Phytomedicine 118 (2023) 154948

Contents lists available at ScienceDirect

Phytomedicine
journal homepage: www.elsevier.com/locate/phymed

Original Article

Efficacy and safety of gastrointestinal microbiome supplementation for

allergic rhinitis: A systematic review and meta-analysis with trial
sequential analysis
Dongliang Liu, Xilu Wang, Hang Zhang *
Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, PR China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Allergic rhinitis (AR) is a non-infective chronic inflammatory disease of nasal mucosa.
Gastrointestinal microbiome Purpose: To evaluate the efficacy and safety of gastrointestinal microbiome supplementation (GMS) for patients
Probiotics with allergic rhinitis (AR), concerning improvement on symptoms and signs, laboratory outcomes, quality of life,
Prebiotics
and medication scores.
Synbiotics
Methods: Five English databases were searched up to Dec 12th, 2022. Probiotics, prebiotics, and synbiotics were
Allergic rhinitis
Systematic Review main therapies or adjuvants in experimental groups. Systematic reviews and meta-analyses were conducted
based on the Cochrane systematic review method by using RevMan 5.4 Software, with meta-influence analyses,
subgroup-analyses, meta-regression, and publication bias performed for exploration of heterogeneity by Stata
V.14. Trial sequential analyses were performed by TSA 0.9, and quality of the results was accessed through the
GRADE-pro GDT.
Results: Finally, extracted from 53 articles, 65 RCTs involving 3,634 participants with sound worldwide repre­
sentativeness were included. Primary results showed better improvement in GMS groups on TNSS (WMD=1.05, P
for WMD=0.004, 95%CI:0.34 to 1.76), overall nasal condition (WMD=1.25, P for WMD<0.001, 95%CI:0.90 to
1.61), overall quality of life (WMD=6.16, P for WMD<0.001, 95%CI:4.92 to 7.40) and medication score
(WMD=0.42, P for WMD=0.42, 95%CI:-0.06 to 0.90).However, GMS groups were inferior than the controls
concerning reduction on serum total IgE (WMD=-1.81) and ratios of serum Th1/Th2 (WMD=-1.06). Meta-
regressions suggested significant (p<0.05) variations of the effects in some comparisons. In addition, results of
sub-group analyses firstly revealed potential influence between final results and the variables above. Instantly
after intervention, the GRADE levels of evidence were sound, including “High ⨁⨁⨁⨁” in 10, “Moderate
⨁⨁⨁◯” in 33, and “Low ⨁⨁◯◯” in nine comparisons. However, overall certainties decreased obviously
during follow-ups.
Conclusion: Overall, our pooled results firstly revealed that GMS yielded acceptable benefits for patients with AR
compared with controls with sound certainties, after balancing the benefits and harms.

Introduction rhinorrhea and sneezing, and some allergic rhino-conjunctivitis symp­

toms like ocular itching and watery eyes, and even throat symptoms,
Allergic rhinitis (AR) is a non-infective chronic inflammatory disease may occur in patients with AR (Wheatley and Togias, 2015). These
of nasal mucosa, which is mainly mediated by immunoglobulin E (IgE) symptoms are significant risks in decreasing of sleep quality, daily ac­
after allergic individuals are exposed to allergens (Zhang et al., 2021). tivity, practical ability, and emotional health varying from different
Common symptoms of AR include nasal congestion, nasal itching, severities and durations (Meltzer, 2016). With a worldwide prevalence

Abbreviations: AR, allergic rhinitis; CI, confidence interval; ECP, eosinophilic cationic protein; GRADE, grading of recommendations assessment, development and
evaluation system; GMS, gastrointestinal microbiome supplementation; IFN, interferon; IGE, immunoglobulin e; IL, interleukin; IS, Required information size; RCT,
Randomized controlled trial; RR, Risk ratio; TGF, Transforming growth factor; TNF, Tumor necrosis factor; TNSS, Total nasal symptom score; VAS, Visual analogue
scale; WMD, Weighted mean difference.
* Corresponding author.
E-mail address: [email protected] (H. Zhang).

https://doi.org/10.1016/j.phymed.2023.154948
Received 12 April 2023; Received in revised form 7 June 2023; Accepted 1 July 2023
Available online 2 July 2023
0944-7113/© 2023 Elsevier GmbH. All rights reserved.
D. Liu et al. Phytomedicine 118 (2023) 154948

for about 10% to 20%, AR was estimated had caused 30 to 50 billion studies manually for trials.
euros in EU countries considering health care burden and reduction of
labor efficiency (Bousquet et al., 2020; Brozek et al., 2010). Inclusion criteria
In addition to avoiding exposure to individual-specific allergen,
currently, standard interventions for AR include intranasal corticoste­ (1) Studies in which participants were diagnosed clinically as AR in
roids, intranasal or oral antihistamines, oral leukotriene receptor an­ accordance with public guidelines, regardless of age, gender,
tagonists, and intranasal decongestants (Sharma et al., 2022; Terada and race, country and other demographic items, and severity, type of
Kawata, 2022). However, some side effects (such as dry mouth, AR;
drowsiness, and insomnia) of the interventions were noticed, and even (2) Prospective randomized controlled trials (RCTs).
followed by drug dependence and resistance (Gross et al., 2019; Won (3) Trials in which GMS (including probiotics, prebiotics, or syn­
et al., 2021). Furthermore, non-surgical new therapies including sub­ biotics) was applied as the only or main therapy in experimental
lingual immunotherapy, subcutaneous immunotherapy, and targeted groups. Participants in control groups received placebos, blank
biologic treatment are increasingly considered by AR patients in a (or wait-list) controls, or routine AR therapies. No participant in
limited scale due to relatively long onset of action, high requirement on control groups obtain any type of GMS.
adherence, and large costs (Kulalert et al., 2022; Yu et al., 2020). In (4) Primary outcomes included the total nasal symptom score
addition, a diversified and balanced gastrointestinal microfloral is sig­ (TNSS), visual analogue scale (VAS) scores of total nasal symp­
nificant in shaping host immune development and regulating immune toms, decrease on serum IgE, increase on ratios of serum Th1/
disorders, which is helpful in allergic diseases (Wilczyńska et al., 2019). Th2, overall improvement on quality of life, and reduction on AR
As an arising non-pharmacological approach, GMS, including probiotics, medication scores.
prebiotics, and synbiotics mainly, are playing roles in prevention and (5) Trials published in English only.
treatment of polycystic ovary syndrome (Hadi et al., 2020), nonalco­
holic fatty liver disease (Hadi et al., 2019), AR (Das, 2012; Li et al., Study selection and data extraction
2023), and also in some other allergic and immune diseases (Adjibade
et al., 2022; Wu et al., 2022).Colonizing in gastrointestinal tracts, pro­ Two authors (DL l and H Z) searched the online databases listed
biotics, a kind of bacteria, could provide health benefits to the host when above and recorded the titles and abstracts of all the articles. Two au­
administered in adequate amounts (Quigley, 2019).Previous studies thors (DL l and XL W) assessed the eligibility of these articles and made
demonstrated that probiotics can upregulate interleukin (IL)-10, IL-12, decisions on every research (inclusion or exclusion) independently. If
and interferon (IFN) systemically, stimulate pre-Th1 immune they did not reach the same decision, the concerned articles were dis­
response, and reduce Th2 cytokines (Das, 2012; Li et al., 2023).Pre­ cussed with a third reviewer (H Z). Two reviewers (DL l and H Z)
biotics are non-digestible and can serve as substrates by normal intes­ extracted data independently from each study. Differences of extracted
tinal flora for selectively stimulating one or several species of existing data were solved after discussion with a third reviewer (H Z).
probiotics and inhibiting the growth of harmful bacteria (Markowiak
and Śliżewska, 2017). Synbiotics refer to mixed products of probiotics Quality assessment
and prebiotics, or added with vitamins and trace elements (Markowiak
and Śliżewska, 2017). Quality of all the articles included in this review was independently
However, evidence concerning relieving on signs and symptom, evaluated by two reviewers (DL l and H Z) using the Cochrane Collab­
changes on laboratory findings, improvement on quality of life, and oration risk of bias tool by RevMan 5.4 software. This tool concerns
decrease on medication scores are still controversial with a growing seven areas, including random sequence generation, allocation
number of trials performed to explore therapeutic effects of GMS for AR. concealment, blinding of participants and personnel, blinding of
The aim of this systematic review and meta-analysis is to fill the vacancy outcome assessment, incomplete outcome data, selective reporting, and
above with rigorous design and comprehensive analyses, and incorpo­ other bias. Any disagreement was resolved by discussions with a fourth
rate new evidence about GMS for patients with AR from published high- reviewer (H Z).
quality RCTs. In addition, safety of the intervention, quality of outcomes
and strength of evidence recommendations were also measured for Statistical analysis
better clinical application.
Statistics were analyzed with RevMan V.5.4, Stata V.14 and TSA 0.9
Material and methods software. Effect sizes were evaluated as weighted mean difference
(WMD) for continuous outcomes, and as risk ratio (RR) for binary out­
Protocol and registration comes with their 95% confidence intervals (CI). The Q and I2 tests were
performed to examine heterogeneity, with I2>50% indicating signifi­
This systematic review was registered in PROSPERO with the regis­ cant heterogeneity. Fixed or random-effects model was applied with
tration number CRD42023388835(available from https://www.crd. p<0.05 indicating significant differences for effect sizes.
york.ac.uk/PROSPERO/#myprospero). If the heterogeneity was still obvious (I2>50%) after random-effects
model applied and no less than five trials were included, then meta-
Search strategy influence analysis (for sensitivity analysis) was conducted to identify
potential outlier, and to remove certain corresponding study if rational
Five English databases, including PubMed, Scopus, Cochrane Li­ interpretation is available (Cumpston et al., 2019). Otherwise, for
brary, Medline and Embase were searched from their inception until comparisons with no less than 10 trials included, meta-regression and
December 16th, 2022. The PRISMA agreement was followed in decision regression-based sub-group analyses were planned to identify potential
of search strategy and inclusion criteria (Page et al., 2021)]. Two subsets variables leading to high heterogeneity with interpretation. Variables of
of terms were searched with the term ‘AND’, including GMS (e.g. sub-group analyses and meta regression were selected based on previous
‘microecologics’, ‘microbioecologics’, ‘gastrointestinal microbiome’, meta-analyses, research, and the PICOS principle. Boundary values of
‘gastrointestinal microb’, ‘probiotic’, ‘lactobacillus’, ‘prebiotic’, and quantitative variables were identified as mean or median value based on
‘synbiotic’) and condition of AR (‘allergic rhinitis’, ‘AR’, ‘anaphylactic their statistical distributions.
rhinitis’ and ‘hay fever’). Two authors processed the searches indepen­ Exploration of publication bias by Egger’s tests were performed if no
dently, and we also searched the references of the original and review less than ten trials were included, together with trim and fill test for

