Abstract
Background: Although various treatments are developed against COVID-19 variants, probiotic, and synbiotic adjunct therapy with several benefits such as safety, low cost, and availability could be needed for preventing or treating COVID-19 infection.
Objective: The present systematic review aimed to assess the prophylactic efficacy of the probiotic, prebiotic, and synbiotic administration against COVID-19.
Methods: The protocol of this systematic review was registered at the PROSPERO (Code number: CRD42023418900). The Scopus, Cochrane Library, Web of Sciences, and PubMed databases were systematically searched to define the clinical trials published up to November 2022 in the English language. The comparison of the incidence of COVID-19 disease and levels of specific antibodies against SARS-cov2 between the intervention and placebo groups were evaluated in this systematic review.
Results: According to the five included trials, four indicated the incidence of COVID-19, and no significant differences were observed between the probiotic and placebo groups during 1, 2, or 3 months of follow-up in the mentioned studies. Regarding the antibody assays against SARS-Cov2 including IgM, IgG, or IgA reported by three eligible trials, there were no significant differences between the intervention and control groups.
Conclusion: It seems that the administration of single or multi-strain probiotics or synbiotics had no prophylactic effects in different populations such as high-risk staff exposed to COVID-19, elderly nursing home residents, healthy adults, and household contact with COVID-19 patients during 1-to-3-months of intervention.
The COVID-19 pandemic was announced by World Health Organization (WHO) on March 12, 2020, about 3 months after the first report of this disease in December 2019 in Wuhan, China.1 This disease is caused by a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and commonly involves respiratory tracts. This virus can affect both the upper and lower respiratory systems.2
The economic burden of this disease was very high. As mentioned in a recently published systematic review, the main source of the high cost was in-hospital requirements such as intensive care unit (ICU) stay and mechanical ventilation. Productivity losses were among the indirect costs.3
The prevention strategies such as facial masks, hand washing, and social distancing had some benefits;4 however, there was a tendency to use oral medications, supplements, or herbal medicine for the prevention of COVID-19 in the general population.5,6 Some of these strategies seemed to be useful, as they could strengthen the immune system.7-10 Immune system stimulation by various immunomodulators may help the human immune system to overcome or prevent viral/bacterial infections.11
Recently, probiotics have attracted much attention as they can modulate the immune system. Some types of probiotics can regulate and balance the T-helper 1/T-helper 2 immune response.11 Also, their interactions in the intestine can lead to the production of interferons (IFNs) and facilitate the bactericidal functions of macrophages.12 It is indicated that dysbiosis is related to the severity of the disease through inflammation.13 The gut microbiota influences lung homeostasis, as the immune cells migrate from the gut to the pulmonary epithelium, previously trained in the epithelium of the intestine by the gut microbiota.14,15
Studies suggest the involvement of probiotics/synbiotics in reducing the viral load and the modulation of inflammatory responses against COVID-19,16,17 although some research presents inconsistencies with these findings. Khodadoostan et al.,18 Li et al.,19 and Neris Almeida Viana et al.20 did not find any significant improvement or remarkable differences in C-reacitve protein levels between those who received probiotics.
King et al.,21 in a recent systematic review and meta-analysis of more than 3000 healthy individuals, found probiotics reduced the number of absent working days through shorter illness episodes. D’Ettorre et al.22 found the progression of respiratory failure in those who used added multi-strain probiotics to the usual therapy was about 8-fold lower compared with the patients under routine therapy.
Some studies support the protective influences of probiotics against COVID-19 and other infections, as well as its therapeutic role.11,23 Wang et al.24 reported short-period consumption of probiotics could protect medical staff from respiratory tract infections. Slykerman and Li25 reported the symptoms of viral illnesses were reduced during the administration of probiotics in nurses. Rodriguez JAM et al.26 indicated the heat-treated probiotic Saccharomyces cerevisiae, which is enriched by selenium and zinc, could stimulate the immune system compared with placebo. They conducted this trial on healthy volunteers who received influenza or COVID-19 vaccines.
Since there is not any pooled and unique evidence about the prophylactic effects of probiotics on COVID-19 infection, the current systematic review was conducted to determine the randomized controlled trials that assessed the protective role of probiotics against COVID-19 in healthy individuals. The results could shed light on future prophylaxis against COVID-19, especially for healthcare providers and caregivers.
Materials and Methods
Search Strategy
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines were applied for the current systematic review.27 This systematic review was registered at PROSPERO (www.crd.york.ac.uk/PROSPERO) as CRD42023418900. The Databases, including PubMed, Web of Science, Cochrane Library, and SCOPUS were searched from inception to November 2022. The selected keywords were probiotic, prebiotic, synbiotic, or symbiotic combined with COVID-19 or Corona or SARS-COV. The search terms were adapted for each database. We also search the related keywords in Google Scholar to find out more relevant trials. The reference list of recent related reviews and trials was carefully assessed to avoid missing any relevant randomized controlled trials (RCTs).
Selection Criteria
Only randomized controlled trials published in the English language were entered into the current review. Observational studies as well as non-randomized trials were not included in this review. The intended PICO (population, intervention, control, and outcome) was as follows: P refers to any population that was not affected by COVID-19 at the time of the intervention. I refers to the consumption of probiotics, prebiotics, or synbiotics. C refers to the control group not using the mentioned interventions. O refers to the outcome of interest, which was the incidence of COVID-19 in the study groups. We also looked for specific antibodies against COVID-19 in the articles.
Data Extraction and Quality Assessment
After careful reading of the articles, data were extracted in Excel sheets by two authors (ME, MK). The extracted information of each study was the author`s name, year of publication, the characteristics of the study population, and the specific details of the intervention and control groups such as dose, strains, and duration of intervention.
The quality assessment of all included studies was conducted by two authors using the Jadad scale. Conflicts were resolved by discussion. This scale scores between 0 to 5. A total score of more than 3 was considered sufficient quality.28
Results
Summary of Searches
A total of 1,503 studies were identified based on our search, and 544 of them were duplicates (Figure 1). Among the remaining articles, 869 were determined to be irrelevant according to the title or abstract, and 105 studies were evaluated using the full text. As shown in Figure 1, 26 publications were assessed for eligibility, and 21 of them were excluded due to the therapeutic effect of the intervention or irrelevant outcome. Finally, five clinical trials were included in the present systematic review.
PRISMA flow chart for selection of relevant studies
Study Characteristics and Quality of Included Studies
The details of included trials containing PICO and quality assessment are summarized in Table 1. Three trials were performed in Spain,26,29,30 and the two remaining articles were conducted in Iran31 and the United States.32 The populations of the Rodriguez-Blanque30 and Ahanchian31 studies consisted of high-risk hospital workers who were exposed to COVID-19 infection. The trials performed by Rodriguez JAM et al.26 and Fernández-Ferreiro et al.29 evaluated the prophylactic effect of probiotics in elderly nursing home residents who administered the first dose of the COVID-19 vaccine, and healthy adult subjects who received the COVID-19 vaccine or healthcare workers, respectively. The participants exposed to household contact (≥1 year) with the COVID-19 patient during the past 7 days were assessed in the Wischmeyer et al. study.32
Characteristics of the included studies
Three trials determined the effect of single-strain probiotic supplements as an intervention group relative to the placebo group within 1 month,32 2 months,30 or 3 months.29 Ahanchian et al.31 compared synbiotic capsules including multi-strain probiotics and fructooligosaccharide prebiotic (n=29) versus placebo (n=31) for 1 month. Another study conducted by Rodriguez JAM et al.26 administered the probiotic formulation (ABB C1) containing Saccharomyces (S.) cerevisiae yeast with 1,3/1,6-glucan, selenium, and zinc for the intervention group, and maltodextrin as the placebo during 35 days. The follow-up time of included studies varied from 35 days to 90 days (Table 1). According to the Jadad score, all trials received total scores of 331 or 426,29,30,32 and were defined as high-quality studies.
Outcomes
As shown in Table 1 and Figure 2, the incidence of COVID-19 infection was indicated in four trials.29-32 The highest incidence of COVID-19 was demonstrated by Wischmeyer et al.32 in the probiotic (12%) and control (20%) groups after 2 months, versus 0% and 9.6% in the trial conducted by Ahanchian et al.,31 respectively. The Rodriguez-Blanque et al.30 study indicated the incidence of COVID-19 was 1.5% in both groups for 2 months. In contrast, the Fernández-Ferreiro et al.29 trial reported higher COVID-19 incidence in the intervention group (11%) compared to the placebo (8%) after 3 months of follow-up (Figure 2).
The incidence of COVID-19 infection in intervention and control groups of included studies
The descriptions of clinical and paraclinical outcomes is presented in Table 2. Based on laboratory findings, the antibody assays against SARS-Cov2 including IgG, IgM, or IgA were evaluated in three studies.26,29,30 Accordingly, Fernández-Ferreiro et al.29 demonstrated the geometric mean of both IgG and IgA antibodies was higher in the intervention vs. placebo group after 57 days of follow-up. Moreover, the mean secretion of IFN-γ and transforming growth factor (TGF)-β cytokines was reported as 1.36±3.41 pg/mL and 11.84±2.95 pg/mL in the probiotic group versus 1.04±3.08 pg/mL and 12.12±3.36 pg/mL in the placebo group, respectively.29
Clinical symptoms, laboratory findings, and other outcomes in intervention and control groups of included studies.
The study performed by Rodriguez JAM et al.26 revealed the mean levels of IgM were higher in the intervention group versus placebo group after 35 days. Additionally, the mean numbers of CD3+, CD4+, and CD8+ T-cells were assessed only in the mentioned trial and demonstrated in Table 2. The stool samples of participants were evaluated in the Wischmeyer trial32 to determine the abundance of the L. rhamnosus probiotic strain. Based on their results, the intervention group had a considerably higher abundance of L. rhamnosus GG (LGG) relative to the placebo.
As shown in Table 2, the clinical manifestations were reported in four included studies.26,30-32 Ahanchian et al.31 determined lower respiratory, gastrointestinal (GI), and other symptoms in the synbiotic group compared to the control group for 2 months. As mentioned in the Wischmeyer et al.32 study, the frequency of most symptoms was lower in the probiotic versus placebo group after 28 days. In contrast, Rodriguez JAM et al.26 assessed higher GI symptoms including nausea, vomiting, and diarrhea (n=6) in the intervention group relative to the control group (n=4). The details of other outcomes indicated by included studies such as frequency of symptomatic subjects, duration of COVID-19 symptoms, hospitalization, and mortality are described in Table 2.
Discussion
The present systematic review assessed the efficacy of the probiotic, prebiotic, and synbiotic supplements for preventing COVID-19 infection. Based on five included clinical trials, the incidence of COVID-19 was defined in all RCTs29-32 except the Rodriguez JAM study26. According to other included trials, no significant differences were found regarding the incidence of COVID-19 between the probiotic and placebo groups during one, two, or three months29,30,32.
The clinical symptoms assessed by Ahanchian et al. such as the respiratory, GI, and other signs were higher in the placebo relative to the synbiotic group, with no statistically significant difference between the groups31. Additionally, the Rodriguez JAM et al.26 study revealed the total GI manifestations had a decreased trend in participants who received ABB C1® supplement than the placebo. However, no significant difference was defined between the mentioned groups.
As reported by Wischmeyer et al.,32 the participants who received the single-strain probiotic demonstrated a significantly lower frequency of clinical symptoms during 28 days of contact with household persons infected by COVID-19 disease relative to the placebo group. Time to COVID-19 detection was significantly longer in the intervention group compared to the control, and no hospitalization or mortality was indicated in the two groups. Rodriguez-Blanque et al.30
presented that three of the healthcare staff who were randomized to the single-stain probiotic or placebo group revealed COVID-19 symptoms with a mean duration of 4±1 days. Accordingly, the results of COVID-19 incidence and clinical manifestations evaluated by included trials were similar during the different follow-up time points.
Regarding the specific antibody assays against SARS-Cov2 infection, the Fernández-Ferreiro et al.29 study indicated the levels of IgG and IgA had no significant differences between the K8 probiotic and control groups at 56 days followed by completed vaccination. Among the mentioned volunteers, the number of 11 and 8 subjects were infected by COVID-19 in the K8 and placebo groups, respectively, and only the IgG levels were significantly higher in the probiotic group compared to the control. The authors suggested the administration of K8 in elderly participants may stimulate specific immunity against SARS-Cov2 infection. Based on INF-γ, and TGF-β cytokines assessed in this study, there were no significant differences between the K8 probiotic and placebo groups, as well as subgrouping by the populations who were infected with COVID-19 disease.
The serum level of IgG antibody was also compared between the participants who received the single-strain K8 probiotic or placebo in the Rodriguez-Blanque et al. study.30 The specific levels of IgG were significantly higher in the K8 group compared to the placebo, but only in subjects that assessed ≥ 81 days after the first dose of vaccine administered. Overall, the IgG levels significantly declined during the follow-up times. This study recommended that the usage of the K8 probiotic supplement could support sustaining the humoral immunity produced by the COVID-19 vaccine in healthcare staff over time.
The study conducted by Rodriguez JAM et al.26 indicated the serum levels of specific IgG and IgM were higher in ABB C1 formulation compared to the placebo; however, no statistically significant differences were found between the two groups during 35 days of treatment. Moreover, the mean changes of lymphocytes assessed including CD3+, CD4+, and CD8+ were increased in the intervention group followed by the administration of the first booster COVID-19 vaccine dosage. In contrast, the changes in the mentioned lymphocytes were decreased in the control, and no significant differences were evaluated between the groups. As the secondary outcomes detected in this trial, the serum levels of zinc and selenium enhanced in the ABB C1 and decreased in the placebo group. The authors concluded the utilization of ABB C1 supplement provided the absorbable micro-nutrients that improved the immune responses against COVID-19 infection.
Wischmeyer et al.32 investigated the fecal microbiota and reported a significant difference in the overall stool microbiota structure between the L. rhamnosus probiotic and placebo groups. They suggested the LGG probiotic strain could be well-tolerated and changed the structure of the gut microbiome in exposed household contacts. The high tolerance26 and safety29,30 of different types of probiotic supplements were also proved in other included studies.
The systematic review and meta-analysis of one clinical trial and five cohort observational studies were investigated by Allen et al.33 to determine the therapeutic or prophylactic effects of probiotic administration compared to the control. However, the included studies were only related to the treatment efficacy of probiotics in participants who were infected by COVID-19. The meta-analysis was performed for mortality, the severity of COVID-19 disease, and ICU admission or mechanical ventilation. The included RCT revealed no significant difference between the probiotic and placebo groups regarding the mentioned outcomes;34 however, the retrospective studies had controversy for the benefit of utilizing the probiotic supplement. This meta-analysis indicated that probiotic therapy had no significant association with mortality, COVID-19 progression, and the ICU admission or ventilation required. Additionally, this review demonstrated that probiotics were associated with improved respiratory signs, while the duration of COVID-19 disease and hospitalization were increased based on descriptive variables.
Tian et al.35 also reviewed the clinical trials and observational cohort studies to reveal the therapeutic effect of probiotic administration in comparison with the control group. The results of the meta-analysis illustrated probiotics significantly enhanced the frequency of COVID-19 patients who had improved clinical signs and decreased the duration of COVID-19 symptoms and hospital admission relative to the control. Moreover, the duration of some manifestations such as diarrhea, dyspnea, and cough was improved in the probiotic group, whereas, it did not affect fatigue, fever, and headache signs. According to the inflammatory biomarker assays, probiotics could significantly reduce the serum levels of C-reactive protein. This meta-analysis recommended probiotic therapy might improve the GI and respiratory manifestations within the gut-lung axis.
Strengths and Limitations
The main strength of the current systematic review was the extensive search strategy of RCTs, which included probiotics, prebiotics, and synbiotics agents. The limitations of this research were the limited number of RCTs in this subject and the heterogeneity across the included populations in each single study, such that we could not pool the data for meta-analysis.
Conclusion
Although the duration and frequency of COVID-19 symptoms were reduced in those who received probiotics/synbiotics, these ratios did not show statistically significant differences between intervention and placebo groups. Both single and multi-strain probiotics had no obvious prophylactic effects in reducing the incidence of COVID-19 infection. More high-quality RCTs are recommended for high-risk individuals who are exposed to this infection.
Acknowledgments
The authors would like to thank Clinical Research Development Unit of Ghaem Hospital for cooperation in database search.
Footnotes
Disclosures: The authors declare they have no conflicts of interest or financial support related to this work.
Author Contributions: MK: Conceptualization, Investigation, Database search, Checking the quality, Data extraction, Writing the draft, Supervision. ME: Data curation, Database search, Checking the quality, Data extraction, Writing the draft, Reviewing, and Editing.
- Received July 24, 2023.
- Revision received March 16, 2024.
- Accepted April 18, 2024.
References
- 1.↵Ciotti M, Ciccozzi M, Terrinoni A, Jiang WC, Wang CB, Bernardini S. The COVID-19 pandemic. Crit Rev Clin Lab Sci. 2020;57(6):365-388. doi:10.1080/10408363.2020.1783198.
- 2.↵Darbandi A, Asadi A, Ghanavati R, The effect of probiotics on respiratory tract infection with special emphasis on COVID-19: Systemic review 2010-20 [published correction appears in Int J Infect Dis. 2021 Sep;110:337. doi: 10.1016/j.ijid.2021.08.002]. Int J Infect Dis. 2021;105:91-104. doi:10.1016/j.ijid.2021.02.011
- 3.↵Richards F, Kodjamanova P, Chen X, Economic burden of COVID-19: a systematic review. Clinicoecon Outcomes Res. 2022;14:293-307. doi:10.2147/CEOR.S338225.
- 4.↵Manikandan N. Are social distancing, hand washing and wearing masks appropriate measures to mitigate transmission of COVID-19? Vacunas. 2020;21(2):136-137. doi:10.1016/j.vacun.2020.09.001.
- 5.↵Wahab MSA, Hamdi H, Ali AA, The use of herbal and dietary supplements for COVID-19 prevention: A survey among the public in a Malaysian suburban town. J Herb Med. 2023;39:100650. doi:10.1016/j.hermed.2023.100650.
- 6.↵ALkharashi NA. The consumption of nutritional supplements and herbal products for the prevention and treatment of COVID-19 infection among the Saudi population in Riyadh. Clin Nutr Open Sci. 2021;39:11-20. doi:10.1016/j.nutos.2021.09.001
- 7.↵Moukayed M. A Narrative Review on the Potential Role of Vitamin D3 in the Prevention, Protection, and Disease Mitigation of Acute and Long COVID-19. Curr Nutr Rep. 2023;12(2):215-223. doi:10.1007/s13668-023-00471-2
- 8.Nicoll R, Henein MY. COVID-19 Prevention: Vitamin D Is Still a Valid Remedy. J Clin Med. 2022;11(22):6818. doi:10.3390/jcm11226818.
- 9.Komal KJ, Kumar J, Sen A. The role of vitamin C: From prevention of pneumonia to treatment of Covid-19. Mater Today Proc. 2022. doi:10.1016/j.matpr.2022.11.213.
- 10.↵Sarkar PK, Das Mukhopadhyay C. Mechanistic insights from the review and evaluation of ayurvedic herbal medicines for the prevention and management of COVID-19 patients. J Herb Med. 2022;32:100554. doi:10.1016/j.hermed.2022.100554.
- 11.↵Adnan ML, Pramaningtyas MD. Probiotics as promising immunomodulatory agents to prevent COVID-19 infection: a narrative review. International Journal of Medical Students. 2020;8(2):121-125. https://doi.org/10.5195/ijms.2020.486
- 12.↵Zhang H, Yeh C, Jin Z, Prospective study of probiotic supplementation results in immune stimulation and improvement of upper respiratory infection rate. Synth Syst Biotechnol. 2018;3(2):113-120. doi:10.1016/j.synbio.2018.03.001.
- 13.↵Linares-García L, Cárdenas-Barragán ME, Hernández-Ceballos W, Bacterial and Fungal Gut Dysbiosis and Clostridium difficile in COVID-19: A Review. J Clin Gastroenterol. 2022;56(4):285-298. doi:10.1097/MCG.0000000000001669
- 14.↵Belkaid Y, Harrison OJ. Homeostatic Immunity and the Microbiota. Immunity. 2017;46(4):562-576. doi:10.1016/j.immuni.2017.04.008.
- 15.↵Gutiérrez-Castrellón P, Gandara-Martí T, Abreu Y Abreu AT, Probiotic improves symptomatic and viral clearance in Covid19 outpatients: a randomized, quadruple-blinded, placebo-controlled trial. Gut Microbes. 2022;14(1):2018899. doi:10.1080/19490976.2021.2018899
- 16.↵De Boeck I, Cauwenberghs E, Spacova I, Randomized, Double-Blind, Placebo-Controlled Trial of a Throat Spray with Selected Lactobacilli in COVID-19 Outpatients. Microbiol Spectr. 2022;10(5):e0168222. doi:10.1128/spectrum.01682-22
- 17.↵Vaezi M, Ravanshad S, Akbari Rad M, Zarrinfar H, Kabiri M. The effect of synbiotic adjunct therapy on clinical and paraclinical outcomes in hospitalized COVID-19 patients: A randomized placebo-controlled trial. J Med Virol. 2023;95(2):e28463. doi:10.1002/jmv.28463.
- 18.↵Khodadoostan M, Aghadavood Marnani M, Moravejolahkami AR, Askari G, Iraj B. Effect of synbiotics on inflammatory markers and white blood cell count in COVID-19 patients: a randomized, double-blind, placebo-controlled clinical trial. Nutrition & Food Science 2022;53(4):714-725. doi:10.1108/NFS-06-2022-0195
- 19.↵Li Q, Cheng F, Xu Q, The role of probiotics in coronavirus disease-19 infection in Wuhan: A retrospective study of 311 severe patients. Int Immunopharmacol. 2021;95:107531. doi:10.1016/j.intimp.2021.107531.
- 20.↵Neris Almeida Viana S, do Reis Santos Pereira T, de Carvalho Alves J, Benefits of probiotic use on COVID-19: A systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2024;64(10):2986-2998. doi:10.1080/10408398.2022.2128713
- 21.↵King S, Glanville J, Sanders ME, Fitzgerald A, Varley D. Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions: a systematic review and meta-analysis. Br J Nutr. 2014;112(1):41-54. doi:10.1017/S0007114514000075.
- 22.↵d’Ettorre G, Ceccarelli G, Marazzato M, Challenges in the Management of SARS-CoV2 Infection: The Role of Oral Bacteriotherapy as Complementary Therapeutic Strategy to Avoid the Progression of COVID-19. Front Med (Lausanne). 2020;7:389. doi:10.3389/fmed.2020.00389.
- 23.↵Kurian SJ, Unnikrishnan MK, Miraj SS, Probiotics in Prevention and Treatment of COVID-19: Current Perspective and Future Prospects. Arch Med Res. 2021;52(6):582-594. doi:10.1016/j.arcmed.2021.03.002.
- 24.↵Wang Q, Lin X, Xiang X, Oropharyngeal Probiotic ENT-K12 Prevents Respiratory Tract Infections Among Frontline Medical Staff Fighting Against COVID-19: A Pilot Study. Front Bioeng Biotechnol. 2021;9:646184. doi:10.3389/fbioe.2021.646184.
- 25.↵Slykerman RF, Li E. A randomized trial of probiotic supplementation in nurses to reduce stress and viral illness. Sci Rep. 2022;12(1):14742. doi:10.1038/s41598-022-19104-9.
- 26.↵Rodriguez JAM, Bifano M, Roca Goma E, Effect and Tolerability of a Nutritional Supplement Based on a Synergistic Combination of β-Glucans and Selenium- and Zinc-Enriched Saccharomyces cerevisiae (ABB C1®) in Volunteers Receiving the Influenza or the COVID-19 Vaccine: A Randomized, Double-Blind, Placebo-Controlled Study. Nutrients. 2021;13(12):4347. Published 2021 Dec 2. doi:10.3390/nu13124347
- 27.↵Wang Y, Wu Y, Wilson RF, Bleich S, Cheskin L, Weston C, Childhood obesity prevention programs: comparative effectiveness review and meta-analysis. 2013.
- 28.↵Jadad AR, Moore RA, Carroll D, Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials. 1996;17(1):1-12. doi:10.1016/0197-2456(95)00134-4.
- 29.↵Fernández-Ferreiro A, Formigo-Couceiro FJ, Veiga-Gutierrez R, Effects of Loigolactobacillus coryniformis K8 CECT 5711 on the Immune Response of Elderly Subjects to COVID-19 Vaccination: A Randomized Controlled Trial. Nutrients. 2022;14(1):228. doi:10.3390/nu14010228.
- 30.↵Rodriguez-Blanque R, Sánchez-García JC, Cobos-Vargas Á, Evaluation of the effect of Loigolactobacillus coryniformis K8 CECT 5711 consumption in health care workers exposed to COVID-19. Front Nutr. 2022;9:962566. doi:10.3389/fnut.2022.962566.
- 31.↵Ahanchian H, Ranjbar A, Reihani H, Synbiotic for Prevention of SARS-Cov2 Infection in High Risk Hospital Staffs: A Randomized Controlled Trial. Open J Nurs. 2021;11(5):281-290. doi:10.4236/ojn.2021.115025.
- 32.↵Wischmeyer PE, Tang H, Ren Y, Daily Lactobacillus Probiotic versus Placebo in COVID-19-Exposed Household Contacts (PROTECT-EHC): A Randomized Clinical Trial. medRxiv 2022. doi:10.1101/2022.01.04.21268275
- 33.↵Allen J, Evans CA, Datta S. Probiotics for preventing or treating COVID-19; a systematic review of research evidence and meta-analyses of efficacy for preventing death, severe disease, or disease progression. Wellcome Open Res. 2022;7(292):292. doi:10.12688/wellcomeopenres.18526.1.
- 34.↵Ivashkin V, Fomin V, Moiseev S, Efficacy of a Probiotic Consisting of Lacticaseibacillus rhamnosus PDV 1705, Bifidobacterium bifidum PDV 0903, Bifidobacterium longum subsp. infantis PDV 1911, and Bifidobacterium longum subsp. longum PDV 2301 in the Treatment of Hospitalized Patients with COVID-19: a Randomized Controlled Trial. Probiotics Antimicrob Proteins. 2023;15(3):460-468. doi:10.1007/s12602-021-09858-5
- 35.↵Tian Y, Ran H, Wen X, Probiotics improve symptoms of patients with COVID-19 through gut-lung axis: a systematic review and meta-analysis. Front Nutr. 2023;10:1179432. doi:10.3389/fnut.2023.1179432
