 3 studies providing 4 comparisons of orally ingested
Figure 3, Figure 3, and Supplemental Table 8). Neither prebiotics versus placebo were identified in the search
the funnel plot (Supplemental Figure 4) nor Egger’s test (Table 2). Given the small sample size, heterogeneous
(P = 0.26) suggested publication bias. interventions, and differences in outcomes reported, meta-
Thirteen studies providing data on 15 probiotic versus analysis was not conducted. Hughes et al. (68), using a
placebo comparisons were included in meta-analyses deter- dose–response design, reported cold or flu duration was
mining the effects of probiotics on the duration of individual reduced by 40% following consumption of 5.0 g/d, but not
RTI episodes. Overall, oral ingestion of probiotics reduced 2.5 g/d, galacto-oligosaccharides in subjects with a BMI (in
the duration of RTI episodes (Hedges’ g: –0.23; 95% CI: kg/m2 ) of 18.5–24.9. Both doses reduced RTI severity, but
–0.39, –0.08; P = 0.004; per-protocol analysis; Figure 5). in the 5.0-g/d intervention, that effect was only observed
Heterogeneity in the fixed-effects model was considerable in individuals experiencing lower stress levels. Nieman et
(I2 = 79.4, P < 0.001). When the 10 studies that provided al. (69) found no effect of β-glucan supplementation on
results as days per RTI episode were meta-analyzed, the incidence or duration of RTI. Similarly, Childs et al. (40) did

Risk Ratio Risk Ratio Rate Ratio Rate Ratio Hedges' g Hedges' g
1 1 Total days Total days RTI
SUB-GROUP
Number of
0.94 0.91 0.78 0.75 -0.17 -0.13
Single
[0.86, 1.02] [0.85, 0.99] [0.70, 0.87] [0.67, 0.84] [-0.35, 0.00] [-0.32, 0.06]
0.87 0.87 0.73 0.72 -0.38 -0.20
Multiple
[0.76, 1.01] [0.77, 1.00] [0.63, 0.84] [0.62, 0.83] [-0.76, 0.00] [-0.41, 0.00]
0.83 0.88 0.62 0.62 -0.02

Bifidobacterium
[0.70, 0.98] [0.80, 0.97] [0.56, 0.69] [0.56, 0.69] [-0.23, 0.18]
0.94 0.92 0.79 0.75 -0.25 -0.19
[0.86, 1.03] [0.84, 1.01] [0.71, 0.87] [0.67, 0.84] [-0.47, -0.03] [-0.39, 0.01]
1.00 1.01 0.82 0.81
Bifido.+Lacto.
[0.85, 1.19] [0.88, 1.15] [0.77, 0.87] [0.76, 0.85]
Species !
0.98 0.85 0.71 0.65 -0.28 -0.03
L.
[0.76, 1.26] [0.63, 1.16] [0.55, 0.92] [0.49, 0.87] [-0.79, 0.22] [-0.23, 0.17]
0.88 0.90
B. animalis ssp.
[0.72, 1.07] [0.81, 1.00]
0.81 0.78 0.59 0.56 -0.47 -0.18

Ferment dairy
[0.64, 1.03] [0.62, 0.99] [0.38, 0.92] [0.34, 0.90] [-1.01, 0.08] [-0.48, 0.11]
0.93 0.93 0.81 0.79 -0.12 -0.15
Other
[0.86, 1.00] [0.87, 0.99] [0.76, 0.87] [0.73, 0.85] [-0.23, -0.01] [-0.31, 0.00]
0.92 0.89 0.88 0.84 -0.06 -0.32

Active
[0.78, 1.09] [0.76, 1.04] [0.71, 1.08] [0.67, 1.04] [-0.36, 0.23] [-0.98, 0.33 ]
0.90 0.91 0.72 0.70 -0.30 -0.12
Other
[0.83, 0.98] [0.84, 0.98] [0.66, 0.78] [0.63, 0.76] [-0.48, -0.11] [-0.23, 0.00]
Number of -0.03 -0.01 -0.08 -0.06 -0.19 -0.08

Multiple vs. Single [-0.18, 0.13] [-0.15, 0.13] [-0.27, 0.10] [-0.26, 0.14] [-0.56, 0.18] [-0.36, 0.20]
-0.14 -0.09 -0.26 -0.21 -0.03

vs. Lacto. [-0.35, 0.07] [-0.27, 0.09] [-0.53, 0.004] [-0.50, 0.07] [-0.34, 0.29]
-0.07 -0.11 -0.25 -0.30 -0.35 0.17

Fermented dairy vs. Other [-0.26, 0.12] [-0.28, 0.07] [-0.45, -0.05] [-0.51, -0.08] [-0.68, -0.02] [-0.21, 0.55]
0.03 -0.01 0.09 0.09 0.22 -0.29

Active vs. Other [-0.15, 0.21] [-0.18, 0.15] [0.04, 0.38] [0.01, 0.38] [-0.13, 0.58] [-0.66, 0.08]
-0.001 -0.003 0.001 -0.002 -0.01 -0.003
[-0.02, 0.01] [-0.02, 0.01] [-0.01, 0.01] [-0.01, 0.01] [-0.05, 0.03] [-0.04, 0.03]
-0.04 -0.06 -0.09 -0.11 -0.16 0.07
Dose (log10
[-0.14, 0.06] [-0.15, 0.03] [-0.21, 0.03] [-0.25, 0.01] [-0.37, 0.06] [-0.12, 0.25]
0.002 -0.02 -0.10 -0.13 -0.22 0.09
Total dose (log10
[-0.13, 0.13] [-0.13, 0.09] [-0.25, 0.05] [-0.29, 0.03] [-0.51, 0.06] [-0.15, 0.34]
FIGURE 3 Summary of subgroup meta-analyses and meta-regressions for effects of orally ingested probiotics on incidence, duration,
and severity of RTIs in nonelderly adults. Subgroup results are presented as effect size [95% CI]. Meta-regression results are presented as β
[95% CI]. Results shaded in green are statistically significant (P < 0.05) and those in yellow are not statistically significant (P ≥ 0.05). Black
shading indicates insufficient data for analysis. Subgroups were analyzed using random-effects meta-analysis using the DerSimonian and
Laird inverse variance method. Meta-regression used the DerSimonian and Laird inverse variance method. See Supplemental Tables 5–10
for P values and measures of heterogeneity. Bifido., Bifidobacterium; ITT, intention-to-treat analysis; Lacto., Lactobacillus; PP, per-protocol
analysis; RTI, respiratory tract infection.
2288 Coleman et al.

