Probiotics for COVID-19: real-time analysis of all 22 studies

Daily Lactobacillus Probiotic versus Placebo in COVID-19-Exposed Household Contacts (PROTECT-EHC): A Randomized Clinical Trial

Wischmeyer et al., medRxiv, doi:10.1101/2022.01.04.21268275 (Preprint)

RCT 182 COVID-19 exposed patients, 91 treated with daily probiotic Lactobacillus rhamnosus GG starting a median of 3 days from exposure, showing lower symptomatic COVID-19 with treatment. There were no hospitalizations or deaths. PROTECT-EHC. NCT04399252.

risk of moderate/severe case, 33.3% lower, RR 0.67, p = 0.15, treatment 16 of 91 (17.6%), control 24 of 91 (26.4%), NNT 11.

risk of symptomatic case, 38.5% lower, RR 0.62, p = 0.02, treatment 24 of 91 (26.4%), control 39 of 91 (42.9%), NNT 6.1.

recovery time, 27.3% lower, relative time 0.73, p = 0.37, treatment 91, control 91.

risk of case, 42.9% lower, RR 0.57, p = 0.17, treatment 8 of 91 (8.8%), control 14 of 91 (15.4%), NNT 15.

Wischmeyer et al., 1/5/2022, Double Blind Randomized Controlled Trial, USA, North America, preprint, 21 authors.

The efficacy of probiotics in patients with severe COVID-19

Wang et al., Annals of Palliative Medicine, doi:10.21037/apm-21-3373 (Peer Reviewed)

Retrospective 156 COVID-19 patients in China, showing that diarrhea was significantly more common in severe/critical cases, and for severe/critical patients experiencing diarrhea, the duration of diarrhea was shorter with probiotic treatment. There was also significant improvements in inflammatory markers and time to PCR-. Details of the treatment and control groups are not supplied.

Wang et al., 12/31/2021, retrospective, China, Asia, peer-reviewed, 8 authors.

Oral booster probiotic bifidobacteria in SARS-COV-2 patients

Bozkurt et al., International Journal of Immunopathology and Pharmacology, doi:10.1177/20587384211059677 (Peer Reviewed)

Small retrospective 44 hospitalized patients in Turkey, showing improved outcomes with probiotic bifidobacterium, however minimal group details are provided (for example, the age of the control patients is unknown), and no adjustments were made.

Excluded in meta analysis: unadjusted results with key group information missing.

Bozkurt et al., 11/25/2021, retrospective, Turkey, Europe, peer-reviewed, 2 authors.

Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial

Leal et al., SSRN, doi:10.2139/ssrn.3949424 (Preprint)

80 patient RCT with 40 patients treated with a comprehensive regimen of nutritional support, showing significantly lower mortality with treatment.

Treatment contained cholecalciferol, vitamin C, zinc, spirulina maxima, folic acid, glutamine, vegetable protein, selenium, resveratrol, omega-3 fatty acids, l-arginine, magnesium, probiotics, and B-complex IV. Adherence was strictly monitored. NCT04507867.

risk of death, 85.7% lower, RR 0.14, p = 0.03, treatment 1 of 40 (2.5%), control 7 of 40 (17.5%), NNT 6.7.

risk of mechanical ventilation, 57.1% lower, RR 0.43, p = 0.31, treatment 3 of 40 (7.5%), control 7 of 40 (17.5%), NNT 10.0.

Excluded in after exclusion results of meta analysis: combined treatments may contribute more to the effect seen.

Leal et al., 10/25/2021, Randomized Controlled Trial, Mexico, North America, preprint, 7 authors, study period 1 September, 2020 - 28 February, 2021, this trial uses multiple treatments in the treatment arm (combined with comprehensive nutritional support) - results of individual treatments may vary.

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

Ivashkin et al., Probiotics Antimicrob Proteins, doi:10.1007/s12602-021-09858-5 (Peer Reviewed)

RCT 200 patients, 99 treated with a probiotic (Lacticaseibacillus rhamnosus PDV 1705, Bifidobacterium bifidum PDV 0903, Bifidobacterium longum subsp. infantis PDV 1911, and Bifidobacterium longum subsp. longum PDV 2301). There was no significant difference in mortality or recovery time, however benefits were seen for diarrhea. NCT04854941.

risk of death, 2.0% higher, RR 1.02, p = 1.00, treatment 4 of 99 (4.0%), control 4 of 101 (4.0%).

risk of mechanical ventilation, 18.4% lower, RR 0.82, p = 1.00, treatment 4 of 99 (4.0%), control 5 of 101 (5.0%), NNT 110.

risk of ICU admission, 27.1% lower, RR 0.73, p = 0.77, treatment 5 of 99 (5.1%), control 7 of 101 (6.9%), NNT 53.

recovery time, 4.8% lower, relative time 0.95, p = 0.47, treatment 99, control 101.

