Efficacy of nutraceuticals (probiotics or prebiotics or synbiotics) in the prevention or treatment of COVID -19: a systematic review and meta-analysis

Figures & data

Figure 1. PRISMA Flow diagram detailing the selection of studies.

Table 1. Characteristics of included studies.

Review ID (Country)	Study design	Sample size details	Inclusion criteria	Exclusion criteria	Characteristics of study participants	Intervention details	Comparison group	Outcomes	Conclusion	Comments
(Reino-Gelardo et al., 2023) (Spain)	Prospective, non-blinded, RCT (NCT04666116)	Total: N = 139 IG:n = 70 CG: n = 69	1. RT-PCR-positive COVID-19 patients 2. Patients required >48 hours of hospital admission	1. age <18 years 2. Hospital discharge in the first 48 hours.	Age (Mean ± SD): IG: 70 ± 16 years CG: 69 ± 17 years Male/Female ratio: IG: 40/30 CG: 38/31	Standard treatment + Probiotics and prebiotics (Gasteel Plus), one stick daily (300 mg), dissolved in water	Standard treatment	Outcomes of interest:1. Days of hospitalization (days) Outcomes not of interest:1. Duration of gastrointestinal symptoms (days).	Gasteel Plus showed protective benefits in severe COVID-19 cases, facilitating faster recovery from digestive symptoms and reducing hospital stays.	Gasteel Plus contains Bifidobacterium lactis BPL1, Bifidobacterium longum ES, Lactobacillus rhamnosus CNCM I-4036, in 1:1:1 ratio and FOS (200 mg)
(Gutiérrez-Castrellón et al., 2022) (Mexico)	single-centre, parallel, quadruple-blinded, RCT (NCT04517422)	Total: N = 293 IG: n = 147 CG: n = 146	1. Symptomatic COVID-19 outpatient 2. Age 18 to 60 years 2. Positive RT-qPCR for the SARS-CoV2 RdRp gene 4. SpO2 ≥ 90% 5. Ability to understand study procedures.	1. Uncontrolled diabetes and systolic hypertension 2. BMI ≥40 Kg/m^2. 3. Coagulopathy and acute pancreatitis. 4. Chronic constipation and diarrhoea or IBD 7. Currently immunosuppressed 8. Severe respiratory disease 9. Probiotic or antibiotic use within 2 days before entering the study 10. Pregnancy or lactation.	Age (Median, IQR): IG: 34 (26–45) years CG: 39 (27–49) years Male/Female ratio: IG: 68/82 CG: 71/79	AB21 probiotic capsules (Lactiplantibacillus plantarum KABP033, L. plantarum KABP022, L. plantarum KABP023 and Pediococcus acidilactici KABP021 at a dose of ≥2 × 10^9 total CFU, with a maltodextrin carrier for 30 days	Placebo capsules containing the maltodextrin carrier	Outcomes of interest:1. No of Death at Day 30 2. Hospitalized (moderate/severe) n,% 3. Adverse events Outcomes not of interest:1. Complete remission (n,%) 2. Days of ICU stay	Probiotic supplementation was found to be well-tolerated compared to placebo.	Future studies should replicate these findings and elucidate its mechanism of action.
(Araimo et al., 2021) (Italy)	Single centric, Open-label, RCT. (NCT04366089)	Total: 28 IG: 14 CG:14	1. Age > 18 years 2. Nasopharyngeal swab positive for COVID-19 3.COVID-19 stages III 4.Hospitalized in wards	1.COVID-19 StagIV-VI–VI 2.Hospitalization in ICUs 3.Pregnancy 4. G6PD Deficiency 5.Patients who deny consent 6.Contra- indications oxygen-ozoneone therapy	Age (Mean ± SD): IG: 63.3 ± 12.2 years CG: 60.1 ± 14.4 years Male/Female ratio: IG: 9/5 CG: 7/7	Standard care (referred to as ‘ad interim BAT: antibacterial + antiinflammatoryanti-cytokineine) + Probiotics (SivoMixx* one sachet every 12 h for 7 days) + Oxygen-ozone therapy (5 × 10^3 mcg of ozone for 7 days)	Standard care (referred to as ‘ad interim BAT: antibacterial, anti-inflammatory + anticytokine	Outcomes of interest: 1.No of Deaths: Day 7, 14, 30 2. Adverse events Outcomes not of interest: 1.Requiring orotracheal intubation	Systemic ozone therapy is safe in critically‐ill COVID‐19 patients Efficacy of ozone autohemotherapy including probiotic supplements as an adjunct in COVID‐19 remains unclear.	There is a discrepancy in data reported in the abstract and in the result section. However, we have taken data from the result section
