The Potential of Probiotics as Ingestible Adjuvants and Immune Modulators for Antiviral Immunity and Management of SARS-CoV-2 Infection and COVID-19
Abstract
:1. Introduction
2. Gut Mucosal Immune Function and Influence of Commensal Microbiome and Probiotics
2.1. The Gut Microbiome
2.2. Structure–Functionality of the Gut Mucosa
2.3. Probiotic-Derived Metabolites Modulate Host Immunity
3. Immunomodulatory and Antiviral Capability of Probiotics
4. COVID-19: Infection by SARS-CoV-2
5. Antiviral Immunity and SARS-CoV-2 Immunopathology
5.1. Innate Immunity
5.2. Adaptive Immunity
5.3. Viral Immune Evasion Mechanisms
Viral Immune Evasion Response | Infection/Pathology | Reference |
---|---|---|
Recognition by PRRs | M inhibits RIG-1,MDA5, and MAVS 9b inhibits interaction between RIG-1 and MAVS Nsps-3,-4,-6 encode double-membrane vesicles, hiding dsRNA from RLRs N protein binds TRIM25, preventing RIG-1 actn | [134] |
Type I IFN production and signalling | Nsp-1 degrades IFN mRNA Nsp-1blocks STAT-1 phosphorylation—delaying type I IFN production Nsp6 inhibits TBK1 phosphorylation of IRF7 7a destabilises TBK1, inhibiting IRF3 phosphorylation SARS-CoV-2 ORF6 inhibits downstream IFNα signalling Nsps-1,-3,-13,-14, ORFs-6,-8, M and N inhibit IFN type I-induced ISG gene expression N protein binds TRIM25, preventing RIG-1 actn and reduction in IFNβ production IAV Nsp1 inhibits RIG-1-IFNβ production SARS-CoV-2 ORF3b—potent antagonist of IFN prodn via suppression of IRF3 nuclear translocation | [134,135,136,137,138] |
Anti-inflammatory cytokine production | Nsp3 ORF9b and M inhibit NFκB activation SARS-CoV-2 strongly induces AM IL-10 prodn | [88] |
Suppression of MHC expression | MHC I expression inhibited by ORF3a and ORF7a SARS downregulates DC MHC II expression MERS downregulates Mϕ MHC II SARS-CoV-2 ORF8 downregulates T cell MHC I | [87,139] |
Suppression of NK cell activation | NKG2A upregulation—inhibits NK-mediated cell cytotoxicity (also on CD8+ Tc) Increased IL-6 and IL-10 inhibit STAT-3-dependent NK activation Both IL-6 and IL-10 increase NKG2A expression | [140,141] |
Inhibition of Cell-mediated immunity
| SARS-CoV-2 ORF3B antagonism of IFN production. NKG2A upregulation—inhibits CD8+ Tc-mediated cell cytotoxicity (also on NKs) SARS downregulates DC MHC II and B7 expression Antigenic mutation of M protein | [100,142,143] |
Inhibition of Humoral Immunity
| Omicron variant—high mutational burden in S protein: increased Ab evasion. SARS downregulates DC MHC II and B7 expression | [144,145] |
Inhibition of receptor binding | Flexible RBD in S trimers: RBD exposed in standing state. Lying state—RBD not exposed, hence reduced binding, infection and immunogenicity | [146] |
5.4. SARS-CoV-2 Infects and Affects Tissues/Organs Distal to the Gut–Lung Axis
6. Probiotics Reduce COVID-19 Symptoms of the Gut Mucosa via the Gut–Lung Axis
6.1. The Potential Role of Probiotics in the Prophylaxis of SARS-CoV-2 Infection and Pathology
6.2. The Potential Role of Probiotics in the Treatment of SARS-CoV-2 Associated Secondary Infection
7. Summary and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study Ref. Clinical Trial Identifier | Study Title Study Focus | Probiotic Intervention | Procedure Synopsis | Country & Start/Completion of Study [Reference] |
---|---|---|---|---|
NCT05080244 No results | Probiotics: reduce occurrence of long COVID-19 | ProB—2 strains (ProB strains not disclosed) | 618 patients, RCT. 2 capsules/d for 10d, then 1/d to day 25. | Quebec, Canada Oct 2021/Dec 2022. [193] |
NCT04621071 No results | Probiotics: reduce duration & symptoms of COVID-19 | ProB—2 strains (ProB strains not disclosed) | 17 patients, RCT. 2 capsules/d for 10d, 1 capsule/d to day 25. | Quebec, Canada Jan 2021/Oct 2021. [194] |
NCT05474144 No results | Efficacy of ProB in patients with severe COVID-19 infection | SmartProbio C 19 strains + inulin + maltodextrin | 83 patients, RCT. Triple masking. Twice/d, 2 wks. | Brno, Czech Republic. Nov 2021/April 2022. [195] |
NCT04390477 No results | Evaluate effect of ProB in COVID-19 | ProB strains (not disclosed) & maltodextrin | 41 participants No masking. 1 capsule per day for 30 d. | Alicante, Spain May 2020/March 2021. [196] |
NCT04458519 No results | i/n ProB reductn of symptom severity in COVID-19 | Probiorinse L.lactis W136 | 23 participants, single blinded, for 14d | Montreal, Canada July 2020/May 2021 [197] |
NCT04937556 No results | ProB supplementn in IR of COVID-19 participants | L. salivarius, Vit D + Zinc | 41 participants randomised triple masking, 28 d | Madrid, Spain Oct 2021/March 2022. [198] |
NCT04734886 No results | ProB supplementn on SARS-CoV-2 Ab IR after COVID19 | L.reuteri DSM17938 + Vit D | 161 participants Quadruple masking, daily for 6 months | Orebro, Sweden Nov 2020/Sept 2021. [199] |
NCT05043376 No results | ProB S. salivarius K12 for hospitalised (non-ICU) patients with COVID-19 | BLIS K12 Streptococcus salivarius K12. | 50 participants randomised, open label. Daily, to day 14. | Lahore, Pakistan Sept 2021/Nov 2021. [200] |
NCT05175833 No results | Oral ProB and secondary bacterial pneumonia in severe COVID-19 | Oral gel ProB Streptococcus salivarius K12 & L.brevis CD2 | 70 participants Randomised, quadruple masking, 7 d course | Passo Fundo, Brazil Sept 2020/Jan 2021. [201] |
NCT04847349 No results | Live microbials to boost SARS-CoV-2 immunity | Dietary supplement OL-1 (ProB consortium, strains not disclosed) | 54 participants Randomised Quadruple masking, daily 21 d | New Jersey USA April 2021/Jan 2022. [202] |
NCT04462627 No results | Reduction of COVID-19 transmission to healthcare professionals | Dietary supplement probiotic (Probactiol Plus—Metagenics) B.lactis Bi-07; L.acidophilus NCFM | 566 participants, open-label, no masking. | Brussels, Belgium April 2020/April 2022. [203] |
NCT04798677 No results | Efficacy & tolerability of ABBC1 in volunteers receiving influenza or COVID-19 vaccine. | ABBC1: beta-1,3/1,6-glucan + inactivated Saccharomyces cerevisiae (with Se, Zn) | 72 participants RCT, triple masking. 30 d supplementn | Barcelona, Spain Oct 2020/Sept 2021. [204] |
NCT04517422 No results | Efficacy of L.plantarum & P.acidilactici in adults with SARS-CoV-2 & COVID-19 | L.plantarum CECT30292, CECT7484, CECT7485y & P.acidilactici CECT7483 with maltodextrin. | 300 participants. RCT, quadruple masking. 1 dose per day over 30 d dietary supplementn | Mexico City, Mexico Aug 2020/Feb 2021 [205] |
NCT04399252 No results | Effect of Lactobacillus on the microbiome of household contacts exposed to COVID-19 | L.rhamnosus GG | 182 participants. RCT, triple masking. 2 capsules per day over 28 d. | North Carolina, USA June 2020/July 2021. [206] |
NCT04507867 Results available. | Effcect of a NSS to reduce complications in patients with COVID-19 and comorbidities in stage III. | Nutritional Support System: i/m Vit B1,B6,B12. Saccharomyces boulardii CNCM I-745 “Floratil” | 80 participants. RCT, triple masking. 1 capsule, twice a day over 6 d. | Mexico State, Mexico. Sept 2020/April 2021. [207] |
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Tomkinson, S.; Triscott, C.; Schenk, E.; Foey, A. The Potential of Probiotics as Ingestible Adjuvants and Immune Modulators for Antiviral Immunity and Management of SARS-CoV-2 Infection and COVID-19. Pathogens 2023, 12, 928. https://doi.org/10.3390/pathogens12070928
Tomkinson S, Triscott C, Schenk E, Foey A. The Potential of Probiotics as Ingestible Adjuvants and Immune Modulators for Antiviral Immunity and Management of SARS-CoV-2 Infection and COVID-19. Pathogens. 2023; 12(7):928. https://doi.org/10.3390/pathogens12070928
Chicago/Turabian StyleTomkinson, Sophie, Cloe Triscott, Emily Schenk, and Andrew Foey. 2023. "The Potential of Probiotics as Ingestible Adjuvants and Immune Modulators for Antiviral Immunity and Management of SARS-CoV-2 Infection and COVID-19" Pathogens 12, no. 7: 928. https://doi.org/10.3390/pathogens12070928