Ivashkin et al., 10/13/2021, Randomized Controlled Trial, Russia, Europe, peer-reviewed, 11 authors.

A Randomized Controlled Trial of the Efficacy of Systemic Enzymes and Probiotics in the Resolution of Post-COVID Fatigue

Rathi et al., Medicines, doi:10.3390/medicines8090047 (Peer Reviewed)

RCT 200 long-COVID patients in India, 100 treated with ImmunoSEB and ProbioSEB CSC3, showing improved recovery of post-COVID-19 fatigue with treatment. CTRI/2021/05/033576.

Rathi et al., 8/30/2021, peer-reviewed, 3 authors.

Oxygen Sparing Effect of Bacteriotherapy in COVID-19

Ceccarelli et al., Nutrients, doi:10.3390/nu13082898 (Peer Reviewed)

Prospective analysis of 69 severe COVID-19 patients requiring non-invasive oxygen therapy, 40 treated with probiotic formulation SLAB51, showing lower oxygen requirements and higher blood levels of pO2, O2Hb and SaO₂ with treatment. Authors suggest that enzymes in SLAB51 could reduce oxygen requirements in intestinal cells, resulting in more oxygen available for other organs.

risk of death, 70.4% lower, RR 0.30, p = 0.42, treatment 0 of 40 (0.0%), control 1 of 29 (3.4%), NNT 29, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 81.9% lower, RR 0.18, p = 0.15, treatment 1 of 40 (2.5%), control 4 of 29 (13.8%), NNT 8.9.

Ceccarelli et al., 8/23/2021, prospective, Italy, Europe, peer-reviewed, 10 authors.

Probiotics use is associated with improved clinical outcomes among hospitalized patients with COVID-19

Zhang et al., Therapeutic Advances in Gastroenterology, doi:10.1177/17562848211035670 (Peer Reviewed)

Retrospective 375 patients in China, 179 treated with probiotics (Bifidobacterium, Lactobacillus, and Enterococcus), showing improved clinical outcomes with treatment.

hospitalization time, 13.6% lower, relative time 0.86, p = 0.009, treatment 150, control 150, PSM.

time to clinical improvement, 14.3% lower, relative time 0.86, p = 0.02, treatment 150, control 150, PSM.

time to viral-, 16.7% lower, relative time 0.83, p < 0.001, treatment 150, control 150, PSM.

Zhang et al., 8/4/2021, retrospective, China, Asia, peer-reviewed, 14 authors.

Probiotics Intake as Adjunct Therapy for Infected Health-Care with SARS COV-2

Veterini et al., Indian Journal of Forensic Medicine & Toxicology, 15:2 (Peer Reviewed)

Small case control analysis with 15 probiotics patients and 15 contol patients, showing no significant differences. PCR tests were only done weekly. Dosage is unknown. 115/LOE/301.4.2/IX/2020.

time to viral-, 29.0% lower, relative time 0.71, p = 0.22, treatment 15, control 15.

Excluded in after exclusion results of meta analysis: the observered difference in duration could be caused by the baseline difference in Ct values.

Veterini et al., 6/30/2021, retrospective, Indonesia, South Asia, peer-reviewed, 6 authors.

Oropharyngeal Probiotic ENT-K12 Prevents Respiratory Tract Infections Among Frontline Medical Staff Fighting Against COVID-19: A Pilot Study

Wang et al., Front. Bioeng. Biotechnol., doi:10.3389/fbioe.2021.646184 (Peer Reviewed)

Prophylaxis RCT in China with 98 healthcare workes in close contact with COVID-19 patients treated with Bactoblis oropharyngeal probiotic containing S. thermophilus ENT-K12, and 95 control patients, showing lower incidence of respiratory infections with treatment (none were confirmed COVID-19, details of testing are not provided).

Wang et al., 6/24/2021, peer-reviewed, 13 authors.

Efficiency of application of sorbed probiotics in complex therapy of pneumonia caused by SARS-CoV-2

Meskina et al., Therapeutic Archive, doi:10.26442/00403660.2021.04.200835 (Peer Reviewed)

RCT 100 pneumonia patients in Russia, showing faster symptom resolution with probiotic treatment (B. bifidum 1).

Meskina et al., 6/1/2021, Randomized Controlled Trial, Russia, Europe, peer-reviewed, 5 authors.