(Ivashkin et al., 2023) Moscow, Russia Federation	Randomized, controlled, single-center, open-label trial (NCT04854941)	Total: N = 200 IG:n = 99 CG:n = 101	1.Age: 18–75 years 2.Confirmed COVID-19 by PCR on nasopharyngeal and oropharyngeal swabs 3. Admitted patients	1. Age: > 75 years or < 18 years 2. Consumption of probiotics for 3 months prior to admission 3. History of intolerance to probiotics or their components 4.Refusal to participate. 5.Pregnant women 6.Cancer or mental illness 7. Severe renal dysfunction (GFR < 50 mL/ min) 8.Discontinued consumption of probiotics.	Age IG: 65 (59–71) years CG: 64 (54–70) years Male/Female ratio: IG: 44/55 CG: 48/53	Standard Care (Dexamethasone + antiviral, antibacterial + anticoagulant + anticytokine) + Probiotics Probiotics Dosage: Tds for no more than 14 days)	Standard Care (Dexamethasone + antiviral, antibacterial + anticoagulant + anticytokine	Outcomes of interest: 1.Days of hospitalization: 2.No. of deaths n 3.No. of adverse events Outcomes not of interest: 1.Admission to 2.Need for mechanical ventilation 3.Oxygen support 4.Duration of oxygen support 5.Biomarkers	No effect on mortality Effective in preventing hospital-acquired diarrhea and treating diarrhea associated with COVID-19	Probiotics include Lacticasei­bacillus rhamnosus PDV 1705, Bifdobacterim bifdum PDV 0903, Bifdobacterim longum subsp. infantis PDV 1911, Bifdobacterium longum subsp. longum PDV 2301
(Abhijit Rathi et al., 2021) (India)	Randomized, multicentric, double-blind placebo-controlled trial. (CTRI/2021/05/033576)	Total 200 IG: 100 CG: 100	1.Aged ≥18 and ≤75 years 2.Not suffering from active SARS-CoV-2 with a complaint of post-COVID fatigue/ muscle weakness. 3.History of COVID-19 in past 4.Non-pregnant, non-lactating women 5.Able to take the drug orally	1.Critical condition 2.FOS: ≤90% 3. PaO2/ FiO2:≤300 mmHg 4.Respiratory failure 6.Viral pneumonia 7.Unable to take food or drugs 8Consumption of another oral probiotic during the trial 9.Pregnancy 10.Allergic conditions 11.Hb < 8 mg/dL	Age (years); SD; Range- IG: 41.29 ± 13.0 (20–75) CG: 41.17 ± 12.9 (20–75) Males: Females (%)- IG: 65:35 CG: 62:38. Subjects with co-morbidities (%)- IG: 17 CG: 12 Days to enrolment post negative COVID test; Range- IG: 18.5 (2 to 48) CG: 20.6 (4 to 87)	ImmunoSEB (500 mg/capsule) + ProbioSEB CSC3 (5 billion CFUs /capsule) ProbioSEB CSC3 contains Bacillus coagulans LBSC, B.subtilis PLSSC and B.clausii 088AE	Placebo as maltodextrin for 14 days	Outcomes of interest: Nil Outcome not of interest Free of fatigue (91% vs. 15%)	Supplementation of ImmunoSEB + ProbioSEB CSC3 for 14 days resolves post-COVID-19 physical and mental fatigue. It is also effective in the recovery of COVID-19 patients if presc ribed early.	ImmunoSEB (multi-enzyme formulation of Peptizyme SP, bromelain, amylase, lysozyme, peptidase, catalase, papain, glucoamylase and lactoferrin) Fatigue assessment was done by CFQ-11 (self-report instrument).