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D. Liu et al. Phytomedicine 118 (2023) 154948

further identification of the stability [20]. p<0.05 indicates significant America (Peru) (Galvan Calle et al., 2022), 1 in Oceania (Australia) [61],
differences for meta-regression, and p<0.1 for Egger’s test. In addition, and 1 in Africa (Egypt) (Nabil et al., 2020). As for the participants, 15
trial sequential analyses were performed by TSA 0.9 with type I error (28.30%) studies (Anania et al., 2021; Dennis-Wall et al., 2017; Ivory
α=0.05 and type II error β=0.1, aiming at examining and minimizing the et al., 2008; Ivory et al., 2013; Kawase et al., 2009; Mårtensson et al.,
impact of type 1 errors due to sparse data and repeated significance 2022; Miraglia Del Giudice et al., 2017; Moyad et al., 2009; Nembrini
testing following updates with new trials (Thorlund et al., 2011). We et al., 2015; Ouwehand et al., 2009; Ried et al., 2022; Wassenberg et al.,
also conducted penalized test for further verification. Strength of evi­ 2011; Yonekura et al., 2009) focused on seasonal AR, and 20 (37.74%)
dence recommendations for effect estimation in each outcome was studies (Ahmed et al., 2019; Chen et al., 2010; Costa et al., 2014; Deh­
evaluated by The Grading of Recommendations Assessment, Develop­ navi et al., 2019; Harima-Mizusawa et al., 2016; Ishida et al., 2005;
ment and Evaluation system (GRADE) pro GDT (Schünemann et al., Jalali et al., 2019; Jan et al., 2011; Kang et al., 2020; Lin et al., 2013; Lin
2013). et al., 2014; Lue et al., 2012; Meng et al., 2019; Nishimura et al., 2009;
Sadeghi-Shabestari et al., 2020; Sumadiono et al., 2018; Wang et al.,
Results 2004; Xu et al., 2016; Yamashita et al., 2020) focused on perennial or
persistent AR. The participants had been suffering from AR for at least
Study inclusion one year as reported, and seasonal allergens (such as grass pollen, cedar
pollen, and parietaria pollen) in 20 (37.74%) studies (Anania et al.,
Initially, 3634 articles were searched from the five online databases, 2021; Ciprandi et al., 2005; Costa et al., 2014; Dölle et al., 2014; Gotoh
but none met the criteria for gray literature inclusion when scanning in et al., 2009; Harata et al., 2017; Helin et al., 2002; Ishida et al., 2005;
local libraries for printed article. After 1923 duplicated articles were Ivory et al., 2008; Ivory et al., 2013; Jerzynska et al., 2016; Kawase
removed, 1471 of the resting 1711 articles were excluded based on titles et al., 2009; Koyama et al., 2010; Miraglia Del Giudice et al., 2017;
and abstracts in two rounds of screening. Then, the remaining 240 ar­ Nabil et al., 2020; Nagata et al., 2010; Nembrini et al., 2015; Ried et al.,
ticles were downloaded for further selection, and among which 187 2022; Xu et al., 2016) and non-seasonal allergens (such as dust mite,
articles were excluded with reasons. Eventually, 65 trials from 53 arti­ dust, dog, and shrimp) in 17 (32.08%) studies (Chen et al., 2010; Har­
cles (three articles with double sub-trials, five three-arm studies, and one ima-Mizusawa et al., 2016; Ishida et al., 2005; Jan et al., 2011; Kang
three-arm study were recombined to 20 trials for comparison) were et al., 2020; Lin et al., 2013; Lin et al., 2014; Lue et al., 2012; Mår­
included (Ahmed et al., 2019; Anania et al., 2021; Chen et al., 2010; tensson et al., 2022; Nishimura et al., 2009; Tamura et al., 2007; Was­
Ciprandi et al., 2005; Costa et al., 2014; Dehnavi et al., 2019; Dennis-­ senberg et al., 2011; Xiao et al., 2007; Xiao et al., 2006; Xiao et al., 2006;
Wall et al., 2017; Dölle et al., 2014; Galvan Calle et al., 2022; Gio­ Yonekura et al., 2009) were reported as positive testing allergens. In
vannini et al., 2007; Gotoh et al., 2009; Harata et al., 2017; screening, 17 (32.08%) studies (Anania et al., 2021; Chen et al., 2010;
Harima-Mizusawa et al., 2016; Helin et al., 2002; Ishida et al., 2005, Costa et al., 2014; Dölle et al., 2014; Harima-Mizusawa et al., 2016;
2005; Ivory et al., 2008, 2013; Jalali et al., 2019; Jan et al., 2011; Jer­ Ivory et al., 2013; Jerzynska et al., 2016; Lue et al., 2012; Moyad et al.,
zynska et al., 2016; Kang et al., 2020; Kawase et al., 2009; Koyama et al., 2009; Nembrini et al., 2015; Nishimura et al., 2009; Ouwehand et al.,
2010; Li et al., 2022; Lin et al., 2013; Lin et al., 2014; Lue et al., 2012; 2009; Peng and Hsu, 2005; Wang et al., 2004; Wassenberg et al., 2011;
Mårtensson et al., 2022; Meng et al., 2019; Miraglia Del Giudice et al., Xu et al., 2016) performed both allergen skin-prick and serum-IgE tests
2017; Moyad et al., 2009; Nabil et al., 2020; Nagata et al., 2010; Nasrin for inclusion criteria, and 24 (45.28%) studies (Dehnavi et al., 2019;
et al., 2017; Nembrini et al., 2015; Nishimura et al., 2009; Ouwehand Giovannini et al., 2007; Gotoh et al., 2009; Harata et al., 2017; Helin
et al., 2009; Peng and Hsu, 2005; Ried et al., 2022; Sadeghi-Shabestari et al., 2002; Ishida et al., 2005; Ishida et al., 2005; Ivory et al., 2008;
et al., 2020; Singh et al., 2013; Sumadiono et al., 2018; Tamura et al., Jalali et al., 2019; Jan et al., 2011; Kang et al., 2020; Kawase et al., 2009;
2007; Wang et al., 2004; Wardani and Fatmawati, 2019; Wassenberg Koyama et al., 2010; Lin et al., 2013; W. Y. Lin et al., 2014; Mårtensson
et al., 2011; Xiao et al., 2007; Xiao et al., 2006; Xiao et al., 2006; Xu et al., 2022; Miraglia Del Giudice et al., 2017; Nabil et al., 2020; Sade­
et al., 2016; Yamashita et al., 2020; Yonekura et al., 2009). Based on ghi-Shabestari et al., 2020; Singh et al., 2013; Sumadiono et al., 2018;
suggestion from reviewer, we performed extra search on the Web of Wardani and Fatmawati, 2019; Xiao et al., 2007; Xiao et al., 2006; Xiao
Sciences (ISI) database, and no more new inclusion was identified et al., 2006; Yonekura et al., 2009) conducted either of the tests. As for
beyond the five databases. (Figure S1) interventions, GMS alone versus placebo were applied in 44 (67.69%)
trials (Chen et al., 2010; Dennis-Wall et al., 2017; Dölle et al., 2014;
Study characteristics Giovannini et al., 2007; Gotoh et al., 2009; Harata et al., 2017; Har­
ima-Mizusawa et al., 2016; Helin et al., 2002; Ishida et al., 2005; Ishida
The 53 included studies, with 4527 children, adolescent, or adult et al., 2005; Ivory et al., 2008; Ivory et al., 2013; Jan et al., 2011; Kang
participants, were all published in English. Among them, 32 were con­ et al., 2020; Kawase et al., 2009; Koyama et al., 2010; Li et al., 2022; Lin
ducted in Asia (Japan, Indonesia, Iran, Pakistan, Korea, Mainland China et al., 2013; Mårtensson et al., 2022; Meng et al., 2019; Miraglia Del
and Taiwan) (Ahmed et al., 2019; Chen et al., 2010; Dehnavi et al., Giudice et al., 2017; Moyad et al., 2009; Nagata et al., 2010; Nembrini
2019; Gotoh et al., 2009; Harata et al., 2017; Harima-Mizusawa et al., et al., 2015; Nishimura et al., 2009; Ouwehand et al., 2009; Peng and
2016; Ishida et al., 2005; Ishida et al., 2005; Jalali et al., 2019; Jan et al., Hsu, 2005; Ried et al., 2022; Singh et al., 2013; Tamura et al., 2007; M.
2011; Kang et al., 2020; Kawase et al., 2009; Li et al., 2022; Lin et al., F. Wang et al., 2004; Wardani and Fatmawati, 2019; Wassenberg et al.,
2013; Lin et al., 2014; Lue et al., 2012; Meng et al., 2019; Nagata et al., 2011; Xiao et al., 2007; Xiao et al., 2006; Xiao et al., 2006; Xu et al.,
2010; Nasrin et al., 2017; Ouwehand et al., 2009; Ried et al., 2022; 2016; Yamashita et al., 2020; Yonekura et al., 2009), mainly, and
Sumadiono et al., 2018; Tamura et al., 2007; Wardani and Fatmawati, routine therapies (such as oral antihistamine, local corticosteroid) or
2019; Xiao et al., 2007; Xiao et al., 2006; Xiao et al., 2006; Xu et al., immunotherapy (including sublingual, specific, or cluster immuno­
2016; Yamashita et al., 2020; Yonekura et al., 2009), 15 in Europe (Italy, therapy) was also conducted in the other trials. No participant received
Switzerland, Germany, Sweden, UK, Finland, Poland, and France) GMS in the control groups. Specifically, multispecies of GMS were
(Anania et al., 2021; Ciprandi et al., 2005; Costa et al., 2014; Dölle et al., selected in 20 trials (30.77%) (Anania et al., 2021; Dehnavi et al., 2019;
2014; Giovannini et al., 2007; Helin et al., 2002; Ivory et al., 2008; Ivory Dennis-Wall et al., 2017; Galvan Calle et al., 2022; Giovannini et al.,
et al., 2013; Jerzynska et al., 2016; Mårtensson et al., 2022; Miraglia Del 2007; Harata et al., 2017; Jalali et al., 2019; Kang et al., 2020; Kawase
Giudice et al., 2017; Nembrini et al., 2015; Singh et al., 2013; Wassen­ et al., 2009; Koyama et al., 2010; Miraglia Del Giudice et al., 2017;
berg et al., 2011), 3 in North America (Canada, and USA) (Dennis-Wall Nasrin et al., 2017; Ouwehand et al., 2009; Sadeghi-Shabestari et al.,
et al., 2017; Koyama et al., 2010; Moyad et al., 2009), 1 in South 2020; Wardani and Fatmawati, 2019; Wassenberg et al., 2011; Xiao

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D. Liu et al. Phytomedicine 118 (2023) 154948