Synbiotic for Prevention of SARS-Cov2 Infection in High Risk Hospital Staffs: A Randomized Controlled Trial

Ahanchian et al., Open Journal of Nursing, doi:10.4236/ojn.2021.115025 (Peer Reviewed)

Small RCT 60 healthcare workers in Iran, showing lower cases with treatment but without statistical significance. Once daily oral synbiotic capsule (Lactocare®) containing 1 billion CFU L. (Lactobacillus) casei, L. rhamnosus, Streptococcus thermophilus, Bifidobacterium breve, L. acidophilus, Bifidobacterium infantis, L. bulgaricus, and Fructooligosacharide. IRCT-20101020004976N6.

respiratory symptoms, 73.3% lower, RR 0.27, p = 0.35, treatment 1 of 29 (3.4%), control 4 of 31 (12.9%), NNT 11.

risk of case, 85.3% lower, RR 0.15, p = 0.24, treatment 0 of 29 (0.0%), control 3 of 31 (9.7%), NNT 10, relative risk is not 0 because of continuity correction due to zero events.

Ahanchian et al., 5/31/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Iran, Middle East, peer-reviewed, 14 authors.

Probiotic improves symptomatic and viral clearance in Covid19 outpatients: a randomized, quadruple-blinded, placebo-controlled trial

Gutiérrez-Castrellón et al., Gut Microbes, doi:10.1080/19490976.2021.2018899 (preprint 5/24/2021) (Peer Reviewed)

RCT 293 outpatients in Mexico, 147 treated with a probiotic composed of three L. plantarum strains (KABP022, KABP023 and KABP033) and one P. acidilacti strain (KABP021), showing improved recovery with treatment. There were no hospitalizations or deaths. NCT04517422.

risk of no recovery, 34.7% lower, RR 0.65, p < 0.001, treatment 69 of 147 (46.9%), control 105 of 146 (71.9%), NNT 4.0.

Gutiérrez-Castrellón et al., 5/24/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Mexico, North America, peer-reviewed, 9 authors.

A possible probiotic (S. salivarius K12) approach to improve oral and lung microbiotas and raise defenses against SARS-CoV-2

Di Pierro, F., Minerva Medica, doi:10.23736/S0026-4806.20.06570-2 (Review) (Peer Reviewed)

Review of the potential use of S. salivarius K12 for COVID-19. Author notes that strain K12 of Streptococcus salivarius may reduce occurrence of viral upper respiratory tract infections, possibly due to its ability to stimulate IFN-γ release and to activate natural killer cells without triggering aggressive inflammatory responses.

Di Pierro et al., 4/7/2021, peer-reviewed, 1 author.

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK)

Holt et al., Thorax, doi:10.1136/thoraxjnl-2021-217487 (Peer Reviewed)

Prospective survey-based study with 15,227 people in the UK, showing lower risk of COVID-19 cases with vitamin A, vitamin D, zinc, selenium, probiotics, and inhaled corticosteroids; and higher risk with metformin and vitamin C. Statistical significance was not reached for any of these. Except for vitamin D, the results for treatments we follow were only adjusted for age, sex, duration of participation, and test frequency. NCT04330599. COVIDENCE UK.

risk of case, 30.4% lower, RR 0.70, p = 0.11, treatment 20 of 909 (2.2%), control 426 of 14,318 (3.0%), NNT 129, adjusted, OR converted to RR, minimally adjusted, group sizes approximated.

Excluded in after exclusion results of meta analysis: significant unadjusted confounding possible.

Holt et al., 3/30/2021, prospective, United Kingdom, Europe, peer-reviewed, 34 authors, study period 1 May, 2020 - 5 February, 2021.

Targeting the Microbiome With KB109 in Outpatients with Mild to Moderate COVID-19 Reduced Medically Attended Acute Care Visits and Improved Symptom Duration in Patients With Comorbidities

Haran et al., medRxiv, doi:10.1101/2021.03.26.21254422 (Preprint)

RCT 350 COVID+ outpatients in the USA, 174 treated with prebiotic KB109 (a microbiome metabolic therapy candidate), showing lower combined hospitalization, ER, and urgent care visits with treatment. NCT04414124.

risk of death, 66.5% lower, RR 0.33, p = 1.00, treatment 0 of 174 (0.0%), control 1 of 176 (0.6%), NNT 176, relative risk is not 0 because of continuity correction due to zero events, death two weeks after study withdrawal.

risk of hospitalization, 59.5% lower, RR 0.40, p = 0.45, treatment 2 of 174 (1.1%), control 5 of 176 (2.8%), NNT 59, including treatment period.

risk of hospitalization/ER/urgent care, 50.0% lower, RR 0.50, p = 0.13, treatment 7 of 169 (4.1%), control 15 of 181 (8.3%), NNT 24.

time to resolution of symptoms, 20.3% lower, relative time 0.80, p = 0.10, treatment 169, control 172.