FOS: Fructoligosaccharides, IBD: Inflammatory bowel disease, BAT: Best Available Therapy, G6PD: glucose-6-phosphate dehydrogenase, HCQS: hydroxychloroquine, CRP: C-Reactive protein, VSS: Ventilatory support system, PCT: procalcitonin, KFT: Kidney function test, LFT: Liver function test, PCR: Polymerase Chain Reaction, GFR: glomerular filtration rate, FOS- Finger Oxygen Saturation, PaO2- Pressure in arterial blood, Hb- Hemoglobin Concentration, FiO2- Fraction of inspired oxygen, *SivoMixx: Streptococcus therphilus, DSM322245, Bifidobacterium,lactis DSM32246, Bifidobacterium lactis DSM32247, Lactobacillus acidophilus DSM32241, Lactobacillus helveticus DSM32242, Lactobacillus para-casei DSM32243, Lactobacillus plantarum DSM32244, Lactobacillusbrevis DSM2796.

Figure 2. Risk of bias summary: review authors’ judgments about each risk of bias item for each included study.

Figure 3. Forest plot of comparison: Standard care + Probiotics verses Standard care, outcome: Days of hospitalization Number of deaths.

Figure 4. Forest plot of comparison: Standard care + Probiotics verses Standard care, outcome: Deaths.

Table 2. Summary of findings table for comparison: standard care + nutraceuticals (probiotics/prebiotics/synbiotics) compared to standard care.

Standard care + nutraceuticals (probiotics/prebiotics/synbiotics) compared to standard care for Covid-19
Patient or population: Covid-19 Intervention: Standard care + nutraceuticals (probiotics/prebiotics/synbiotics) Comparison: Standard care only
Outcomes	Anticipated absolute effects*(95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Importance
	Risk with standard care only	Risk with standard care + nutraceuticals (probiotics/prebiotics/synbiotics)
Deaths	43 per 1,000	44 per 1,000 (13 to 148)	RR 1.02 (0.30 to 3.41)	228 (2 RCTs)	⨁⨁◯◯ Low^a,b,c	Important Outcome
Adverse events	286 per 1,000	31 per 1,000 (3 to 540)	RR 0.11 (0.01 to 1.89)	28 (1 RCT)	⨁⨁◯◯ Low^c,d	Important Outcome
Days of hospitalisation	The mean days of hospitalisation was 0	MD 1.62 lower (3.09 lower to 0.14 lower)	–	339 (2 RCTs)	⨁◯◯◯ Very low^,c,e	Important Outcome

* The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; MD: mean difference; RR: risk ratio.

GRADE Working Group grades of evidence:

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Explanations

a. The QoE was downgraded by one level as the included studies did not report the method of randomization and were open-labeled RCTs.

b. The QoE was downgraded by one level as both the individual included studies as well as the pooled analysis did not report significant benefit or harm.

c. The sample size is below the OIS.

d. The QoE was downgraded by one level as the included study did not report the method of randomization and was open-labeled RCT.

e. The QoE was downgraded by one level due to the presence of heterogeneity (I²=73%).

Table 3. Summary of findings table for comparison: Nutraceuticals (Probiotics/Prebiotics/Synbiotics) verses placebo.

Nutraceuticals (probiotics/prebiotics/synbiotics) compared to placebo for Covid-19
Patient or population: Covid-19 Intervention: Nutraceuticals (probiotics/prebiotics/synbiotics) Comparison: Placebo
Outcomes	Anticipated absolute effects*(95% CI)		Relative effect (95% CI)	№ of participant (studies)	Certainty of the evidence (GRADE)	Importance
	Risk with placebo	Risk with Nutraceuticals (Probiotics/Prebiotics/Synbiotics) verses Placebo
Adverse events	420 per 1,000	273 per 1,000 (197 to 378)	RR 0.65 (0.47 to 0.90)	300 (1 RCT)	⨁⨁⨁◯ Moderate^a	Important Outcome

* The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence:

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Explanations

^aThe QoE is downgraded by one level as the sample size is less than the Optimal Information Size (OIS).

Table 4. Characteristics of excluded studies.

SN	Study	Reason for exclusion
1.	(Akour, 2020)	The study design is not relevant
2.	(Giannoni et al., 2020)	Study design is not relevant
3.	(Angurana & Bansal, 2021)	Study design is not relevant
4.	(He et al., 2020)	Study design is not relevant
5.	(Gohil et al., 2021)	Study design is not relevant
6.	(Shahbazi et al., 2020)	Study design is not relevant
7.	(Paknahad & Moravejolahkami, 2021)	Study design is not relevant
8.	(Tateno et al., 2020)	Population not of interest
9.	(Peng et al., 2021)	Study design is not relevant
10.	(Louca et al., 2021)	Study design is not relevant
11.	(Gouda et al., 2021)	Study design is not relevant
12.	(Taghinezhad-S et al., 2021)	Study design is not relevant
13.	(Patra et al., 2021)	Study design is not relevant
14.	(Heidari et al., 2021)	Study design is not relevant
15.	(Kullar et al., 2021)	Study design is not relevant
16.	(Baindara et al., 2021)	Study design is not relevant
17.	(Darbandi et al., 2021)	Study design is not relevant
18.	(Li et al., 2021)	Study design is not relevant
19.	(Sevillano-Jiménez et al., 2022)	outcome not of interest
20.	(Blackett et al., 2022)	population not of interest
21.	(Nistor-Cseppento et al., 2022)	population not of interest
22.	(Forsgård et al., 2023)	population not of interest
23.	(De Boeck et al., 2022)	outcome not of interest
24.	(Hasslöf et al., 2022)	population not of interest
25.	(Slykerman & Li, 2022)	population not of interest
26.	(Vaezi et al., 2023)	outcome not of interest
27.	(Akbarzadeh et al., 2022)	population not of interest
28.	(Leal-Martínez et al., 2022)	outcome not of interest
29.	(Fernández-Ferreiro et al., 2022)	outcome not of interest
30.	(Slykerman et al., 2022)	population not of interest
31.	(Rayyan et al., 2023)	population not of interest
32.	(Wong et al., 2023)	population not of interest
33.	(Vázquez-Frias et al., 2023)	population not of interest
34.	(Nobile & Puoci, 2023)	population not of interest
35.	(Bangar et al., 2023)	population not of interest

Table 5. Characteristics of ongoing studies.