et al., 2006), and 32 (49.23%) trials (Anania et al., 2021; Chen et al., 2009; Koyama et al., 2010; Li et al., 2022; Lin et al., 2013; Lin et al.,
2010; Costa et al., 2014; Dehnavi et al., 2019; Ivory et al., 2008; Ivory 2014; Lue et al., 2012; Mårtensson et al., 2022; Meng et al., 2019;
et al., 2013; Jalali et al., 2019; Jan et al., 2011; Jerzynska et al., 2016; Miraglia Del Giudice et al., 2017; Moyad et al., 2009; Nagata et al.,
Kang et al., 2020; Koyama et al., 2010; Li et al., 2022; Lin et al., 2013; 2010; Nembrini et al., 2015; Nishimura et al., 2009; Ouwehand et al.,
Miraglia Del Giudice et al., 2017; Moyad et al., 2009; Nagata et al., 2009; Peng and Hsu, 2005; Ried et al., 2022; Sadeghi-Shabestari et al.,
2010; Ouwehand et al., 2009; Peng and Hsu, 2005; Ried et al., 2022; 2020; Singh et al., 2013; Tamura et al., 2007; Wang et al., 2004; War­
Sadeghi-Shabestari et al., 2020; Singh et al., 2013; Tamura et al., 2007; dani and Fatmawati, 2019; Wassenberg et al., 2011; Xiao et al., 2007;
Wang et al., 2004; Wassenberg et al., 2011; Xiao et al., 2006; Xiao et al., Xiao et al., 2006; Xiao et al., 2006; Yamashita et al., 2020; Yonekura
2006; Yamashita et al., 2020; Yonekura et al., 2009) took protective et al., 2009), and was applied in 47 (87.04%) studies for outcome
measures for activity of GMS during storage. Overall, participants took assessment (Ahmed et al., 2019; Anania et al., 2021; Chen et al., 2010;
no less than five billion CFU of GMS per day in 27 trials (41.54%) Ciprandi et al., 2005; Costa et al., 2014; Dehnavi et al., 2019; Dölle et al.,
(Galvan Calle et al., 2022; Gotoh et al., 2009; Harata et al., 2017; Helin 2014; Giovannini et al., 2007; Gotoh et al., 2009; Harata et al., 2017;
et al., 2002; Ishida et al., 2005; Ishida et al., 2005; Ivory et al., 2008; Harima-Mizusawa et al., 2016; Helin et al., 2002; Ishida et al., 2005;
Ivory et al., 2013; Jalali et al., 2019; Kang et al., 2020; Kawase et al., Ivory et al., 2008; Ivory et al., 2013; Jalali et al., 2019; Jan et al., 2011;
2009; W. Y. Lin et al., 2014; Lue et al., 2012; Mårtensson et al., 2022; Jerzynska et al., 2016; Kang et al., 2020; Kawase et al., 2009; Koyama
Miraglia Del Giudice et al., 2017; Nembrini et al., 2015; Ouwehand et al., 2010; Li et al., 2022; Lin et al., 2013; Lin et al., 2014; Lue et al.,
et al., 2009; Peng and Hsu, 2005; Ried et al., 2022; Tamura et al., 2007; 2012; Mårtensson et al., 2022; Meng et al., 2019; Miraglia Del Giudice
Wassenberg et al., 2011; Xiao et al., 2007; Xiao et al., 2006; Yonekura et al., 2017; Moyad et al., 2009; Nagata et al., 2010; Nembrini et al.,
et al., 2009), and interventions were performed more than eight weeks 2015; Nishimura et al., 2009; Ouwehand et al., 2009; Peng and Hsu,
in 30 (46.15%) trials (Anania et al., 2021; Dölle et al., 2014; Galvan 2005; Ried et al., 2022; Sadeghi-Shabestari et al., 2020; Singh et al.,
Calle et al., 2022; Giovannini et al., 2007; Harata et al., 2017; Helin 2013; Wassenberg et al., 2011; Xiao et al., 2007; Xiao et al., 2006; Xiao
et al., 2002; Ishida et al., 2005; Ivory et al., 2008; Ivory et al., 2013; Jan et al., 2006; Yamashita et al., 2020; Yonekura et al., 2009).
et al., 2011; Jerzynska et al., 2016; Kawase et al., 2009; T. Y. Lin et al., Intention-to-treat analysis (ITT) or Per-protocol analysis (PP) was
2013; Lue et al., 2012; Moyad et al., 2009; Nabil et al., 2020; Nasrin mentioned in 11 (20.37%) studies (Ahmed et al., 2019; Anania et al.,
et al., 2017; Ouwehand et al., 2009; Peng and Hsu, 2005; Xiao et al., 2021; Chen et al., 2010; Costa et al., 2014; Dölle et al., 2014; Galvan
2006; Xiao et al., 2006; Xu et al., 2016; Yamashita et al., 2020; Yone­ Calle et al., 2022; Giovannini et al., 2007; Jalali et al., 2019; Nembrini
kura et al., 2009).Some baseline characteristics were not reported in et al., 2015; Ried et al., 2022; Yamashita et al., 2020) concerning
several studies, but were declared as comparable between groups dropout if happened, and 29 trials reported protocol or registration
(p>0.05). In addition, for study designing of the articles, 16 (30.19%) ahead of experiment (Chen et al., 2010; Dehnavi et al., 2019; Dennis-­
(Costa et al., 2014; Giovannini et al., 2007; Harima-Mizusawa et al., Wall et al., 2017; Galvan Calle et al., 2022; Ishida et al., 2005; Ivory
2016; Ivory et al., 2013; Jalali et al., 2019; Jerzynska et al., 2016; Kang et al., 2013; Jalali et al., 2019; Kang et al., 2020; Koyama et al., 2010; l.
et al., 2020; Meng et al., 2019; Miraglia Del Giudice et al., 2017; Moyad Li et al., 2022; Meng et al., 2019; Miraglia Del Giudice et al., 2017; Nabil
et al., 2009; Nabil et al., 2020; Nishimura et al., 2009; Ried et al., 2022; et al., 2020; Nembrini et al., 2015; Ouwehand et al., 2009; Ried et al.,
Tamura et al., 2007; Wardani and Fatmawati, 2019; Xu et al., 2016) 2022; Sadeghi-Shabestari et al., 2020; Singh et al., 2013; Sumadiono
conducted in more than one centers, and only 16 articles reported power et al., 2018; Wang et al., 2004; Wardani and Fatmawati, 2019; Was­
analyses on sample sizes (Costa et al., 2014; Dennis-Wall et al., 2017; senberg et al., 2011; Xiao et al., 2007; Xiao et al., 2006; Xiao et al., 2006;
Galvan Calle et al., 2022; Giovannini et al., 2007; Harima-Mizusawa Yamashita et al., 2020; Yonekura et al., 2009) (Figs. 1, S2).
et al., 2016; Ivory et al., 2008; Jalali et al., 2019; Miraglia Del Giudice
et al., 2017; Moyad et al., 2009; Nembrini et al., 2015; Peng and Hsu, Pooled results of GMS for AR
2005; Ried et al., 2022; Sadeghi-Shabestari et al., 2020; Singh et al.,
2013; Wassenberg et al., 2011; Yamashita et al., 2020), while some Effects of GMS for relieving nasal and ocular symptoms
other items were not detailed or reported in some trials. (Tables S1–S3). Instantly after intervention, pooled results favored GMS groups with
significantly more reduction on TNSS (WMD=1.05, P for WMD=0.004,
Assessment of quality and bias 95%CI:0.34 to 1.76, I2 =86%) (Galvan Calle et al., 2022; Kang et al.,
2020; Lue et al., 2012; Mårtensson et al., 2022; Meng et al., 2019; Nabil
According to the Cochrane risk of bias tool (Cumpston et al., 2019), et al., 2020; Nembrini et al., 2015; Ried et al., 2022; Singh et al., 2013),
the randomization sequences and allocation concealments were total VAS scores of nasal symptoms (WMD=1.25, P for WMD<0.001,
described clearly and appropriately in 20 (37.04%) (Anania et al., 2021; 95%CI:0.90 to 1.61, I2 =99%) (Anania et al., 2021; Chen et al., 2010;
Chen et al., 2010; Costa et al., 2014; Dennis-Wall et al., 2017; Gio­ Ciprandi et al., 2005; Costa et al., 2014; Dehnavi et al., 2019; Dennis-­
vannini et al., 2007; Ivory et al., 2013; Jalali et al., 2019; Jerzynska Wall et al., 2017; Galvan Calle et al., 2022; Gotoh et al., 2009; Jalali
et al., 2016; Kang et al., 2020; Li et al., 2022; Lin et al., 2013; Mår­ et al., 2019; Jan et al., 2011; Kang et al., 2020; Koyama et al., 2010; l. Li
tensson et al., 2022; Moyad et al., 2009; Ried et al., 2022; Sade­ et al., 2022; Lin et al., 2013; Lue et al., 2012; Miraglia Del Giudice et al.,
ghi-Shabestari et al., 2020; Sumadiono et al., 2018; Tamura et al., 2007; 2017; Peng and Hsu, 2005; Tamura et al., 2007; M. F. Wang et al., 2004;
Xiao et al., 2006; Xiao et al., 2006; Yamashita et al., 2020), and 12 Xu et al., 2016; Yonekura et al., 2009), and of ocular symptoms
(22.22%) studies respectively (Chen et al., 2010; Costa et al., 2014; (WMD=0.52, P for WMD=0.002, 95%CI:0.19 to 0.86, I2 =99%)
Dennis-Wall et al., 2017; Gotoh et al., 2009; Ivory et al., 2008; Ivory compared with controls (Costa et al., 2014; Gotoh et al., 2009; Jan et al.,
et al., 2013; Jalali et al., 2019; Koyama et al., 2010; Mårtensson et al., 2011; Li et al., 2022; Lin et al., 2013; Lue et al., 2012; Peng and Hsu,
2022; Ouwehand et al., 2009; Yamashita et al., 2020; Yonekura et al., 2005; Tamura et al., 2007; M. F. Wang et al., 2004; Xiao et al., 2006;
2009), with no trial in high bias. Specially-assigned blinding for both Yonekura et al., 2009). Specifically, results of meta-analyses favored
participants and personnel was applied in 46 (85.19%) studies (Ahmed GMS groups with more reduction on VAS scores of nasal itching
et al., 2019; Anania et al., 2021; Chen et al., 2010; Costa et al., 2014; (WMD=0.07, P for WMD=0.55, 95%CI:-0.15 to 0.28, I2 =97%) (Har­
Dehnavi et al., 2019; Dennis-Wall et al., 2017; Dölle et al., 2014; Gio­ ima-Mizusawa et al., 2016; Jalali et al., 2019; Kang et al., 2020; Kawase
vannini et al., 2007; Gotoh et al., 2009; Harata et al., 2017; Har­ et al., 2009; Li et al., 2022; Lin et al., 2013; Lin et al., 2014; Lue et al.,
ima-Mizusawa et al., 2016; Helin et al., 2002; Ishida et al., 2005; Ishida 2012; Meng et al., 2019; Ried et al., 2022; Xiao et al., 2006), sneezing
et al., 2005; Ivory et al., 2008; Ivory et al., 2013; Jalali et al., 2019; Jan (WMD=0.16, P for WMD=0.16, 95%CI:-0.05 to 0.38, I2 =96%) (Har­
et al., 2011; Jerzynska et al., 2016; Kang et al., 2020; Kawase et al., ima-Mizusawa et al., 2016; Jalali et al., 2019; Kang et al., 2020; Kawase