Study Name Statistics for each study RTI/Total Risk ratio and 95% CI
Risk Lower Upper Z- p-
Probiotic Placebo
Ratio limit limit Value Value
Ahrén 2021 (51) 0.87 0.82 0.93 -4.27 0.00 1768 / 103 2040 / 104
Altadill 2021 (52) 0.86 0.71 1.05 -1.51 0.13 183 / 14 213 / 14
Berggren 2011 (54) 0.73 0.67 0.8 -6.92 0.00 849 / 37 1161 / 37
de Vrese 2005 (34) 0.83 0.76 0.89 -4.74 0.00 1106 / 77 1362 / 78
Gleeson 2011 (56) 0.67 0.59 0.76 -6.44 0.00 426 / 13 637 / 13
Gleeson 2016 (58) 1.14 1.00 1.30 1.98 0.05 494 / 53 414 / 50
Hor 2018 (59) 0.74 0.71 0.78 -12.6 0.00 3142 / 75 4228 / 75
Jespersen 2015 (36) 0.83 0.79 0.86 -8.65 0.00 3800 / 63 4618 / 63
Kekkonen 2007 (31) 1.45 1.22 1.72 4.28 0.00 323 / 16 226 / 16
Langkamp-Henken 2015 [R0052] (29) 1.01 0.77 1.31 0.05 0.96 222 / 17 74 / 6
Michalickova 2016 (64) 0.67 0.51 0.87 -2.95 0.00 88 / 5 132 / 5
Schroder 2015 (68) 0.74 0.68 0.81 -6.47 0.00 820 / 30 1105 / 30
Shida 2017 (69) 0.31 0.22 0.42 -7.25 0.00 49 / 12 160 / 12
Smith 2013 (70) 0.84 0.75 0.94 -3.10 0.00 564 / 26 690 / 27
Tiollier 2007 (73) 0.90 0.71 1.14 -0.85 0.39 132 / 2 140 / 2
West 2011 (76) 1.04 0.89 1.21 0.48 0.63 321 / 12 331 / 13
West 2014 [Bl-04] (30) 0.63 0.56 0.71 -7.54 0.00 643 / 66 470 / 31
West 2014 [NCFM, Bi-07] (30) 0.79 0.70 0.88 -4.08 0.00 770 / 64 470 / 31
Zhang 2018 (77) 0.32 0.24 0.41 -8.40 0.00 70 / 16 221 / 16
0.77 0.71 0.83 -6.35 0.00
0.1 0.2 0.5 1 2 5 10

FIGURE 4 Forest plot for the effects of orally ingested probiotics versus placebo on the total days of illness due to RTIs in nonelderly
adults. Intention-to-treat random-effects meta-analysis using DerSimonian and Laird inverse variance method. Lower and upper limits are
the 95% CIs. Individual study effect estimates (squares; sized by study weight) and pooled effects (diamond) are plotted. Heterogeneity
from the fixed-effects model: I2 = 91.4, P < 0.001. RTI, total days of respiratory tract infection; Total, total person years of
exposure.
not find any effect of xylo-oligosaccharides on the incidence of RTIs (rate ratio = 0.64; 95% CI: 0.52, 0.79; P < 0.002;
of RTI. fixed-effects I2 = 0, P = 0.64) and total days of illness (rate
ratio = 0.64; 95% CI: 0.52, 0.78; P < 0.001; fixed-effects
I2 = 82.3, P = 0.003).
Effects of orally ingested synbiotics on incidence,
duration, and severity of RTIs
Only 2 studies providing 5 comparisons of orally ingested Risk of bias
synbiotic versus placebo comparisons were identified in the The overall risk of bias for a majority of the included studies
search (Table 2). Meta-analysis was conducted using the total was rated as “some concerns” (Figure 7 and Supplemental
number of RTIs and total days of illness with RTI reported Figure 7). That overall rating was frequently due to not
for the 4 synbiotic interventions studied by Pregliasco et al. enough information being provided to determine if results
(70). The synbiotic interventions reduced the total number were analyzed in accordance with a prespecified analysis plan
of RTIs (rate ratio = 0.66; 95% CI: 0.53, 0.80; P < 0.001; (domain 5).
fixed-effects I2 = 0, P = 0.57) and the total days of illness
(rate ratio = 0.65; 95% CI: 0.55, 0.78; P < 0.001; fixed- Discussion
effects I2 = 78.1, P = 0.01) in ITT analyses. Results were This systematic review identified 39 studies conducted in
similar in the per-protocol analysis for both total number nonelderly adults that assessed effects of at least 1 orally

Study Name Statistics for each study Hedges’ g and 95% CI
Hedges’s Lower Upper Z- p-
g limit limit Value Value
Ahrén 2021 (51) 0.00 -0.13 0.13 0.00 1.00
Altadill 2021 (52) -0.14 -0.51 0.23 -0.74 0.46
de Vrese 2005 (34) -0.16 -0.34 0.03 -1.69 0.09
Gleeson 2011 (56) 0.06 -0.45 0.57 0.25 0.81
Gleeson 2016 (58) -0.06 -0.31 0.19 -0.47 0.64
Jespersen 2015 (36) -0.16 -0.28 -0.04 -2.57 0.01
Kekkonen 2007 (31) 0.27 -0.09 0.63 1.47 0.14
Langkamp-Henken 2015 [R0052] (29) 0.12 -0.20 0.45 0.75 0.45
Langkamp-Henken, 2015 [R0071] (29) -0.25 -0.57 0.07 -1.51 0.13
Langkamp-Henken 2015 [R0033] (29) -0.16 -0.49 0.16 -1.00 0.32
Michalickova 2016 (64) -0.85 -1.51 -0.2 -2.57 0.01
Shida 2017 (69) -1.04 -1.47 -0.62 -4.83 0.00
Smith 2013 (70) -0.32 -0.60 -0.04 -2.25 0.02
Tiollier 2007 (73) -0.07 -0.64 0.49 -0.26 0.00
Zhang 2018 (77) -1.18 -1.54 -0.81 -6.33 0.00
-0.23 -0.39 -0.08 -2.91 0.00
-1.00 -0.50 0.00 0.50 1.00

FIGURE 5 Forest plot for the effects of orally ingested probiotics versus placebo on the duration of respiratory tract infection episodes in
nonelderly adults. Per-protocol random-effects meta-analysis using DerSimonian and Laird inverse variance method. Lower and upper
limits are the 95% CIs. Individual study effect estimates (squares; sized by study weight) and pooled effects (diamond) are plotted.
Heterogeneity from the fixed-effects model: I2 = 79.4, P < 0.001.
ingested probiotic intervention on the incidence, duration, what have been reported in recent meta-analyses on the topic,
or severity of RTIs, but far fewer studies assessing effects which have ranged from an 11% to 47% reduction in the
of orally ingested prebiotics or synbiotics on the same risk or odds of experiencing at least 1 RTI (15, 16, 18) and
outcomes and in the same population. The main finding a 0.8- to 2.7-d reduction in the duration of individual RTI
was that orally ingested probiotic interventions, relative episodes (15, 16, 20). Discrepancies in effect sizes are likely
to matched placebo, modestly reduced the incidence, du- attributable to differences in the inclusion and exclusion
ration, and severity of RTIs in nonelderly adults. Meta- criteria used for each systematic review. Specifically, Wang et
regression indicated that those benefits did not signifi- al. (18) included only studies conducted in children, Hao et
cantly differ by the number of strains, genus, or dose al. (15) and Li et al. (16) focused on upper-RTI rather than
of probiotic administered, or the duration of treatment. all RTIs while including few studies conducted in nonelderly
However, the physical activity level of the population studied adult populations, and King et al. (20) restricted their review
and whether fermented dairy products were used as the to only studies using Lactobacillus or Bifidobacterium while
delivery matrix did influence effects of probiotic interven- including studies in children and non-RTI outcomes. Find-
tions on the total days of illness due to RTI. Whether ings from this meta-analysis therefore extend that evidence
orally ingested prebiotic and synbiotic interventions confer base by revealing that orally ingested probiotic interventions
similar protection against RTIs in nonelderly adults remains provide modest reductions in the incidence, duration, and
unclear. severity of RTIs across a large selection of studies using dif-
The finding that probiotics reduced RTI burden is ferent probiotic types and conducted within nonelderly adult
consistent with recent meta-analyses (15, 16, 18, 20). Herein, populations.
that reduction was attributable to both a slight 9% decrease in Statistical heterogeneity across probiotic studies was
the risk of experiencing 1 or more RTI (Figure 2) and a small moderate to considerable for overall analyses and ranged
(Hedges’ g = –0.23; Figure 5) ∼1 d/RTI episode reduction from none to considerable for subgroup analyses, with
in the mean duration of individual RTI episodes, resulting in greater heterogeneity seen with RTI duration and severity
a 23% lower daily rate of RTI illness during the intervention than incidence. The number of studies included in this
period (Figure 4). These effect sizes are at the lower end of analysis provided an opportunity to examine population-
2290 Coleman et al.

Study Name Statistics for each study Hedges’ g and 95% CI
Hedges’s Lower Upper Z- p-
g limit limit Value Value
Ahrén 2021 (51) 0.07 -0.06 0.20 1.04 0.30
Berggren 2011 (52) -0.17 -0.41 0.07 -1.38 0.17
de Vrese 2005 (34) -0.15 -0.34 0.03 -1.62 0.11
Gleeson 2011 (56) -0.13 -0.64 0.38 -0.49 0.62
Gleeson 2016 (58) -0.03 -0.28 0.22 -0.26 0.80
Kumpu 2015 (61) -0.40 -1.02 0.23 -1.25 0.21
Michalickova 2016 (64) 0.15 -0.47 0.78 0.48 0.63
Shida 2017 (69) 0.04 -0.36 0.43 0.18 0.86
Smith 2013 (70) -0.35 -0.63 -0.07 -2.43 0.01
Turner 2017 (74) 0.21 -0.16 0.57 1.11 0.27
West 2011 (76) -0.89 -1.27 -0.52 -4.65 0.00
Zhang 2018 (77) -0.60 -0.94 -0.25 -3.39 0.00
-0.16 -0.29 -0.03 -2.37 0.02
-1.00 -0.50 0.00 0.50 1.00

FIGURE 6 Forest plot for the effects of orally ingested probiotics versus placebo on the severity of respiratory tract infections in
nonelderly adults. Per-protocol random-effects meta-analysis using DerSimonian and Laird inverse variance method. Lower and upper
limits are the 95% CIs. Individual study effect estimates (squares; sized by study weight) and pooled effects (diamond) are plotted.
Heterogeneity from the fixed-effects model: I2 = 65.1, P < 0.001.
and intervention-related factors that may contribute to that may be less effective, for reducing RTI incidence, duration,
heterogeneity. Notably, subgroup analyses suggested that, in and severity in physically active populations (Figure 3).
aggregate, orally ingested probiotics may not be effective, or Those findings are generally consistent with results of a
recent meta-analysis that reported that probiotics did not
reduce RTI incidence or duration, but did reduce RTI
Arising from the severity, in physically active adults (14). Findings also
randomization process
align with recent systematic reviews that have described
Due to deviations from
intended interventions inconsistent effects of orally ingested probiotics on markers
Due to missing
of immune function and measures of RTI burden in athletes,
outcome data inconsistencies that may be attributable to differences in
In measurement the intervention strains and training loads of the study
of the outcome populations (19, 71). Reasons why probiotics may be less
In selection effective for reducing RTI burden, or have less consistent
of the reported result
effects, in physically active populations are unclear. However,
Overall risk of bias exercise with adequate rest and recovery may favorably
0% 25% 50% 75% 100% modulate the gut microbiota and support immune function
(72, 73). Physically active adults generally also have other
Low risk Some concerns High risk
lifestyle behaviors that may reduce RTI risk such as high-
quality diets (74). Possibly, probiotics do not provide any
FIGURE 7 Risk-of-bias assessment for all studies identified in the additional immune benefit in this context. On the other hand,
systematic review. Phrases not in bold font are sources of bias. high levels of exercise without adequate rest and recovery
Assessed using the Cochrane risk-of-bias assessment tool version may compromise immune function and increase RTI risk,
2.0. Plot produced using robvis (McGuinness LA, Higgins JPT. although this is controversial (72). Given the relatively small
Risk-of-bias VISualization (robvis): An R package and Shiny web app number of studies, the range of population physical activity
for visualizing risk-of-bias assessments. Res Syn Meth 2020;1–7;
levels (e.g., recreationally active to elite athletes in training),
https://mcguinlu.shinyapps.io/robvis/).
and the variety of different interventions studied, more

research is warranted to better define if, when, and which oral assumed that all compounds and formulations will have the
ingestion of probiotics may confer benefit for reducing RTI same effects as was evidenced by the few studies included
burden in physically active adults. in this review (40, 68–70). The effects of orally ingested
In addition to population-based differences, effects of prebiotics and synbiotics on RTI burden in nonelderly adults
probiotics on RTI burden may be genus-, species-, or strain- therefore remain a significant knowledge gap.
specific and vary by the dose or form of administration (7). Strengths of this systematic review and meta-analysis
Herein, dose and duration of orally ingested probiotics were include the comprehensive search strategy, extensive sub-
not associated with reductions in RTI incidence, duration, group and meta-regression analyses to identify sources of
or severity, and while subgroup analyses suggested potential heterogeneity, and inclusion of both ITT and per-protocol
genus-level differences, those differences were not statisti- analyses. However, the analyses generally did not extend
cally significant in the meta-regressions (Figure 3). Too few to examining interactions between effect modifiers (e.g.,
strains were tested in multiple studies to provide adequate population type and genus of probiotic strain), assess con-
power to detect strain-level differences, and whether single founding in meta-regression analyses (e.g., more favorable
or multiple strains were used in the intervention largely effects of fermented dairy may be an artifact of the strains
did not impact results. However, analyses did suggest that used), or consider whether investigators analytically verified
using fermented dairy products as an oral delivery matrix the composition of the intervention and placebo products.
for probiotics may result in greater reductions in days of This analysis also included several limitations resulting from
illness due to RTI relative to other forms of oral delivery. the available literature. These limitations included a lack of
One reason may relate to the fermentation process itself. relevant studies on orally ingested prebiotics and synbiotics,
Specifically, lactic acid bacteria used in dairy fermentations some concerns regarding various sources of bias among most
and as probiotics may increase the bioavailability of im- of the studies included, and evidence of publication bias
munomodulatory nutrients in milk (75). Additionally, lactic for certain outcomes. Additionally, not all included studies
acid bacteria used in fermentation and added to probiotic reported data for all outcomes or reported all outcomes in
supplements metabolize nutrients within milk, producing a a format that could be used for meta-analysis. Finally, few
variety of bioactive immunomodulatory compounds during strains were tested in multiple studies, making it difficult to
and after the fermentation process, such as lactic acid, SCFAs, identify strain-specific effects.
various peptides and amino acids, polysaccharides, vitamins, In conclusion, this systematic review and meta-analysis
and antimicrobial compounds (76, 77). Collectively, these extends previous meta-analyses relying primarily on studies
findings suggest that effects of orally ingested probiotics on of pediatric populations, by demonstrating that orally in-
reducing RTI incidence, duration, and severity in nonelderly gested probiotics also reduce the incidence, duration, and
adults are relatively consistent across the different interven- severity of RTIs in nonelderly adult populations. Effect
tion compositions, doses, and durations tested, and might sizes were generally modest and, despite heterogeneity in
be enhanced using fermented dairy as a delivery matrix. results between studies, were relatively consistent across the
However, results should not be interpreted as indicating different intervention compositions, doses, and durations.
that all products are equally effective and are limited by Whether these observations apply to orally ingested prebi-
small numbers of studies within certain subgroups, most otics or synbiotics should be an objective of future research,
notably a lack of multiple studies using the same strain or as should further elucidation of sources of heterogeneity in
strain combinations. Further, results should be interpreted study results and analyses of the cost-benefit ratio of orally
cautiously given the substantial-to-considerable level of ingested probiotics in relation to RTIs. Further, replication of
heterogeneity observed in many of the analyses, evidence of positive findings for individual probiotic strains and strain
publication bias for RTI incidence, and that few studies were combinations in high-quality randomized controlled trials is
considered to have a low overall risk of bias. necessary in order to conclusively identify the most effective
Few studies identified for inclusion in this systematic strains and dosing strategies.
review tested effects of prebiotics or synbiotics. This is some-
what surprising given evidence that probiotics, prebiotics, Acknowledgments
and synbiotics improve markers of immune function or RTI- The authors acknowledge the US Department of Defense
related outcomes in cell models and in studies of animals, Tri-Service Microbiome Consortium for establishing the
infants, and children (9, 10). Most salient to the present collaborative infrastructure that inspired and facilitated
study are 2 recent meta-analyses. In one, both orally ingested this work. The authors acknowledge Dr. Chad Porter, Dr.
prebiotic and synbiotic interventions were reported to lower Sandra Isidean, Dr. Michael Goodson, and Jason Soares
the odds of experiencing RTIs by ∼25% and increase NK for assistance in conceptualizing the systematic review,
cell cytotoxicity ex vivo (12). In another, orally ingested and Dr. Andrew Young for editorial review. The authors’
synbiotics were found to lower the incidence of RTIs by 16% responsibilities were as follows—JPK: designed the research;
(13). However, both meta-analyses were largely based on JPK and ES: designed the search strategy; ES: conducted the
studies in pediatric populations. As with probiotics, it cannot literature search; JLC, AH-M, SDS, JTA, RTA, HSF, ASB,
be assumed that any effects of prebiotics or synbiotics on RTI and JPK: screened abstracts; JLC, AH-M, SDS, JTA, RTA,
burden will generalize to all populations, nor should it be and JPK: screened full texts; JLC, AH-M, JTA, SDS, and
2292 Coleman et al.

JPK: extracted data and conducted risk-of-bias assessments; review and meta-analysis of randomized controlled trials. Evid-Based
JPK: analyzed the data; JLC and JPK: wrote the manuscript; Complement Altern Med 2020;2020:1. doi: 10.1155/2020/8734140.
17. Emre IE, Eroğlu Y, Kara A, Dinleyici EC, Özen M. The effect
JPK: has final primary responsibility for final content; and all
of probiotics on prevention of upper respiratory tract infections
authors: read and approved the final manuscript. in the paediatric community—a systematic review. Benef Microbes
2020;11(3):201–11.
18. Wang Y, Li X, Ge T, Xiao Y, Liao Y, Cui Y, et al. Probiotics for prevention
Data Availability and treatment of respiratory tract infections in children: a systematic
Data will be made available upon reasonable request. review and meta-analysis of randomized controlled trials. Medicine
(Baltimore) 2016;95(31):e4509. doi: 10.1097/md.0000000000004509.
19. Möller GB, da Cunha Goulart MJV, Nicoletto BB, Alves FD, Schneider
References CD. Supplementation of probiotics and its effects on physically active
1. GBD 2016 Causes of Death Collaborators. Global, regional, individuals and athletes: systematic review. Int J Sport Nutr Exercise
and national age-sex specific mortality for 264 causes of death, Metab 2019;29(5):481–92.
1980–2016: a systematic analysis for the Global Burden of 20. King S, Glanville J, Sanders ME, Fitzgerald A, Varley D. Effectiveness of
Disease Study 2016. Lancet North Am Ed 2017;390(10100): probiotics on the duration of illness in healthy children and adults who
1151–210. develop common acute respiratory infectious conditions: a systematic
2. Jin X, Ren J, Li R, Gao Y, Zhang H, Li J, et al. Global burden review and meta-analysis. Br J Nutr 2014;112(1):41–54.
of upper respiratory infections in 204 countries and territories, 21. Agans RT, Giles GE, Goodson MS, Karl JP, Leyh S, Mumy KL, et al.
from 1990 to 2019. EClinicalMedicine 2021;37:100986. doi: Evaluation of probiotics for warfighter health and performance. Front
10.1016/j.eclinm.2021.100986. Nutr 2020;7:70. doi: 10.3389/fnut.2020.00070.
3. Cherry DK, Burt CW, Woodwell DA. National Ambulatory Medical 22. Martin SA, Pence BD, Woods JA. Exercise and respiratory tract viral
Care Survey: 2001 summary. Adv Data 2003(337):1–44. infections. Exerc Sport Sci Rev 2009;37(4):157–64.
4. Fendrick AM, Monto AS, Nightengale B, Sarnes M. The economic 23. Parasher A. COVID-19: current understanding of its pathophysiology,
burden of non-influenza-related viral respiratory tract infection in the clinical presentation and treatment. Postgrad Med J 2021;97(1147):312–
United States. Arch Intern Med 2003;163(4):487–94. 20.
5. Flannery B, Kondor RJG, Chung JR, Gaglani M, Reis M, Zimmerman 24. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al.
RK, et al. Spread of antigenically drifted influenza A(H3N2) viruses and RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ
vaccine effectiveness in the United States during the 2018–2019 season. 2019;366:l4898. doi: 10.1136/bmj.l4898.
J Infect Dis 2020;221(1):8–15. 25. Tsafnat G, Glasziou P, Choong MK, Dunn A, Galgani F, Coiera E.
6. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem Systematic review automation technologies. Syst Rev 2014;3(1):74. doi:
J 2017;474(11):1823–36. 10.1186/2046-4053-3-74.
7. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. 26. Durlak JA. How to select, calculate, and interpret effect sizes. J Pediatr
Expert consensus document. The International Scientific Association Psychol 2009;34(9):917–28.
for Probiotics and Prebiotics consensus statement on the scope and 27. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al.
appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol Cochrane handbook for systematic reviews of interventions. Available
2014;11(8):506–14. from: www.training.cochrane.org/handbook.
8. Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen 28. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis
SJ, et al. Expert consensus document: the International Scientific detected by a simple, graphical test. BMJ 1997;315(7109):629–34.
Association for Probiotics and Prebiotics (ISAPP) consensus statement 29. Langkamp-Henken B, Rowe CC, Ford AL, Christman MC, Nieves C,
on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol Jr, Khouri L, et al. Bifidobacterium bifidum R0071 results in a greater
2017;14(8):491–502. proportion of healthy days and a lower percentage of academically
9. Swanson KS, Gibson GR, Hutkins R, Reimer RA, Reid G, Verbeke stressed students reporting a day of cold/flu: a randomised, double-
K, et al. The International Scientific Association for Probiotics and blind, placebo-controlled study. Br J Nutr 2015;113(3):426–34.
Prebiotics (ISAPP) consensus statement on the definition and scope of 30. West NP, Horn PL, Pyne DB, Gebski VJ, Lahtinen SJ, Fricker PA,
synbiotics. Nat Rev Gastroenterol Hepatol 2020;17(11):687–701. et al. Probiotic supplementation for respiratory and gastrointestinal
10. Sanders ME, Merenstein DJ, Reid G, Gibson GR, Rastall RA. Probiotics illness symptoms in healthy physically active individuals. Clin Nutr
and prebiotics in intestinal health and disease: from biology to the clinic. 2014;33(4):581–7.
Nat Rev Gastroenterol Hepatol 2019;16(10):605–16. 31. Kekkonen RA, Vasankari TJ, Vuorimaa T, Haahtela T, Julkunen I,
11. Karl JPC. Gut microbiota-targeted interventions for reducing the Korpela R. The effect of probiotics on respiratory infections and
incidence, duration, and severity of respiratory tract infections in gastrointestinal symptoms during training in marathon runners. Int J
healthy non-elderly adults. Mil Med 2021;186(3-4):e310–18. Sport Nutr Exercise Metab 2007;17(4):352–63.
12. Williams LM, Stoodley IL, Berthon BS, Wood LG. The effects of 32. Habermann W, Zimmermann K, Skarabis H, Kunze R, Rusch V. [The
prebiotics, synbiotics, and short-chain fatty acids on respiratory tract effect of a bacterial immunostimulant (human Enterococcus faecalis
infections and immune function: a systematic review and meta-analysis. bacteria) on the occurrence of relapse in patients with chronic recurrent
Adv Nutr 2022;13(1):167–92. bronchitis]. Arzneimittelforschung 2001;51(11):931–7.
13. Chan CKY, Tao J, Chan OS, Li HB, Pang H. Preventing respiratory tract 33. Habermann W, Zimmermann K, Skarabis H, Kunze R, Rusch
infections by synbiotic interventions: a systematic review and meta- V. [Reduction of acute recurrence in patients with chronic
analysis of randomized controlled trials. Adv Nutr 2020;11(4):979–88. recurrent hypertrophic sinusitis by treatment with a bacterial
14. Łagowska K, Bajerska J. Effects of probiotic supplementation on immunostimulant (Enterococcus faecalis bacteriae of human origin)].
respiratory infection and immune function in athletes: systematic Arzneimittelforschung 2002;52(8):622–7.
review and meta-analysis of randomized controlled trials. J Athl Train 34. de Vrese M, Winkler P, Rautenberg P, Harder T, Noah C, Laue C,
2021;56(11):1213–23. et al. Effect of Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP
15. Hao Q, Dong BR, Wu T. Probiotics for preventing acute 07/3, B. bifidum MF 20/5 on common cold episodes: a double blind,
upper respiratory tract infections. Cochrane Database Syst Rev randomized, controlled trial. Clin Nutr 2005;24(4):481–91.
2015;(2):CD006895. doi: 10.1002/14651858.CD006895.pub3. 35. Guillemard E, Tanguy J, Flavigny A, de la Motte S, Schrezenmeir J.
16. Li L, Hong K, Sun Q, Xiao H, Lai L, Ming M, et al. Probiotics for Effects of consumption of a fermented dairy product containing the
preventing upper respiratory tract infections in adults: a systematic probiotic Lactobacillus casei DN-114 001 on common respiratory and

gastrointestinal infections in shift workers in a randomized controlled 51. Kumpu M, Kekkonen RA, Korpela R, Tynkkynen S, Järvenpää
trial. J Am Coll Nutr 2010;29(5):455–68. S, Kautiainen H, et al. Effect of live and inactivated Lactobacillus
36. Jespersen L, Tarnow I, Eskesen D, Morberg CM, Michelsen B, rhamnosus GG on experimentally induced rhinovirus colds:
Bügel S, et al. Effect of Lactobacillus paracasei subsp. paracasei, L. randomised, double blind, placebo-controlled pilot trial. Benef
casei 431 on immune response to influenza vaccination and upper Microbes 2015;6(5):631–9.
respiratory tract infections in healthy adult volunteers: a randomized, 52. Tapiovaara L, Kumpu M, Mäkivuokko H, Waris M, Korpela R,
double-blind, placebo-controlled, parallel-group study. Am J Clin Nutr Pitkäranta A, et al. Human rhinovirus in experimental infection after
2015;101(6):1188–96. peroral Lactobacillus rhamnosus GG consumption, a pilot study. Int
37. Meng H, Lee Y, Ba Z, Peng J, Lin J, Boyer AS, et al. Consumption of Forum Allergy Rhinology 2016;6(8):848–53.
Bifidobacterium animalis subsp. lactis BB-12 impacts upper respiratory 53. Michael DR, Jack AA, Masetti G, Davies TS, Loxley KE, Kerry-Smith
tract infection and the function of NK and T cells in healthy adults. Mol J, et al. A randomised controlled study shows supplementation of
Nutr Food Res 2016;60(5):1161–71. overweight and obese adults with lactobacilli and bifidobacteria reduces
38. Haywood BA, Black KE, Baker D, McGarvey J, Healey P, Brown bodyweight and improves well-being. Sci Rep 2020;10(1):4183. doi:
RC. Probiotic supplementation reduces the duration and incidence of 10.1038/s41598-020-60991-7.
infections but not severity in elite rugby union players. J Sci Med Sport 54. Michalickova D, Minic R, Dikic N, Andjelkovic M, Kostic-Vucicevic M,
2014;17(4):356–60. Stojmenovic T, et al. Appl Physiol Nutr Metab 2016;41(7):782–9.
39. Cox AJ, Pyne DB, Saunders PU, Fricker PA. Oral administration of the 55. Nishihira J, Moriya T, Sakai F, Kabuki T, Kawasaki Y, Nishimura
probiotic Lactobacillus fermentum VRI-003 and mucosal immunity in M. Lactobacillus gasseri SBT2055 stimulates immunoglobulin
endurance athletes. Br J Sports Med 2010;44(4):222–6. production and innate immunity after influenza vaccination in healthy
40. Childs CE, Röytiö H, Alhoniemi E, Fekete AA, Forssten SD, Hudjec adult volunteers: a randomized, double-blind, placebo-controlled,
N, et al. Xylo-oligosaccharides alone or in synbiotic combination parallel-group study. Funct Foods Health Dis 2016;6(9):544. doi:
with Bifidobacterium animalis subsp. lactis induce bifidogenesis and 10.31989/ffhd.v6i9.284.
modulate markers of immune function in healthy adults: a double- 56. Pumpa KL, McKune AJ, Harnett J. A novel role of probiotics in
blind, placebo-controlled, randomised, factorial cross-over study. Br J improving host defence of elite rugby union athlete: a double blind
Nutr 2014;111(11):1945–56. randomised controlled trial. J Sci Med Sport 2019;22(8):876–81.
41. Ahrén IL, Hillman M, Nordström EA, Larsson N, Niskanen TM. 57. Rizzardini G, Eskesen D, Calder PC, Capetti A, Jespersen L, Clerici
Fewer community-acquired colds with daily consumption of M. Evaluation of the immune benefits of two probiotic strains
Lactiplantibacillus plantarum HEAL9 and Lacticaseibacillus paracasei Bifidobacterium animalis ssp. lactis, BB-12® and Lactobacillus paracasei
8700:2. A randomized, placebo-controlled clinical trial. J Nutr ssp. paracasei, L. casei 431® in an influenza vaccination model:
2021;151(1):214–22. a randomised, double-blind, placebo-controlled study. Br J Nutr
42. Altadill T, Espadaler-Mazo J, Liong MT. Effects of a lactobacilli 2012;107(6):876–84. doi: 10.1017/s000711451100420x.
probiotic on reducing duration of URTI and fever, and use 58. Schröder C, Schmidt S, Garbe E, Röhmel J, Giersiepen K. Effects
of URTI-associated medicine: a re-analysis of a randomized, of the regular intake of the probiotic Lactobacillus reuteri (DSM
placebo-controlled study. Microorganisms 2021;9(3):528. doi: 17938) on respiratory and gastrointestinal infections in a workplace
10.3390/microorganisms9030528. setting: a double-blind randomized placebo-controlled trial. BMC Nutr
43. Chong HX, Yusoff NAA, Hor YY, Lew LC, Jaafar MH, Choi SB, 2015;1(1):3. doi: 10.1186/2055-0928-1-3.
et al. Lactobacillus plantarum DR7 improved upper respiratory tract 59. Shida K, Sato T, Iizuka R, Hoshi R, Watanabe O, Igarashi T,
infections via enhancing immune and inflammatory parameters: et al. Daily intake of fermented milk with Lactobacillus casei strain
a randomized, double-blind, placebo-controlled study. J Dairy Sci Shirota reduces the incidence and duration of upper respiratory tract
2019;102(6):4783–97. infections in healthy middle-aged office workers. Eur J Nutr 2017;56(1):
44. Berggren A, Lazou Ahrén I, Larsson N, Önning G. Randomised, 45–53.
double-blind and placebo-controlled study using new probiotic 60. Smith TJ, Rigassio-Radler D, Denmark R, Haley T, Touger-Decker R.
lactobacilli for strengthening the body immune defence against viral Effect of Lactobacillus rhamnosus LGG® and Bifidobacterium animalis
infections. Eur J Nutr 2011;50(3):203–10. ssp. lactis BB-12® on health-related quality of life in college students
45. de Vrese M, Winkler P, Rautenberg P, Harder T, Noah C, Laue C, et al. affected by upper respiratory infections. Br J Nutr 2013;109(11):1999–
Probiotic bacteria reduced duration and severity but not the incidence 2007.
of common cold episodes in a double blind, randomized, controlled 61. Strasser B, Geiger D, Schauer M, Gostner JM, Gatterer H, Burtscher M,
trial. Vaccine 2006;24(44-46):6670–4. et al. Probiotic supplements beneficially affect tryptophan-kynurenine
46. Gleeson M, Bishop NC, Oliveira M, Tauler P. Daily probiotic’s metabolism and reduce the incidence of upper respiratory tract
(Lactobacillus casei Shirota) reduction of infection incidence in athletes. infections in trained athletes: a randomized, double-blinded, placebo-
Int J Sport Nutr Exercise Metab 2011;21(1):55–64. controlled trial. Nutrients 2016;8(11):752. doi: 10.3390/nu8110
47. Gleeson M, Bishop NC, Oliveira M, McCauley T, Tauler P, Lawrence C. 752.
Effects of a Lactobacillus salivarius probiotic intervention on infection, 62. Sugimura T, Takahashi H, Jounai K, Ohshio K, Kanayama M, Tazumi
cold symptom duration and severity, and mucosal immunity in K, et al. Effects of oral intake of plasmacytoid dendritic cells-stimulative
endurance athletes. Int J Sport Nutr Exercise Metab 2012;22(4):235–42. lactic acid bacterial strain on pathogenesis of influenza-like illness and
48. Gleeson M, Bishop NC, Struszczak L. Effects of Lactobacillus casei immunological response to influenza virus. Br J Nutr 2015;114(5):727–
Shirota ingestion on common cold infection and herpes virus antibodies 33.
in endurance athletes: a placebo-controlled, randomized trial. Eur J 63. Tiollier E, Chennaoui M, Gomez-Merino D, Drogou C, Filaire E,
Appl Physiol 2016;116(8):1555–63. Guezennec CY. Effect of a probiotics supplementation on respiratory
49. Hor Y-Y, Lew L-C, Lau AS-Y, Ong J-S, Chuah L-O, Lee Y-Y, infections and immune and hormonal parameters during intense
et al. Probiotic Lactobacillus casei Zhang (LCZ) alleviates respiratory, military training. Mil Med 2007;172(9):1006–11.
gastrointestinal & RBC abnormality via immuno-modulatory, anti- 64. Turner RB, Woodfolk JA, Borish L, Steinke JW, Patrie JT, Muehling
inflammatory & anti-oxidative actions. J Funct Foods 2018;44: LM, et al. Effect of probiotic on innate inflammatory response and
235–45. viral shedding in experimental rhinovirus infection—a randomised
50. Kalima K, Lehtoranta L, He L, Pitkäniemi J, Lundell R, Julkunen I, controlled trial. Benef Microbes 2017;8(2):207–15.
et al. Probiotics and respiratory and gastrointestinal tract infections in 65. Vaisberg M, Paixão V, Almeida EB, Santos JMB, Foster R, Rossi M, et al.
Finnish military conscripts—a randomised placebo-controlled double- Daily intake of fermented milk containing Lactobacillus casei Shirota
blinded study. Benef Microbes 2016;7(4):463–71. (Lcs) modulates systemic and upper airways immune/inflammatory
2294 Coleman et al.

responses in marathon runners. Nutrients 2019;11(7):1678. doi: 71. Jäger R, Mohr AE, Carpenter KC, Kerksick CM, Purpura M, Moussa A,
10.3390/nu11071678. et al. International Society of Sports Nutrition position stand: probiotics.
66. West NP, Pyne DB, Cripps AW, Hopkins WG, Eskesen DC, Jairath J Int Soc Sports Nutr 2019;16(1):62. doi: 10.1186/s12970-019-0329-0.
A, et al. Lactobacillus fermentum (PCC®) supplementation and 72. Simpson RJ, Campbell JP, Gleeson M, Krüger K, Nieman DC, Pyne DB,
gastrointestinal and respiratory-tract illness symptoms: a randomised et al. Can exercise affect immune function to increase susceptibility to
control trial in athletes. Nutr J 2011;10(1):30. doi: 10.1186/1475-2891- infection? Exerc Immunol Rev 2020;26:8–22.
10-30. 73. Walsh NP, Oliver SJ. Exercise, immune function and respiratory
67. Zhang H, Yeh C, Jin Z, Ding L, Liu BY, Zhang L, et al. Prospective infection: an update on the influence of training and environmental
study of probiotic supplementation results in immune stimulation and stress. Immunol Cell Biol 2016;94(2):132–39.
improvement of upper respiratory infection rate. Synth Syst Biotechnol 74. Joo J, Williamson SA, Vazquez AI, Fernandez JR, Bray MS. The
2018;3(2):113–20. influence of 15-week exercise training on dietary patterns among young
68. Hughes C, Davoodi-Semiromi Y, Colee JC, Culpepper T, Dahl adults. Int J Obesity 2019;43(9):1681–90.
WJ, Mai V, et al. Galactooligosaccharide supplementation reduces 75. García-Burgos M, Moreno-Fernández J, Alférez MJM, Díaz-Castro
stress-induced gastrointestinal dysfunction and days of cold or flu: J, López-Aliaga I. New perspectives in fermented dairy products
a randomized, double-blind, controlled trial in healthy university and their health relevance. J Funct Foods 2020;72:104059. doi:
students. Am J Clin Nutr 2011;93(6):1305–11. https://doi.org/10.1016/j.jff.2020.104059.
69. Nieman DC, Henson DA, McMahon M, Wrieden JL, Davis JM, Murphy 76. Marco ML, Sanders ME, Gänzle M, Arrieta MC, Cotter PD, De Vuyst
EA, et al. Beta-glucan, immune function, and upper respiratory tract L, et al. The International Scientific Association for Probiotics and
infections in athletes. Med Sci Sports Exerc 2008;40(8):1463–71. Prebiotics (ISAPP) consensus statement on fermented foods. Nat Rev
70. Pregliasco F, Anselmi G, Fonte L, Giussani F, Schieppati S, Soletti Gastroenterol Hepatol 2021;18(3):196–208.
L. A new chance of preventing winter diseases by the administration 77. Marco ML, Heeney D, Binda S, Cifelli CJ, Cotter PD, Foligné B, et al.
of synbiotic formulations. J Clin Gastroenterol 2008;42(Suppl 3): Health benefits of fermented foods: microbiota and beyond. Curr Opin
S224–33. Biotechnol 2017;44:94–102. doi: 10.1016/j.copbio.2016.11.010.

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REVIEW

Orally Ingested Probiotics, Prebiotics, and

Introduction worldwide public health issues (1). RTI symptoms often

2278 Coleman et al.

Biotics and respiratory tract infections 2279

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Study, year; country

Biotics and respiratory tract infections

Study, year; country

Study, year; country

Biotics and respiratory tract infections

Study, year; country

Study, year; country

Biotics and respiratory tract infections

0.1 0.2 0.5 1 2 5 10

Prebiotic interventions consisted of galacto-oligosaccharides Eﬀects of orally ingested probiotics on incidence,

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Biotics and respiratory tract infections 2287

0.83 0.88 0.62 0.62 -0.02

0.81 0.78 0.59 0.56 -0.47 -0.18

0.92 0.89 0.88 0.84 -0.06 -0.32

Number of -0.03 -0.01 -0.08 -0.06 -0.19 -0.08

-0.14 -0.09 -0.26 -0.21 -0.03

-0.07 -0.11 -0.25 -0.30 -0.35 0.17

0.03 -0.01 0.09 0.09 0.22 -0.29

2288 Coleman et al.

Michalickova 2016 (64) 0.67 0.51 0.87 -2.95 0.00 88 / 5 132 / 5

Shida 2017 (69) 0.31 0.22 0.42 -7.25 0.00 49 / 12 160 / 12

Zhang 2018 (77) 0.32 0.24 0.41 -8.40 0.00 70 / 16 221 / 16

0.77 0.71 0.83 -6.35 0.00

0.1 0.2 0.5 1 2 5 10

Biotics and respiratory tract infections 2289

-1.00 -0.50 0.00 0.50 1.00

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-1.00 -0.50 0.00 0.50 1.00

Biotics and respiratory tract infections 2291

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Biotics and respiratory tract infections 2293

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Biotics and respiratory tract infections 2295

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