SN	Recruitment status	Study Id	Date of Registration	Country
1.	Recruitment status completed	NCT04399252	May 22, 2020	Durham, North Carolina, United States
2.	Recruitment status completed	NCT04621071	November 9, 2020	Canada, Quebec
3.	Recruitment status completed	NCT04734886	February 2, 2021	Sweden
4.	Recruitment status completed	NCT04507867	August 11, 2020	Mexico
5.	Recruitment status completed	NCT04458519	July 7, 2020	Canada, Quebec
6.	Recruitment status completed	IRCT20161206031255N4	December 7, 2020	Iran
7.	Recruitment status completed	NCT05043376	September 14, 2021	Pakistan
8.	Recruitment status completed	IRCT20101020004976N6	2020-07-18	Iran
9.	Recruiting	NCT05080244	October 15, 2021	Canada, Quebec
10.	Recruiting	NCT04847349	April 19, 2021	United States, New Jersey
11.	No longer in EU/EEA	2020-001597-30	April 9, 2020	United Kingdom
12.	Recruiting	NCT04937556	June 24, 2021	Spain
13.	Not yet recruiting	NCT04907877	June 1, 2021	Ukraine
14.	Recruiting	JPRN-jRCTs021200020	August 25, 2020	Japan
15.	Not Yet Recruiting	CTRI/2021/03/031720	March 4, 2021	India
16.	Recruiting	NCT04813718	March 24, 2021	Austria
17.	Suspended	NCT04793997	March 11, 2021	Belgium
18.	Recruiting	ChiCTR2000029974	31 October 2020	China
19.	Recruiting	NCT04366089	April 28, 2020	Italy
20.	Not yet recruiting	ACTRN12620000480987	April 16, 2020	New Zealand
21.	Recruitment status completed	IRCT20200318046812N3	Jan 12, 2021	Iran
22.	Not yet recruiting	NCT04756466	February 16, 2021	Spain
23.	Recruiting	NCT04366180	April 28, 2020	Spain
24.	Recruiting	NCT04941703	June 28, 2021	United States, Tennessee
25.	Not yet recruiting	NCT04877704	May 7, 2021	United Kingdom
26.	Not yet recruiting	NCT04979065	July 27, 2021	Indonesia
27.	Recruiting	NCT04950803	July 6, 2021	Hong Kong
28.	Recruiting	NCT04420676	June 9, 2020	Austria
29.	Recruiting	NCT04884776	May 13, 2021	Hong Kong

A2 Table 1: Summary of results of dichotomous outcomes reported in individual studies.

	Study ID	No of events in IG	Total No. of participants in IG	No of events in CG	Total No. of participants in CG	Follow up period
Comparison 1: Nutraceuticals (probiotics or prebiotics or synbiotics) as a adjunct to standard treatments verses Standard of care without supplementation of probiotics or prebiotics or symbiotics
Number of cases of COVID-19	–	–	–	–	–	–
Change in disease severity	–	–	–	–	–	–
Number of deaths	(Araimo et al., 2021)	0	14	0	14	7 to 14 days
		01	14	01	14	30 days
	(Ivashkin et al., 2023)	4	99	4	101	Lasted from the time of the inclusion until recovery or death
Adverse events	(Araimo et al., 2021)	No	14	Diarrhoea: 4 (30%)	14	21 days
Comparison 3: Nutraceuticals (probiotics or prebiotics or synbiotics) as an adjunct to standard treatments verses placebo
Number of cases of COVID-19	–	–	–	–	–	–
Change in disease severity	–	–	–	–	–	–
Adverse events	Gutiérrez-Castrellón et al., 2022 (Gutiérrez-Castrellón et al., 2022)	41	150	63	150	30 days p = 0.008
Free of fatigue	(Rathi et al., 2021)	Day 4: Day 11:	Day 4: Day 11:	Day 4: Day 11:	Day 4: Day 11:

A2 Table 2: Summary of results of continuous outcomes reported in individual studies.

Comparison 1: Nutraceuticals (probiotics or prebiotics or symbiotics) as a adjunct to standard treatments) verses Standard of care without supplementation of probiotics or prebiotics or symbiotics
	Study Id	Mean of IG	Total no. of participants in IG	Mean of CG	Total no. of participants in CG	Duration of follow up
Days of hospitalization	(Ivashkin et al., 2023)	11 (10–14) days	99	11 (9–14) days	101	Lasted from the time of the inclusion until recovery or death
	(Reino-Gelardo et al., 2023)	8.7 ± 3.9 days	70	11.6 ± 7.4 days	69		p = 0.007

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Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.