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et al., 2009; Li et al., 2022; Lin et al., 2014; Lue et al., 2012; Meng et al.,
2019; Singh et al., 2013; Xiao et al., 2006; Yonekura et al., 2009), ocular
itching (WMD=0.31, P for WMD=0.23, 95%CI:-0.20 to 0.82, I2 =96%)
(Harima-Mizusawa et al., 2016; Li et al., 2022; Lue et al., 2012; Yama­
shita et al., 2020; Yonekura et al., 2009), and watery eyes (WMD=0.37,
P for WMD=0.003, 95%CI:0.12 to 0.62, I2 =92%) (l. Li et al., 2022; Lue
et al., 2012; Yamashita et al., 2020; Yonekura et al., 2009). However,
results suggested that GMS groups were not superior than the controls
concerning relieving rhinorrhea (WMD=0.00, P for WMD=0.98, 95%
CI:-0.20 to 0.20, I2 =96%), and were inferior than the controls con­
cerning relieving nasal congestion (WMD=-0.11, P for WMD=0.55, 95%
CI:-0.48 to 0.25, I2 =98%) and throat symptoms (WMD=-2.20, P for
WMD=0.18, 95%CI:-5.45 to 1.05, I2 =98%). These were also proved
qualitatively in systematic reviews concerning number of the partici­
pants with improvement on nasal itching (RR=1.07), sneezing
(RR=1.01), ocular symptoms (RR=1.19), and throat symptoms
(RR=0.97). Pooled results of outcomes and during follow-ups are in
Fig. 2, Figs. S3–S13, and Table S4.
After random-effects model applied, the heterogeneities above were
still high (I2> 50%). Outliers were identified by meta-influence analyses
in three comparisons, but no potential extreme trial was excluded for
lacking rational interpretation after full-text comparisons.
Furtherly, meta-regressions and sub-group analyses according to
variations of three aspects were designed, including: 1) Interventions:
experimental intervention, control intervention, number of GMS spe­
cies, dosage form of GMS, activity of GMS, daily dose of GMS, course of
intervention; 2) Participants: sample size, age, gender ratio, type of AR,
duration of AR, positive to seasonal or non-seasonal allergen, allergen
skin-prick or serum-IgE test, clear exclusion of related disease; 3)
Designing: Number of center, clear and appropriate randomization,
blinding, clear performance on comparability of baseline characteristics,
clear and appropriate power analysis, study protocol or registration. The
three groups of variations above were also applied in all meta-
regressions and sub-group analyses of this study.
Results identified the following variables with statistical significance
(p<0.05) for meta-regression in sub-groups, including positive to sea­
sonal or non-seasonal allergen [reduction on TNSS (tau2 = 0.25, I2resid
= 50.80%, Adjusted R2 = 78.69%, p=0.02)], type of AR [reduction on
total VAS scores of nasal symptoms (tau2 = 11.49, I2resid = 98.66%,
Adjusted R2 = 11.56%, p=0.04), of nasal congestion (tau2 = 3.23,
I2resid = 95.88%, Adjusted R2 = 28.20%, p=0.04), of nasal itching (tau2
= 5.69, I2resid = 97.44%, Adjusted R2 = 31.88%, p=0.04), and of rhi­
norrhea (tau2 = 3.21, I2resid = 95.91%, Adjusted R2 = 28.09%,
p=0.04)], allergen skin-prick test or not [reduction on total VAS scores
of nasal symptoms (tau2 = 11.26, I2resid = 98.70%, Adjusted R2 =
13.35%, p=0.03), and of ocular symptoms (tau2 = 3.64, I2resid =
99.01%, Adjusted R2 = 29.80%, p=0.04)], sample size [reduction on
total VAS scores of ocular symptoms (tau2 = 3.33, I2resid = 99.06%,
Adjusted R2 = 35.69%, p=0.02)], and age [reduction on total VAS scores
of ocular symptoms (tau2 = 3.71, I2resid = 99%, Adjusted R2 = 28.31%,
p=0.04)] (Table S5-S11).

Effects of GMS for improving nasal signs

Results of meta-analyses favored GMS groups with more improve­
ment than controls on swelling of nasal mucosa (WMD=0.11, P for
WMD=0.37, 95%CI:-0.13 to 0.36, I2 =89%) (Gotoh et al., 2009; Har­
ima-Mizusawa et al., 2016; Ishida et al., 2005; Tamura et al., 2007;
Yamashita et al., 2020; Yonekura et al., 2009), color of nasal mucosa
(WMD=0.04, P for WMD=0.77, 95%CI:-0.21 to 0.29, I2 =80%) (Har­
ima-Mizusawa et al., 2016; Ishida et al., 2005; Tamura et al., 2007;
Yamashita et al., 2020; Yonekura et al., 2009), amount of mucus in nasal
Fig. 1. Risk of bias summary of the included trials.
cavity (WMD=0.23, P for WMD=0.40, 95%CI:-0.31 to 0.77, I2 =98%)
(Gotoh et al., 2009; Harima-Mizusawa et al., 2016; Ishida et al., 2005;
Tamura et al., 2007; Yamashita et al., 2020; Yonekura et al., 2009), and
attribute of mucus in nasal cavity (WMD=0.35, P for WMD=0.43, 95%
CI:-0.51 to 1.21, I2 =96%) compared with controls (Harima-Mizusawa

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D. Liu et al. Phytomedicine 118 (2023) 154948

Fig. 2. Forest plot of GMS vs. controls for reducing total VAS scores of nasal symptoms.
Note: VAS: Visual analogue scale; GMS: Gastrointestinal microbiome supplementation; SD: Standard deviation; CI: confidence interval.

et al., 2016; Ishida et al., 2005; Tamura et al., 2007; Yamashita et al., cationic protein (ECP) (WMD=0.72, P for WMD=0.16, 95%CI:-0.29 to
2020; Yonekura et al., 2009). Pooled results of the outcomes during 1.73, I2 =83%). In addition, meta-analyses revealed superiority of GMS
follow-ups are in Figure S14, S15, and Table S12. than controls in increasing serum IFN-γ (WMD=7.01, P for WMD=0.01,
After random-effects model applied, the heterogeneities above were 95%CI:1.72 to 12.31, I2 =98%) and transforming growth factor (TGF)-β
still high (I2> 50%), and outlier was not identified by meta-influence (WMD=0.16, P for WMD=0.95, 95%CI:-5.09 to 5.42, I2 =93%). How­
analyses. ever, results suggested that GMS groups were inferior than the controls
concerning reduction on serum total IgE (WMD=-1.81), Japanese cedar
Effects of GMS for regulating serum and nasal lavage laboratory outcomes pollen-specific IgE (WMD=-0.21), house dust-specific IgE
As for changes on serum interleukin levels, pooled evidence favored (WMD=-0.03), birch pollen-specific IgE (WMD=-0.50), IL-17
GMS groups than controls with more reduction on serum IL-1β (WMD=-2.58), and eosinophils (EOS) (WMD=-0.82). Meanwhile, re­
(WMD=0.49, P for WMD=0.01, 95%CI:0.11 to 0.87, I2 =97%) (Ivory sults also showed that GMS groups yielded fewer increase than controls
et al., 2008; Jerzynska et al., 2016; Singh et al., 2013), IL-4 (WMD=7.68, on serum IL-10 (WMD=-0.93), IL-12 (WMD=-9.78), Th1 (WMD=-1.50),
P for WMD<0.001, 95%CI:5.36 to 10.00, I2 =98%) (Dehnavi et al., and ratios of serum Th1/Th2 (WMD=-1.06). Pooled results of outcomes
2019; Kang et al., 2020; Koyama et al., 2010; Lue et al., 2012; Ouwe­ and during follow-ups are in Figs. 3 and S16-S22 and Table S13.
hand et al., 2009; Wardani and Fatmawati, 2019; Wassenberg et al., After random-effects model applied, the heterogeneities above were
2011; Xu et al., 2016), IL-5 (WMD=13.76, P for WMD=0.04, 95% still high (I2> 50%). Outliers were identified by meta-influence analyses
CI:0.74 to 26.77, I2 =99%) (Ivory et al., 2008; Kang et al., 2020; in four comparisons, but no potential extreme trial was excluded for
Ouwehand et al., 2009; Singh et al., 2013; Wassenberg et al., 2011; Xu lacking rational interpretation after full-text comparisons.
et al., 2016), IL-6 (WMD=0.52, P for WMD=0.11, 95%CI:-0.12 to 1.16, Furtherly, meta-regressions and sub-group analyses were performed.
I2 =95%) (Ivory et al., 2008; Jerzynska et al., 2016; Ouwehand et al., Results of meta-regression identified variables with statistical signifi­
2009), IL-8 (WMD=0.52, P for WMD=0.32, 95%CI:-0.51 to 1.55, I2 cance (p<0.05) in the following comparisons, including reduction on
=NA) (Wassenberg et al., 2011), and IL-13 (WMD=18.17, P for total serum IgE[number of GMS species (tau2 = 409.6, I2resid = 95.71%,
WMD=0.14, 95%CI:-5.68 to 42.03, I2 =99%)(Chen et al., 2010; Kang Adjusted R2 = 73.45%, p=0.001), total dose of GMS during the whole
et al., 2020; Singh et al., 2013; Xu et al., 2016). Results also showed that course (tau2 = 816.6, I2resid = 90.50%, Adjusted R2 = 47.07%, p=0.01),
GMS groups yielded more reduction than controls on serum house dust age (tau2 = 454.2, I2resid = 95.84%, Adjusted R2 = 70.56%, p=0.01),
mite-specific IgE (WMD=0.25, P for WMD=0.48, 95%CI:-0.44 to 0.94, I2 type of AR (tau2 = 123.9, I2resid = 89.08%, Adjusted R2 = 91.97%,
=87%), grass pollen -specific IgE (WMD=0.34, P for WMD=0.53, 95% p<0.001), positive to seasonal or non-seasonal allergen (tau2 = 1134,
CI:-0.72 to 1.39, I2 =0%), Th2 (WMD=0.11, P for WMD=0.67, 95% I2resid = 96.17%, Adjusted R2 = 26.49%, p=0.05),clear exclusion of
CI:-0.38 to 0.60, I2 =83%), tumor necrosis factor (TNF-α) (WMD=0.03, related disease (tau2 = 351.2, I2resid = 95.70%, Adjusted R2 = 77.23%,
P for WMD=0.95, 95%CI:-0.77 to 0.82, I2 =97%), and eosinophilic p<0.001), clear and appropriate randomization (tau2 = 401.1, I2resid =

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D. Liu et al. Phytomedicine 118 (2023) 154948

Fig. 3. Forest plot of GMS vs. controls for changing serum interleukin levels.
Note: GMS: Gastrointestinal microbiome supplementation; SD: Standard deviation; CI: confidence interval; IL: Interleukin.

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D. Liu et al. Phytomedicine 118 (2023) 154948

95.83%, Adjusted R2 = 74%, p=0.01), study protocol or registration (tau2 sleep quality (WMD=0.34, P for WMD=0.01, 95%CI:0.10 to 0.59, I2
= 934.3, I2resid = 95.94%, Adjusted R2 = 39.44%, p=0.02)], reduction =91%), emotional health (WMD=0.52, P for WMD=0.11, 95%CI:-0.11
on serum IL-4 [experimental intervention (tau2 = 736.3, I2resid = to 1.15, I2 =0%), daily activity (WMD=0.54, P for WMD=0.001, 95%
98.76%, Adjusted R2 = 49.88%, p=0.01)], and increase on serum IFN-γ CI:0.22 to 0.87, I2 =97%), and practical problems (WMD=0.53, P for
[type of AR (tau2 = 339, I2resid = 96.97%, Adjusted R2 = 30.84%, WMD=0.04, 95%CI:0.02 to 1.05, I2 =98%) compared with controls.
p=0.04), and positive to seasonal or non-seasonal allergen (tau2 = Pooled results of the outcomes and during follow-ups are in Figs. 4, S23,
341.6, I2resid = 98.66%, Adjusted R2 = 30.32%, p=0.03)] S24 and Table S19.
(Tables S14–S18). After random-effects model applied, the heterogeneities above were
still high (I2> 50%). Outliers were identified by meta-influence analyses
Effects of GMS for increasing quality of life in one comparison, but no potential extreme trial was excluded for
In terms of quality of life among the AR patients, pooled evidence lacking rational interpretation after full-text comparisons.
favored GMS groups with significantly more improvement on quality of Furtherly, meta-regressions and sub-group analyses were performed,
life (WMD=6.16, P for WMD<0.001, 95%CI:4.92 to 7.40, I2 =99%), and results of meta-regression identified variables for sub-groups with

Fig. 4. Forest plot of GMS vs. controls for improving sleeping quality, emotion health, daily activity, and practical ability.
Note: GMS: Gastrointestinal microbiome supplementation; SD: Standard deviation; CI: confidence interval.

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D. Liu et al. Phytomedicine 118 (2023) 154948

statistical significance (p<0.05) in improvement on daily activity [age Adverse event reported in trials
(tau2 = 0.35, I2resid = 97.10%, Adjusted R2 = 54.45%, p=0.02), gender
ratio (tau2 = 0.22, I2resid = 96.98%, Adjusted R2 = 71.87%, p=0.01)] GMS specified adverse events were reported in the experimental
(Table S20,S21). groups of five studies (Dölle et al., 2014; Jerzynska et al., 2016; Meng
et al., 2019; Ried et al., 2022; Yonekura et al., 2009), including mild to
Effects of GMS for reducing medication scores moderate diarrhea, abdominal pain and flatulence with occurrences
Last but not least, pooled results favored GMS groups with more from 3% to 15%. However, the events were all spontaneously alleviated
reduction on AR medication scores (WMD=0.42, P for WMD=0.42, 95% without drug treatment in one to several days, and no participant was
CI:-0.06 to 0.90, I2 =98%), and such effects were also observed during dropped-off due to the events.
follow-ups (Figure S25, S26 and Table S22). In addition, 28 studies reported that there was no GMS specified
After random-effects model applied, the heterogeneities above were adverse event, and it was not mentioned in other 21 studies.
still high (I2> 50%), and outlier was not identified by meta-influence
analyses. Trial sequential analysis (TAS) and penalized test
Meta-regressions and sub-group analyses were performed but
without significant (p<0.05) variable identified (Table S23). TAS and penalized tests were conducted on 14 comparisons with no
less than 10 trials included. In TSA, results favored exclusion of the
possibility of false positive and identified enough possibility that GMS

Fig. 5. Trial sequential analysis of GMS vs. controls for reducing the TNSS.
Notes: GMS: Gastrointestinal microbiome supplementation; TNSS: Total nasal symptom scores; RIS: Required information size. This picture showed that 1) Z-cure
(the solid orange line) crossed the RIS (the vertical dotted red line), indicating that the number of included studies has reached the amount required for meta-analysis;
2) Z-cure crossed the conventional boundary of benefit (the horizontal dotted blue line z = 1.96), indicating that the difference of reduction on the TNSS between
GMS groups versus control groups was statistically significant, excluding the possibility of false positive; 3) Z-cure crossed trial sequential monitoring boundary for
benefit (the oblique dotted red line), which indicated that GMS was superior to the controls.

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D. Liu et al. Phytomedicine 118 (2023) 154948

groups were superior to controls concerning 1) reduction on total VAS instability of them(Table S25).
scores of nasal symptoms, 2) overall improvement on quality of life, 3)
improvement on quality of daily activity, 4) reduction on total VAS
scores of ocular symptoms, 5) decrease on serum IL-4, 6) increase on Levels of evidence
serum IFN-γ, and 7) decrease on serum EOS. However, only the first five
comparisons above excluded the possibility of false positive after When evaluated instantly after intervention, levels of evidence for
penalized test, and the first three of them reached estimated number of the majority of outcomes were sound (Table S26–30). Specifically,
studies required information size (RIS). Results of TAS and penalized test overall certainties of evidence were rated as “High ⨁⨁⨁⨁” in several
of other comparisons are listed in Figs. 5, 6, S27-S52 and Table S24. comparisons concerning effects of GMS for relieving nasal and ocular
symptoms (three), for regulating serum and nasal lavage laboratory
outcomes (six), and for increasing quality of life (one). In addition, 33
Testing of publication bias comparisons were rated as “Moderate ⨁⨁⨁◯” certainties, nine as
“Low ⨁⨁◯◯” and without “Very low ◯◯◯◯” rating. However,
Publication bias was suspected in 3 of 14 comparisons with no less certainties of evidence seemed obvious decrease during follow-ups due
than 10 trials included through Egger’s test(Table S25). Trim and fill test to insufficient inclusion in comparisons, for 59 of them were rated as
showed that statistical significances of two in the 14 comparisons were “Low” certainty and only three were rated as “Moderate”
reversed after certain number of missing studies filled, indicating the (Table S26–30).

Fig. 6. Penalized tests of GMS vs. controls for reducing the TNSS.
Notes: GMS: Gastrointestinal microbiome supplementation; TNSS: Total nasal symptom scores; RIS: Required information size. This picture showed that 1) Z-cure
(the solid orange line) crossed the RIS (the vertical dotted red line), indicating that the number of included studies has reached the amount required for meta-analysis;
2) Z-cure crossed the conventional boundary of benefit (the horizontal dotted blue line z=1.96), indicating that the difference of reduction on the TNSS between GMS
groups versus control groups was statistically significant, excluding the possibility of false positive; 3) The penalized Z-cure (the solid green line) crossed the
conventional boundary of benefit (the horizontal dotted blue line z=1.96), indicating that the difference of reduction on the TNSS between GMS groups versus
control groups was statistically significant in penalized tests, further excluding the possibility of false positive.

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D. Liu et al. Phytomedicine 118 (2023) 154948

Discussion Among the included trials in this study, two strains of GMS, Lacto­
bacillus and Bifidobacterium, were most frequently applied. Lactoba­
Till now, this study is the largest and most comprehensive systematic cillus is Gram positive, non-Bacillus, and widely distributed in nature. It
review and meta-analysis of GMS for patients with AR concerning nasal can be isolated from plant surfaces, dairy products, meat products, beer,
and ocular symptoms, nasal signs, serum and nasal lavage laboratory wine, fruit juice, malt juice, fermented dough, sewage, and human and
outcomes, quality of life, and medication scores. The high quality of this animal feces (Kullar et al., 2023). As early as the early 20th century,
study, firstly, lies in its large number of inclusion (53 English studies biologist Mechnikoff (1845–1916) clearly stated in his Nobel Prize
covering 4527 participants) and worldwide representativeness (from all winning “longevity theory” that the daily yogurt consumed by Bulgarian
the six continents in addition to Antarctica). In addition, strict inclusion Balkan residents contains a large amount of lactic acid bacteria, which
criteria were conducted, and meta-regressions and sub-group analyses can colonize the human body and effectively inhibit the growth of
based on multiple variables were reached for better clinical application harmful bacteria, reducing the toxicity of toxins produced by harmful
and benefits for future researches. Further, comprehensive evaluation bacteria in the gut to the entire body. This is an important reason for the
tools for the results were also applied in consideration of detecting and longevity of Bulgarian residents (Chingwaru and Vidmar, 2017; Kumar
dealing with potential heterogeneity, false positive, stability and eval­ et al., 2022). On the one hand, Lactobacillus can significantly activate
uating overall certainty. Generally, pooled results revealed that GMS the phagocytosis of macrophages; on the other hand, because it can
yielded acceptable benefits for patients with AR compared with placebo colonize the intestinal tract, it is equivalent to natural automatic im­
alone, or plus routine therapies or immunotherapies, after balancing the munity (Azad et al., 2018) They can also stimulate peritoneal macro­
benefits (direct effects and indirect reduction on medication scores) and phages, induce interferon production, promote cell division, produce
harms (few mild to moderate gastrointestinal side effects). antibodies and promote cellular immunity, so it can enhance the body’s
Pathogenesis of AR lies to Th1/Th2 cytokine imbalance mainly, and non-specific and specific immune response, improve the body’s resis­
attribute to Toll-like receptor signal pathway and NF-κB signal path tance to disease (Ashraf and Shah, 2014). In 1899, Henry Tissier, a
(Kamekura et al., 2016). Toll-like receptors can recognize potential pediatrician at the Pasteur Institute in France, isolated an anaerobic
pathogens in airway, produce inflammatory factors, and activate cor­ Gram-positive bacterium from the feces of healthy breastfed infants,
responding immune responses. Its pathway can be divided as which was then named Bacillus bifidus. After a century of development,
MyD88-dependent and non-dependent, which can activate downstream especially in recent years, with the development of gut microbiome
NF-κB signal pathway and promote expression of IL-1β, TNF-α and other research, people have increasingly recognized the importance of Bifi­
inflammatory cytokines (Melvin and Ramanathan, 2012). Meanwhile, dobacterium (Hidalgo-Cantabrana et al., 2017). Bifidobacterium can
gene product of IL-1βand TNF-α can activate NF-κB signal pathway inhibit the growth of many intestinal putrefactive bacteria by regulating
directly, thus expanding inflammatory response. Results of our study the normal flora of the intestine, thus reducing the production of some
was different from previous meta-analyses (Farahmandi et al., 2022; intestinal carcinogen (Nowak et al., 2019; Sun et al., 2020). In addition,
Güvenç et al., 2016; Iftikhar et al., 2022; Wang et al., 2022; Zajac et al., studies have found that Bifidobacterium have phagocytic activity that
2015). When were followed instantly after intervention, our results activates macrophages in the body, which helps to suppress tumor cells,
showed that the participants with GMS were better relieved than the and Bifidobacterium can also inhibit tumor growth by inducing
controls on overall nasal (WMD=1.05, 1.25) and ocular (WMD=0.52) apoptosis of tumor cells (Badgeley et al., 2021).
conditions, and on sub-scores including nasal itching (WMD=0.07), A resting-state functional magnetic resonance imaging research
sneezing (WMD=0.16), ocular itching (WMD=0.31), and watery eyes proved that AR patients exhibited lower amplitude of low-frequency
(WMD=0.37). However, negative results were noticed concerning fluctuation values in the precuneus and higher ALFF values in the
reduction on nasal congestion (WMD=-0.11) and rhinorrhea anterior cingulate cortex compared with healthy controls, which were
(WMD=0.00). This was conflicted with the pooled improvement on significantly correlated with the VAS scores, the Rhinoconjunctivitis
nasal signs including swelling (WMD=0.11), color (WMD=0.04) of Quality of Life Questionnaire (RQLQ) scores, and specific IgE (Gao et al.,
nasal mucosa, and amount (WMD=0.23), attribute (WMD=0.35) of 2021). Considering of our findings in this meta-analysis and advances
mucus in nasal cavity. In addition to some positive results such as higher between gastrointestinal ecology, brain and AR in recent years, a po­
reduction on serum house dust mite-specific IgE (WMD=0.25), grass tential but promising connection, the “gut-brain axis (or brain-gut axis)”
pollen-specific IgE (WMD=0.34), IL-1β (WMD=0.49), IL-4 should be noticed. Gut-brain axis is a two-way response system between
(WMD=7.68), IL-5 (WMD=13.76), IL-6 (WMD=0.52), IL-8 gut and brain, which is mediated by neuro-endocrine and connects
(WMD=0.52), IL-13 (WMD=18.17), Th2 (WMD=0.11), TNF-α emotional cognition of the brain and function of peripheral intestines
(WMD=0.03), ECP (WMD=0.72) and more increase on serum IFN-γ (Mayer et al., 2022). Some animal experiments and clinical evidence
(WMD=7.01), TGF-β (WMD=0.16), the conflicts were also noticed be­ suggested that gut microbiome in human intestines plays an indispens­
tween better comprehensive improvement for GMS groups on quality of able role in brain-gut communication. On the one hand, intestinal
life (WMD=6.16), sleep (WMD=0.34), emotional health (WMD=0.52), microflora can affect development and function of brain through the
daily activity (WMD=0.54), practical ability (WMD=0.53), and some axis, on the other hand, brain can also change the structural composition
negative but significant results in serum and nasal lavage laboratory of intestinal microflora in turn (Agirman et al., 2021). A research
outcomes, including fewer decrease on serum total IgE (WMD=-1.81), identified in mice that oral pediococcus pentosaceus not only improved
Japanese cedar pollen-specific IgE (WMD=-0.21), house dust-specific the gut microbial dysbiosis and increased the level of metabolite
IgE (WMD=-0.03), birch pollen-specific IgE (WMD=-0.50), IL-17 γ-aminobutyric acid in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(WMD=-2.58), eosinophils (EOS) (WMD=-0.82), and lower increase (MPTP)-induced mice, but also improve MPTP-induced motor deficits
on serum IL-10 (WMD=-0.93), IL-12 (WMD=-9.78), Th1 (WMD=-1.50), and the accumulation of α-synuclein. Moreover, the probiotics signifi­
ratios of serum Th1/Th2 (WMD=-1.06). Currently, as for basic mecha­ cantly increased the levels of SOD1, Gpx1, and nuclear factor erythroid
nism of probiotics for AR, mainstream researches believe and focus on 2-related factor 2, while it decreased the levels of Keap1 in the brain of
regulating the balance and influence of Th1/Th2 and Treg/Th17 cells MPTP-induced mice (Pan et al., 2022). Another study showed that
Tolerance dendritic cell activity, stimulating Toll-like receptors, and Lacticaseibacillus rhamnosus HA-114 imparted improvement along the
regulating affecting type 2 innate lymphocytes and gut microbiota (Liu microbiota-gut-brain axis, exhibiting beneficial effects on selected be­
et al., 2022). Laboratory data regarding application of prebiotics in haviors, gut microbial diversity, and metabolism in autism spectrum
prevention and treatment of AR are still insufficient, while their ability disorder mice (Pochakom et al., 2022). However, there was no study
to modulate cytokine release seems to be a new approach to the treat­ concerning possible relations between AR and abnormal intestinal
ment of allergic diseases (Kaczynska et al., 2022). microbiota. A review concerning schizophrenia and bipolar disorders

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D. Liu et al. Phytomedicine 118 (2023) 154948

summarized that there were differences in the microbiome between the Author’s contributions
patients and healthy controls, and art of the differences may be induced
by medication application, smoking and certain lifestyles (Genedi et al., Dongliang Liu contributed to the study conception and design.
2019). As a result, neuroimaging studies concerning relations between Dongliang Liu, Xilu Wang, Hang Zhang: collected the data and per­
GBS intervention, results of functional brain imaging, and improvement formed the data analysis. Dongliang Liu, Xilu Wang, Hang Zhang:
on brain-related symptoms of AR, such as sleep, emotional health, and contributed to the interpretation of the data and the completion of fig­
daily activity, are needed in future. ures and tables. Dongliang Liu, Xilu Wang, Hang Zhang: contributed
Publication bias was highly suspected in some results, and more in­ to the drafting of the article and final approval of the submitted version.
clusions were required to meet the RIS for nearly all comparisons ac­
cording to trim and fill tests and trial sequential analyses. More trials Declaration of Competing Interest
with blank or sham controls, and of high quality in designing are needed,
especially on relations between effects of GMS, changes on functional No financial conflict or other relationships for each author to be
brain imaging, and improvement on brain-related symptoms of AR. declared.
In addition, results of meta-regressions and sub-group analyses
identified 11 variables with statistical significance (p<0.05), including Supplementary materials
1) number of GMS species, 2) total dose of GMS during the whole course,
3) type of AR, 4) positive to seasonal or non-seasonal allergen, 5) Supplementary material associated with this article can be found, in
allergen skin-prick test or not, 6) clear exclusion of related disease, 7) the online version, at doi:10.1016/j.phymed.2023.154948.
age, 8) gender ratio, 9) sample size, 10) study protocol or registration,
and 11) clear and appropriate randomization. However, such variables References
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