Orally Ingested Probiotics, Prebiotics, and Synbiotics as Countermeasures for Respiratory Tract Infections in Nonelderly Adults: A Systematic Review and Meta-Analysis

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.

Keywords: common cold; coronavirus; dietary supplement; fermentable fiber; gut microbiome; influenza; respiratory illness; respiratory infection.

FIGURE 1

Flow diagram for screening and selection of studies assessing effects of orally ingested probiotics, prebiotics, or synbiotics on the incidence, duration, or severity of respiratory tract infections in nonelderly adults. RCT, randomized controlled trial.

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.

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.

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.

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.

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.

FIGURE 7

Risk-of-bias assessment for all studies identified in the systematic review. Phrases not in bold font are sources of bias. Assessed using the Cochrane risk-of-bias assessment tool version 2.0. Plot produced using robvis (McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Res Syn Meth 2020;1–7; https://mcguinlu.shinyapps.io/robvis/).