Haran et al., 3/29/2021, Randomized Controlled Trial, USA, North America, preprint, 6 authors, study period 2 July, 2020 - 23 December, 2020.

Probiotics in Prevention and Treatment of COVID-19: Current Perspective and Future Prospects

Kurian et al., Archives of Medical Research, doi:10.1016/j.arcmed.2021.03.002 (Review) (Peer Reviewed)

Review of probiotics role in regulating the immune system and use in viral infections, and studies on the association of microbiota with COVID-19 patients. Authors suggest that probiotics supplementation could reduce COVID-19 morbidity and mortality, and they note that probiotics may suppress the inflammatory cytokine response.

Kurian et al., 3/19/2021, peer-reviewed, 11 authors.

The administration of S. salivarius K12 to children may reduce the rate of SARS-CoV-2 infection

Di Pierro et al., Minerva Medica, doi:10.23736/S0026-4806.21.07487-5 (Peer Reviewed)

Interim report on an RCT for prophylactic treatment with S. salivarius K12, showing significantly lower cases with treatment. Only patients with symptoms or known positive contacts were tested. Trial identification/registration details are not provided.

risk of case, 98.0% lower, RR 0.02, p < 0.001, treatment 0 of 64 (0.0%), control 24 of 64 (37.5%), NNT 2.7, relative risk is not 0 because of continuity correction due to zero events.

Di Pierro et al., 3/12/2021, Randomized Controlled Trial, Italy, Europe, peer-reviewed, 2 authors.

The role of probiotics in coronavirus disease-19 infection in Wuhan: A retrospective study of 311 severe patients

Li et al., International Immunopharmacology, doi:10.1016/j.intimp.2021.107531 (Peer Reviewed)

Retrospective 311 severe condition hospitalized patients in China, 123 treated with probiotics, showing slower viral clearance and recovery with treatment. Authors note that probiotics were able to moderate immunity and decrease the incidence of secondary infections.

risk of no hospital discharge, 11.8% higher, RR 1.12, p = 0.68, treatment 30 of 123 (24.4%), control 41 of 188 (21.8%).

time to discharge, 60.0% higher, relative time 1.60, p < 0.001, treatment 123, control 188.

time to viral-, 35.3% higher, relative time 1.35, p < 0.001, treatment 123, control 188.

Li et al., 3/5/2021, retrospective, China, Asia, peer-reviewed, 7 authors, average treatment delay 13.0 days.

Probiotics: A potential immunomodulator in COVID-19 infection management

Singh et al., Nutrition Research, doi:10.1016/j.nutres.2020.12.014 (Review) (Peer Reviewed)

Review of studies supporting the use of probiotics for respiratory infections and identification of microbial strains potentially beneficial for COVID-19.

Singh et al., 2/13/2021, peer-reviewed, 2 authors.

Potential of the Combination of a Systemic Enzyme Complex and Probiotics administration to Combat COVID-19: A Randomized Open Label Prospective Analysis

Shah et al., Advances in Clinical Toxicology, doi:10.23880/act-16000204 (Peer Reviewed)

Small RCT 60 patients in India, 30 treated with ImmunoSEB and ProbioSEB CSC3, showing faster recovery with treatment. CTRI/2020/09/027685, CTRI/2020/08/027168.

time to clinical improvement, 10.8% lower, relative time 0.89, p = 0.19, treatment 30, control 30.

hospitalization time, 10.6% lower, relative time 0.89, p = 0.18, treatment 30, control 30.

risk of no clinical improvement, 83.3% lower, RR 0.17, p = 0.005, treatment 2 of 30 (6.7%), control 12 of 30 (40.0%), NNT 3.0, day 10 mid-recovery.

risk of no clinical improvement, 3.7% lower, RR 0.96, p = 1.00, treatment 26 of 30 (86.7%), control 27 of 30 (90.0%), NNT 30, day 7.

Shah et al., 2/2/2021, Randomized Controlled Trial, India, South Asia, peer-reviewed, 3 authors, this trial uses multiple treatments in the treatment arm (combined with multi-enzyme formulation) - results of individual treatments may vary.

