Probiotic treatment (Enterococcus faecalis) improves symptoms of seasonal allergic rhinitis: A randomized controlled trial

Although treatment of allergic rhinitis has been proven to be effective, it often does not completely resolve symptoms, is expensive, and related to side effects.1 Previous studies have suggested that probiotics may be a new promising treatment for allergic rhinitis (e.g., Farahmandi et al.2). Here we aimed to test effects of a single bacterial strain, Enterococcus faecalis (Symbioflor®1; Symbiopharm, Herborn, Germany) on symptoms of allergic rhinitis. Beneficial effects of E. faecalis have been reported before,3, 4 but not in seasonal allergic rhinitis. Participants were enrolled starting from springtime 2019 to 2021 (covering the pollen seasons). Out of 125 participants 36 were excluded. In the coronavirus disease 2019 (COVID-19) pandemic, the study was stopped (2020) and continued in 2021 (25 subjects before the pandemic, 64 in 2021). Inclusion criteria were a medical record of allergic rhinitis (either skin-prick test or serum allergen-specific immunoglobulin E [IgE], not older than 24 months), age between 18 and 60 years, and allergic symptoms when starting the study. Exclusion criteria were a medical history of diabetes, gastrointestinal diseases, use of antibiotic medication in the last 6 weeks, pregnancy, known psychiatric or neurological diseases, medical records of perennial allergic rhinitis (because symptoms and provoking factors may be different compared with seasonal allergic rhinitis), chronic rhinosinusitis, or any other chronic nasal conditions such as anatomical alteration. The study was done in accordance with the Declaration of Helsinki, approved by an ethical board (clinical trial DRKS00015804, 2/11/2018), and all patients provided written informed consent. To calculate sample size, we assumed an estimated effect size of f = 0.6, resulting in n = 120 participants.5 The study design consists of a randomized placebo-controlled four-arm study (Figure S1). E. faecalis (PROB) was compared to a double-blind placebo (DBP) and a treatment-as-usual (TAU) control condition. In addition, we applied an open-label placebo condition, the results of which will be reported in a separate publication. After the end of the trial the probiotic was offered to all patients for further 4 weeks. We used E. faecalis (DSM 16440), a Gram-positive probiotic species that is constituent of Symbioflor1® (cells and autolysate of 1.5 × 107 to 4.5 × 107 colony-forming units [CFU]). The control arms used placebo drops including the carrier solution of the probiotic treatment (indistinguishable in color, smell, and taste). Participants completed questionnaires and were then randomized into one of the four arms. The PROB and DBP conditions were kept secluded following a randomization scheme provided by the sponsor. Participants took 30 drops three times each day (groups 1–3) and were told to continue their usual allergic pharmacological treatments. After 4 weeks we invited all participants for a second appointment to examine allergic symptoms. Primary outcome measures were the Combined Symptoms and Medication Score (CSMS)6 and the Rhinitis Quality of Life Questionnaire (RQLQ).7 Secondary endpoint measure was the Total Nasal Symptoms Score (TNSS).8 Comparison of baseline data revealed no differences (including frequency of medical treatments) (all p > 0.10). Dropout of participants was not evenly distributed (eight in DBP, nine in PROB, and none in TAU). One patient (DBP group) reported an adverse effect (gastrointestinal complaints). Results of the CSMS (prestudy to poststudy) showed a greater improvement with the probiotic treatment (PROB) compared to both DBP and TAU with respect to symptoms over the past 12 h (analysis of covariance [ANCOVA] for all three groups with baseline scores as covariate, F (2, 63) = 5.13, p = 0.009, partial eta2 = 0.14) and over the past 2 weeks (F (2, 63) = 3.17, p = 0.049, partial eta2 = 0.09) (Figure 1). Results for the RQLQ also demonstrated stronger improvements for the probiotic group but failed to reach the level of significance (Table 1). TNSS results showed improvements for the PROB group for the last 12 h (F (2, 63) = 7.92, p = 0.001, partial eta2 = 0.20) and the past 2 weeks (F (2, 63) = 3.13, p = 0.050, partial eta2 = 0.09). We found significantly stronger effects for the time before the pandemic (for TNNS and RQLQ) (Table S1). Furthermore, baseline data of allergic symptoms were higher before the pandemic (results are reported in a separate publication). We report beneficial effects of E. faecalis in patients with seasonal allergic rhinitis. Effects for CSMS and TNSS were weaker when assessing the past 2 weeks, which may reflect difficulties rating symptoms over a longer period of time. The lack of effects in RQLQ may be caused by the more general measure of allergy specific health-related quality of life. Our results are in line with similar studies demonstrating beneficial effects of E. faecalis.3, 4, 9 Furthermore, our data showed that allergic symptoms were reduced during the COVID-19 pandemic situation. This is in line with previous studies and might be explained by a reduced confrontation with pollen due to masks, lockdown situations, or psychological factors.10 Some limitations apply. Participants did not undergo nasal endoscopy, which would exclude that symptoms might be caused by other conditions than allergies. Furthermore, dropouts of the study were not evenly distributed over the groups. In addition, standard medical treatment may have affected our results. Moreover, our analysis relies on self-report data. Also, the length of the study represents a short evaluation time and may include spontaneous improvement of the symptoms (e.g., due to the end of a pollen season). Finally, the results should be replicated by further studies with bigger sample sizes. Conceived and designed the experiment: Michael Schaefer, Kurt Zimmermann, Paul Enck. Provided material: Kurt Zimmermann. Performed the study: Michael Schaefer. Analyzed the data: Michael Schaefer. Wrote the paper: Michael Schaefer, Paul Enck. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Michael Schaefer has no competing financial interests to report, Kurt Zimmermann was a former employee of the sponsoring company (SymbioPharm, Herborn, Germany), and Paul Enck is consultant of this company. Paul Enck is also consultant of PrecisionBiotics Ltd. (Cork Ireland). The study adhered to the Declaration of Helsinki and was approved by an ethics committee. All participants gave written informed consent. The data presented in this study are available on request from the corresponding author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.