Oral Bacteriotherapy in Patients With COVID-19: A Retrospective Cohort Study

Ceccarelli et al., Frontiers in Medicine, doi:10.3389/fnut.2020.613928 (Peer Reviewed)

Retrospective 200 severe condition hospitalized patients in Italy, 88 treated with probiotic Sivomixx, showing lower mortality with treatment.

risk of death, 64.2% lower, RR 0.36, p = 0.003, treatment 10 of 88 (11.4%), control 34 of 112 (30.4%), NNT 5.3, adjusted, OR converted to RR.

risk of ICU admission, 15.2% lower, RR 0.85, p = 0.60, treatment 16 of 88 (18.2%), control 24 of 112 (21.4%), NNT 31.

Ceccarelli et al., 1/11/2021, retrospective, Italy, Europe, peer-reviewed, 14 authors.

Probiotics as a Weapon in the Fight Against COVID-19

Stavropoulou et al., Frontiers in Nutrition, doi:10.3389/fnut.2020.614986 (Review) (Peer Reviewed)

Review of the potential benefits of probiotics for COVID-19.

Stavropoulou et al., 12/15/2020, peer-reviewed, 2 authors.

Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app

Louca et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000250 (preprint 11/30/20) (Peer Reviewed)

Survey analysis of dietary supplements showing probiotic usage associated with lower incidence of COVID-19. These results are for PCR+ cases only, they do not reflect potential benefits for reducing the severity of cases. A number of biases could affect the results, for example users of the app may not be representative of the general population, and people experiencing symptoms may be more likely to install and use the app.

risk of case, 8.5% lower, RR 0.92, p = 0.03, OR converted to RR, United Kingdom, all adjustment model.

Louca et al., 11/30/2020, retrospective, United Kingdom, Europe, peer-reviewed, 26 authors.

The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19

Olaimat et al., npj Science of Food, doi:10.1038/s41538-020-00078-9 (Review) (Peer Reviewed)

Review of the immune benefits of probiotics and clinical studies for the preventation and treatment of respiratory infections, recommending trials of probiotics for COVID-19.

Olaimat et al., 10/5/2020, peer-reviewed, 10 authors.

Challenges in the Management of SARS-CoV2 Infection: The Role of Oral Bacteriotherapy as Complementary Therapeutic Strategy to Avoid the Progression of COVID-19

d'Ettorre et al., Frontiers in Medicine, doi:10.3389/fmed.2020.00389 (Peer Reviewed)

Retrospective 70 hospitalized patients in Italy, 28 treated with probiotic Sivomixx, showing lower risk of respiratory failure and faster recovery with treatment.

risk of death, 87.0% lower, RR 0.13, p = 0.14, treatment 0 of 28 (0.0%), control 4 of 42 (9.5%), NNT 10, relative risk is not 0 because of continuity correction due to zero events.

risk of mechanical ventilation, 76.9% lower, RR 0.23, p = 0.51, treatment 0 of 28 (0.0%), control 2 of 42 (4.8%), NNT 21, relative risk is not 0 because of continuity correction due to zero events.

respiratory failure, 88.4% lower, RR 0.12, p = 0.01, treatment 28, control 42, RR approximated with OR.

d'Ettorre et al., 7/7/2020, retrospective, Italy, Europe, peer-reviewed, 17 authors.

Using Probiotics to Flatten the Curve of Coronavirus Disease COVID-2019 Pandemic

Baud et al., Frontiers in Public Health, doi:10.3389/fpubh.2020.00186 (Review) (Peer Reviewed)

Review of data supporting the use of probiotics for COVID-19 and mechanisms of action.

Baud et al., 5/8/2020, peer-reviewed, 5 authors.

Probiotics for preventing acute upper respiratory tract infections

Hao et al., Cochrane Database of Systematic Reviews, doi:10.1002/14651858.CD006895.pub3 (Preprint) (meta analysis)

Meta analysis of 12 RCTs with 3,720 patients showing probiotics reduced acute upper respiratory tract infections.

Hao et al., 1/1/2015, preprint, 3 authors.

Antiandrogens	(meta)	Melatonin	(meta)
Aspirin	(meta)	Metformin	(meta)
Bamlaniv../e..	(meta)	Molnupiravir	(meta)
Bromhexine	(meta)	N-acetylcys..	(meta)
Budesonide	(meta)	Nigella Sativa	(meta)
Cannabidiol	(meta)	Nitazoxanide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Povidone-Iod..	(meta)
Conv. Plasma	(meta)	Probiotics	(meta)
Curcumin	(meta)	Proxalutamide	(meta)
Ensovibep	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Lactoferrin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption