Nutraceuticals and pharmacological to balance the transitional microbiome to extend immunity during COVID-19 and other viral infections

Scope The underlying medical conditions and gut dysbiosis is known to influence COVID-19 severity in high-risk patients. The current review proposed the optimal usage of nutraceuticals & pharmacological interventions can help regulate the protective immune response and balance the regulatory functionality of gut microbiota. Summary Many studies have revealed that the probiotic interventions viz., Lactobacillus rhamnosus, L. plantarum & other bacterial spp. reduce IFNγ & TNF-α and increase IL-4 & IL-10 secretions to control the immunostimulatory effects in upper respiratory tract infection. Dietary fibres utilized by beneficial microbiota and microbial metabolites can control the NF-kB regulation. Vitamin C halts the propagation of pathogens and vitamin D and A modulate the GM. Selenium and Flavonoids also control the redox regulations. Interferon therapy can antagonize the viral replications, while corticosteroids may reduce the death rates. BCG vaccine reprograms the monocytes to build trained immunity. Bifidobacterium and related microbes were found to increase the vaccine efficacy. Vaccines against COVID-19 and season flu also boost the immunity profile for robust protection. Over all, the collective effects of these therapeutics could help increase the opportunities for faster recovery from infectious diseases. Conclusion The nutraceutical supplements and pharmacological medicines mediate the modulatory functionalities among beneficial microbes of gut, which in turn eliminate pathogens, harmonize the activity of immune cells to secrete essential regulatory molecular receptors and adaptor proteins establishing the homeostasis in the body organs through essential microbiome. Therefore, the implementation of this methodology could control the severity events during clinical sickness and reduce the mortalities.


Introduction
The pathophysiological conditions and hyperinflammatory immune responses are the main concerning areas in terms of exploring the COVID-19 severity.The preexisting comorbid conditions such as, diabetes mellitus, rheumatoid arthritis, angioimmunoblastic lymphadenopathy with dysproteinemia, cardiovascular diseases, neurological disorders, other inflammatory disorders and underlying conditions due to misuse of antibiotics etc., are known to increase the susceptibility to dysbiosis, Page 2 of 19 Kaushal Journal of Translational Medicine (2024) 22:847 resulting in prolonged hospitalization in COVID-19 patients escalating mortality rates [1,2].Microbiome research has attained great attention in the past decade because of its beneficial attributes.Bacterial species like, Coprobacillus, Clostridium, Firmicutes, Bacteroides, Proteobacteria and Actinobacteria influence the SARS-CoV-2 infection subsequently increase the disease severity.The altered gut microbiota due to COVID-19 may flare up the early induced 'Cytokine Storm' elevating the levels of IL-1β, IL-6, tumour necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1α (MIP-1α) and Chemokine C-C motif ligand 3 (CCL3) [1,3,4].Additionally, the psychological wellbeing of patients can also be impacted via.crosstalk between gut and brain during illness and dysbiosis [5].
Interferons also provide immune modulatory response to suppress the early viral infection and regulate the α-defensin [6,7].Similarly, corticosteroids (glucocorticoids) suppress the initial infection and have found to control the 62% death rate, but eventually reduced to 28% in patients on ventilators [8,9].Effectiveness of vaccines are also described in literature to attenuate the gut microbiome restoring the essential commensals that activate NOD2 sensors and IgA production contribute to restore the intestinal barrier function [2,10].
Post acute COVID-19 syndrome is described as the chronic form of COVID-19 could last for 6 months or years.The mood disorders and autoimmune dysfunctions manifested as a consequence of infectious disease, genetic, environmental and socioeconomic problems, are the predisposing factors towards developing chronic fatigue syndrome.PACS is likely to be contexed with chronic distress and brain fog with cognitive impairment.The post infection fatigue syndrome has also been documented in case of influenza, dengue, Epstein-Barr virus, enteroviruses, human parvovirus and protozoan infections [5,11].Lack of important nutrients e.g., vitamin C, B, D, sodium and magnesium, zinc, folic acid etc. may worsen the illness [5].
The viruses and bacteriophages distribute the essential regulatory genes required for vital activities and genetic make-up of microflora.Antibiotics associated dysbiosis occurred can be repaired with the help of appropriate probiotics eventually confer the better performance of microbiome, hence, mitigating the risks of poor disease prognosis.WHO had already provided the plans for food and nutrition to people who were supposed to go through the self-quarantine during COVID-19 outbreak in order to strengthen the immunity, irrespective of their acquired disease status.Following the diet regimens including dietary fibres, omega-3-polyunsaturated fatty acids (ω-PUFA), polyphenols, vitamin A, C, D etc. along with probiotics, could help offset the 'cytokine storm' formation.The bioactive compounds, however, must be optimally evaluated and employed for the management of viral diseases and associated chronic fatigue syndrome.The nutraceutical supplements, pharmacological therapeutics and their interactions with microbiota is supposed to unveil the positive immunological activities could impact the disease outcomes [5,[12][13][14][15][16][17].
This review emphasizes the values of optimal use of nutraceuticals (active compounds) and pharmacological sources to moderate the immune response by controlling the hyperactivated macrophages/monocytes to halt the excessive production of cytokines and chemokines.Consequently, these events help release the molecular adaptors, which program the chromatin functionality via histones at transcriptional level to impact the post translational modifications during cell differentiation.Undoubtedly, this approach would be a step forward for the earlier & faster recovery of both asymptomatic and symptomatic patients.

Probiotics
Food and Agriculture Organization (FAO) and World Health Organization (WHO) have defined 'Probiotics' as microbes confer the health benefits to the host [18][19][20].Probiotics (Lactobacillus, Bifidobacterium, and Saccharomyces spp.) and prebiotics (non-digestible food ingredients) attenuate the microbiota and increase GM's survival [20,21].By preserving the gut microflora through bioactive food supplements increase the capability of immune cells to control cytokines' release, TNF-α and activate the reactive oxygen species (ROS) to establish optimal antiviral state [21].The probiotic supplements have been experimented on ARDS and pneumonia in COVID-19 patients on ventilation has shown significant improvement [1].L. rhamnosus GG is safer and efficacious in preventing viral associated pneumonia (VAP) in highrisk ICU population [22,23].However, there is still lack of sufficient peer reviewed information on the probiotic supplements in controlling the ventilation associated pneumonia [24].
The cellular immunity is increased using Enterococcus faecium NCIMB 10415 that provokes IL-6 and IL-8 secretion to fight against the TGEV infection in young piglets.European food safety authority has developed a guidance to use E. faecium in dose dependent manner in animals [25].Certain Bacteroides spp.and Akkermansia muciniphila are known to utilize mucin polyLacNAc via O-glycanases & glycoside hydrolases for their continual survival.However, the excessive usage of mucin could allow pathogens to grow faster to raise the alarm for inflammatory bowel disease (IBD) and even colorectal cancer [26].Table 1 and Fig. 1 represent the comprehensive details on the characteristics and molecular mechanisms of microbiota.The bioactive food supplements, prebiotics, and synbiotics can be utilized as adjunctive therapeutics, attributed to control the secondary infections too [27].The legitimate safety and efficacy of probiotics for the regulatory point of view is yet to be investigated against infectious diseases.

Dietary fibres (DFs)/prebiotics
Dietary fibres (DFs) are the plant derived foods utilized by microbes to yield the beneficial byproducts like SCFAs.These metabolites activate the anti-inflammatory cascade through G-proteins coupled receptors (GPRs) that repress IL-2 and upregulate IL-10 in monocytes.SCFAs also halt TNF-α, IL-1, but regulate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) [28].The consumption of DFs (5 g/day) reduces the level of C-reactive protein (hsCRP), IL-6, TNF-α etc.Therefore, SCFAs promote migration of immune cells near inflammatory sites to clear the pathogens via.ROS to lower the systemic and gut inflammation (Table 1) [28][29][30].The enrichment of diversified beneficial bacteria such as, Bifidobacterium spp.and Lactobacillus spp.inhibit the growth of detrimental pathogens like Clostridium spp.The phenolic compounds rich DFs promote the propagation of Lactobacillus, Bifidobacterium, Akkermansia, and Faecalibacterium, but suppress the growth of Helicobacter Pylori and Staphylococcus spp.[31].

Postbiotics
The postbiotics are the metabolic byproducts of commensals vitally used for many physiological and metabolic functions to maintain the homeostasis effectively [13].The SCFAs, mainly constitute acetate, propionate and butyrate, are recognized by GPRs-GPR 41 & 43.The GPR 41 and GPR 109 in adipose tissues metabolize into acetyl CoA regulating TCA cycle and cell function [32].The colonic low pH, and serum lipid profile are also restored by SCFAs.Overall, effective use of SCFAs strengthen the immune system fighting with pulmonary diseases, hence, reducing the mortalities [28,33,34].SCFAs also increase the TjP integrity against pathogens invasion [35].
SCFAs inhibit the activity of histone deacetylase (HDAC) to control the process of deacetylation and histone crotonylation involving in the post-translational modification facilitating the gene changes, hence, regulate the chromatin architecture critical for epigenetic modification during cell cycle and differentiation [36].The indole and IPA also modulate the cells to produce antibodies (Fig. 1).Exopolysaccharides-homopolymers (cellulose, levan, curdlan, and dextran) and heteropolymers (xanthan, galactan, kefiran) are the biproducts of Lactococcus spp., Streptococcus spp., Leuconostoc spp., that downregulate the IL-1 and TNF-α and upregulate CD8+ and T17 cells (Table 1).Various enzymes like, oxidoreductase, transferase, hydrolases, lyases, isomerases being secreted from Bacillus subtilis, Bacillus licheniformis, Aspergillus niger, and Aspergillus oryzae.Lactobacillus lactis provides every possible aspect of maintaining the homeostasis through anti-inflammatory, antitumor, anticholesterol and antioxidant response (Table 1).Physiological and metabolic pathways are also regulated using cell wall components and cell free components of Lactobacillus spp.[12,13].
The mucin degrading bacteria target the polyLacNAc structures with in oligosaccharide side chains in both humans and animals.These O-glycanase enzymes are the glycoside hydrolase16 (GH16) family indicating their role in mucin break down.This administers the advanced knowledge of mechanisms of mucin breakdown by normal microbiota, could provide a research tool to explore O-glycan for intestinal diseases.Bacteroides spp.and Akkermansia muciniphila utilize mucins for their long -term survival.However, the excessive usage of mucin could allow pathogens to grow faster raise the alarm for inflammatory bowel disease (IBD) and even colorectal cancer [26].
The bioactive food supplements, prebiotics, and synbiotics can be utilized as adjunctive therapeutics, as these modulate DCs and regulate IFNs.Besides, repairing the altered microbiota to boost immunity against SAR-SCoV-2 infection, it also assists in controlling the secondary viral and bacterial infections [27,37].Pathological and modulatory events using probiotics and pre and post biotics are explained in Tables 1 and 2.

Vitamins
Vitamins have adjuvant properties and restore health beneficial bacteria e.g., Bifidobacterium, Lactobacillus, Akkermansia, and Roseburia.The micronutrients execute anti-oxidant function to attenuate immunostimulatory inflammation.Vitamins/antioxidants may alter the circulatory ROS and levels of antioxidant enzymes such as, superoxide dismutase SOD, catalases, peroxiredoxins-PRXs, glutathione peroxidases-GPXs etc., which follow the ascorbate glutathione pathway.Vit.C, D and E can reduce the Firmicutes and Bacteroides (F/B) ratio.Vitamin K deficiency could lead to the poor prognosis of COVID-19.Vit.D via VDR receptors, induces the antimicrobial cathelicidin in macrophages and synthesis of α-defensin & antimicrobial peptides (AMPs), and reduce the production of inflammatory cytokines (Table 1 and Fig. 1) [5,38].The interventional studies have shown that vit.D alters the microbiota  in the nutritional sources facilitate the growth of Bifidobacterium, Lactobacillus, and Roseburia to control the lower ratio of Firmicutes/Bacteroides, consequently the beneficial gut microbes' abundance is enhanced [21,28].l-ascorbic acid-2-glucoside, a form of vitamin C could neutralize/or counteract with oxidative stress, apoptotic responses, and decreased cellular viability caused by Helicobacter pylori.It also holds the anti-Campylobacteriosis and anti-Salmonellosis properties.An oxidized form of vit.C dehydroascorbic acid could inhibit the replication of herpes simplex virus type 1, polio virus type 1 and influenza virus type A and so as to reduce the parasite count too in case of Plasmodium and Trypanosoma.Vitamin D is associated with inhibition of Hsp90mediated proteostasis which governs morphogenesis, by repressing the cyclic AMP-protein kinase A in Candida albicans [30,43].
Vitamins also modulate the health beneficial bacteria e.g., Bifidobacterium, Lactobacillus, Akkermansia, and Roseburia.Vitamin D and E can control the Firmicutes A probable modulatory effect of probiotics with supplements to build ILC 3 homeostasis in gut and the functional integrity of the other body organs [2,20,[29][30][31][32]36] and Bacteroides (F/B) ratio (Fig. 2, Table 1).Vitamin E with selenium and retinoic acid induces the restoration of gut microflora to increase Bacteroidetes and decrease Firmicutes (mice model), thus ameliorating the mucosal inflammations [44].Adjuvant nature of vit.A inhibits norovirus replication and increases Lactobacilli abundance [45].Bile acids and microbiota contribute to optimize the level of vitamin K [46].But vitamin K deficiency could lead to the poor prognosis of COVID-19.
Zinc (Zn) and Selenium help strengthen the immune system.Zn controls the level of inflammatory mediators, activity of O2 and N2, which destroy the host tissues.Ionophore pyrithione blocks SARSCoV-1, polio and influenza replication [49].Zn-pyrithione could halt the growth of deleterious microbes interfering with copper flux and inhibit the ionophore loading in nucleus.Zn also showed a calprotectin-mediated antimicrobial effects in C. difficile [50].
Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and Omega-6 fatty acids intake could reduce 12-21% risk of COVID-19, hence, reduce hospitalization and ventilation.However, in critical cases the higher level of fatty acids has resulted in the formation of 'cytokine storm' in lungs increasing the mortality.Therefore, it is imperative to investigate the risk of dose level with Omega 3 fatty acids [15].ω-3 PUFAs augment the production of SCFAs through Bifidobacterium, Lachnospira, Roseburia, and Lactobacillus [14,51].

Flavonoids
Flavonoid compounds have antioxidant properties to provide protective effects on broad range of disorders viz., cardiovascular, metabolic and neurodegenerative.Antioxidant compounds increase the growth of symbiotic microbes Bifidobacterium spp.and Lactobacillus spp., while hindering the growth of Clostridium spp., Helicobacter pylori, Escherichia coli, and Salmonella typhimurium [17,52].Flavonoids and microbiome interactions could be helpful in the treatment of viral infections.Flavonoids increase Treg and T17 cells and inhibit the pathogens to propagate.They also suppress the TLR4, reduce the 1kB phosphorylation to decrease the nuclear translocation of NF-kB [28,36].A microbial phenolic acid, Desaminotyrosine (DAT), is secreted by Clostridium orbiscindens helping rescued the antibiotic treated influenza-infected mice, via 1 IFN signaling increment stopping the lung pathology [53].

Corticosteroids
The corticosteroids influence NF-kB and activator protein (AP-1) to modulate their effects to activate the transcription of anti-inflammatory factors and reduce the proinflammatory cytokines production, therefore, offset the 'cytokine storm' formation [59].Corticosteroids based therapies were used in SARS outbreak in 2003, and are being used in COVID-19 patients too.A synthetic glucocorticoid methylprednisolone administration in ARDS patients could decrease the risk of death by 62%, but not in all cases [8].In contrary, the corticosteroids also reported to increase the clinical symptoms, inflammation and computed tomography (CT) abnormalities, could remain non-effective during prolonged ventilation and prompt the secondary infections [60].Dexamethasone (DEX), 9-fluoro-glucocorticoid, acquires antiinflammatory and immunosuppressive attributes found to reduce death rates 30% in patients on ventilation and is being widely used to treat asthma, allergies and autoimmune disorders (Table 2) [61].Glucocorticoids influence the gut physiological functions and help retain the growth of Bifidobacterium and Lactobacillus bacteria in mice [62].But higher dose level of corticosterone upregulates the GC receptor expression in peripheral tissues may cause physiological alterations and circadian rhythm disorder [63].The effectiveness of corticosteroids on COVID-19 patients remains conclusive.A meta-analysis of large multinational recovery trials recruiting 20,197 patients (44 studies) using corticosteroids, have shown 28% reduction in mortality rates.However, in another trial with 4451 patients revealed the increasing mortality risks by twofolds [9].

Effects of antibiotics
All antibiotics including broad spectrum antibiotics like neomycin, vancomycin and metronidazole disrupt the microbiome function, thereby, activate the inflammasomes with signature of AP-1/nuclear receptor subfamily 4-group A (NR4A) to disrupt IgG 1 production (post influenza vaccine) and cause lung inflammation via M2 macrophages.The increased activation of Th1 cells and causing tissue pathology through chemokine receptor 1+ (CX3CR1+) in mononuclear phagocytosis (MNP)dependent manner, which also alters the metabolome profile reducing the vaccine response [64].The empirical antibiotics' treatments could lead to the loss of synbiotic bacteria in COVID-19 patients, supporting the fact of avoidance of unnecessary antibiotics use in the treatment of viral pneumonitis.Therefore, GM plays a significant role in antibiotics-host metabolism (xenobiotic) and disposition, which activates the prodrugs e.g., azo drugs to release sulfonamides [65].
The enzymes secreted by gut microbiota help metabolize the antibiotics to facilitate some important reactions e.g., acetylation, deacetylation, decarboxylation, dihydroxylation and demethylation to control the toxicity [65].Given that the new dietary strategies could provide a clue to maintain homeostasis during COVID-19, to optimize the molecular mechanisms linked to health prospects.

Vaccines
Vaccines induce variable response depending upon the population with different ages, nutritional status, immunological response and genetic disorders.Vaccines, nevertheless, regulate the GM to attenuate and strengthen the immune response fighting against various infections.The adjuvant properties of microbiota also increase the vaccine potency and vice-versa (Table 2).Microbiota on different vaccine administration sites may also play a significant role e.g., nucleotide binding oligomerization domain-containing protein 2 (NOD2) sensing is associated with intranasal route and IgA induction is mostly associated with attenuated influenza vaccine.The skin microflora influences the vaccines response given by intradermal route [10].
The live attenuated Bacillus Calmette Guerin (BCG) vaccine provides special protection against Mycobacterium spp.and is being used for many years reducing the infant mortality.The heterologous immune response exerted by this vaccine also protects against other respiratory infections [66].This sort of protection develops in built memory through innate immune cells and reprogram the specific genes in monocytes through regulatory elements associated with histones directly linked to modulate the metabolic and epigenetic disorders, denoted as 'trained immunity' .The monocyte cells (ex-vivo) were found to reprogram the promoter region of genes to produce anti-inflammatory cytokines to regulate the response through GM.Vaccine response may influence the adjuvant properties of GM that activate the innate and adaptive immune response [67].The oral presence of E. coli in antibiotic treated GF mice had helped restoring the antibody response against influenza vaccine.The antibiotics driven dysbiosis may lead to dysregulate the immune response to vaccines, including BCG.In all cases, restoration of commensal microbiota reverted the impaired antibodies response [68].
The serum treated GF mice have revealed that TLR5 were sourced from commensals microflora, responsible to enhance the immune response against influenza vaccine.Similar results obtained using polio and cholera vaccines, have shown a correlation between GM composition and development of systemic and oral immunogenic response against vaccines in infants.The overall adjuvanting traits of commensals, nonetheless, are influenced by various factors such as, vaccine formulation, routes of immunization, to establish the immune regulation and GM stability [69].Besides, the flagellin & peptidoglycan-muramyl dipeptide (MDP) acts agonist of NOD2 sensors to enhance its adjuvant properties against cholera toxin in mice.Similarly, the use of monophosphoryl lipid-A (MPL-A) of LPS to be recognized by TLR 4 could enhance the adaptive response during vaccination [69].
Lower abundance of Bifidobacterium adolescentis could reduce the NAb response using BNT162b2 vaccine.Bifidobacteria regulate the glycolysis pathways to produce lactate, acetate/or propionate being utilized by other commensals effectively, thus, maintain the gut balance to provide the high titre of NAbs against Corona-Vac.Body mass index and body weight are responsible for reducing neutralization titre even with Bifidobacterium adolescentis, Butyricimonas virosa, Adlercreutzia equolifaciens and Asaccharobacter celatus in Corona-Vac vaccine [70].Ruminococcus torques, Eubacterium ventriosum and Streptococcus salivarius are the high responders to vaccines.Prevotella copri and Megamonas spp.are associated with less adverse events.A higher prevalence of Prevotella copri was linked with farnesoid X receptor signaling via modulating bile acid metabolism [71].Megamonas funiformis could ferment glucose into acetate and propionate to maintain homeostasis and Megamonas hypermegale could regulate the T17 helper cells [72].L. plantarum is reported to increase the influenza specific IgA & IgG.The long-term implications of using these commensals to enhance vaccine efficacy and potency are yet to be revealed.

Immunological dynamics
The discussion section is mainly based upon the immunological dynamics involving the immune cells and innate immune entities to modulate the response utilizing nutraceuticals and pharmacological agents through GM (Tables 1, 2

Nutraceutical-immunity dynamics
The prospects of utilizing the probiotics as complementary therapeutics are being increased due to their adjuvant properties on dendritic cells DCs & NK-cells, and induce mucosal Abs secretion, regulate IFNs, produce SCFAs and MAMPs to engage the microbial sensors e.g., PPRs/TLRs regulating the CD4+ T-cells.Probiotics   The G-proteins coupled receptors (GPRs) react with SCFAs to activate the anti-inflammatory cascade, which inhibits IL-2 & upregulate IL-10 production in monocytes.It also controls the pro-inflammatory molecules like TNF-α, IL-1, but regulate NF-kB [28][29][30]36].
There is an inverse correlation between high fibre diets and inflammatory markers of serum CRP, IL-6, IL-18, and TNF-α, thus attenuating the inflammasome complexes [31].The SCFAs secreted through pre and probiotic treatments enter the immune cells and expressed in adipose tissues through GPRs-GPR 41 &43.The receptors GPR 41 and GPR 109 lead SCFAs to metabolize into acetyl CoA to regulate TCA cycle for cell function (Fig. 1) [32,[73][74][75].SCFAs also inhibit the activity of histone deacetylase (HDAC) (Fig. 1) to control the process of deacetylation and histone crontonylation leading to acetylation involved in the post-translational modification, hence, regulating NF-kB [21,28,33,36].HDAC enzymes remove the acetyl groups from lysin residues in the NH2 terminal tails of core histones form more closed chromatin structure to repress the gene expression.Hence, SCFAs naturally help through nucleus to control HDACs facilitating the gene changes to regulate the chromatin architecture critical for epigenetic modification during cell cycle and differentiation.In this way, the immune cells keep themselves in active state during the antigen processing [32,73,74].
Treg cell differentiation also induced via SCFAs, as it plays a role as HADC-inhibitor to intensify the histone acetylation in Foxp3 and Il10 gene loci.It also impedes the stress of inflammatory macrophages and neutrophils being produced during infection.The aryl hydrocarbon receptors/ligands (AHR) were reported to develop innate lymphoid cells (ILC), especially, IL-22 and 3 ILC 3s [32].The indole and IPA also modulate the cells to produce antibodies (Figs. 1 & 2).
Vitamin D via VDR receptors, induces the antimicrobial cathelicidin in macrophages and synthesize α-defensin to control viral replication by synthesizing antimicrobial peptides (AMPs) that damage the envelop structure of influenza A and respiratory syncytial viruses.It reduces the conc. of proinflammatory cytokines, but increase anti-inflammatory cytokines, therefore, increase apoptosis and autophagy through cellular and viral factors controlling the lymphocytopenia [38].It maintains the intestinal integrity and eubiosis [38,40,42,76].Vitamin A, retinoic acid, also plays an important role in regulating the differentiation, maturation, and function of innate immune response.
The ω-3 PUFAs can be metabolized into a range of lipid mediators collectively called as 'Specialized Pro-resolving mediators' such as, prostaglandins, leukotrienes, thromboxanes, maresins, protectins and resolvins are utilized by the immune regulatory system [77].The macrophage cells' activities are influenced through ω-3 PUFAs, which add phospholipids in neutrophils.Dietary ω-3 PUFAs downregulate the IL-2 driven CD4+ and CD8+ T-cell activation and upregulate the Th2 CD4+ T-cells.Hence, the direct suppression of IL-2 induced Th1 cells, indirectly enhance the cross-regulatory function of Th2 cells exert anti-inflammatory effects (Fig. 1) [16].Flavonoids could be useful during infection, as they increase Treg and T17 cell activity.They also suppress the TLR4, reduce the 1kB phosphorylation to reduce the activity of NF-kB [28,36].Flavonoids hinders the growth of pathogens-Clostridium spp., Helicobacter pylori, Escherichia coli, and Salmonella typhimurium [17].

Pharmacological-immunity dynamics
The defeated IFN activities indicate the susceptibility to contract mycobacterial diseases.The interferon α-2 protein receptors i.e., IFNA2 and IFNA6 were reported to be upregulated in hospitalized patients.The IFNA2 is linked with IFN transcription in immune cells to produce cytokines and chemokines.Furthermore, IFNA2 activity decreases with seroconversion, but IFNA6 don't (Fig. 1) [78].SARSCoV-2 virus replication is also inhibited using IFNs in vitro (Vero and Calu3 cells), which induce the STAT1 phosphorylation in late infection [79].
Dexamethasone subsides the inflammatory cells and activates specific neutrophils against the virus, thereby, conforming the synergistic & potent therapeutic effects.Seropositive patients are not supposed to treat straightaway with antibody cocktail.Hence, the supplementation with dexamethasone was initiated in patients even who needed the oxygen support.Moreover, the anti-IL-6 (tocilizumab and sarilumab) is advised in patients who require oxygen having CRP level < 50 [80].
The antibiotics driven dysbiosis could alter the functions of many immune cells increasing the hyperactivity of intestinal macrophages and activation of pro-inflammatory helper T cells (Th) with depleted microflora, therefore, highly impeded SCFAs level increase the opportunity to contract more resistant infections [80].The activation of M2 macrophages in lungs promote the allergic airway inflammation.The increased activation of Th1 cells causing tissue pathology through chemokine receptor 1 (CX3CR1+) & mononuclear phagocytosis (MNP)-dependent manner tend to alter the metabolome profile could diminish the vaccine response [64,82].GM metabolite IPA displays antibiotic properties against MDR Mycobacterium spp.and non-Mycobacterial spp., which is a deamination analogue of tryptophan and acts as an allosteric inhibitor to the tryptophan secreted by Mycobacterium and blocks the synthesis of latter amino acids in vitro & in vivo [83].
The trained immunity produced by BCG could confer the protection against SARSCoV-2, including elderlies.It can also improve the protection against the HPV warts, increase the Ab production against influenza A (H1N1) and encephalomyocarditis, reduce the clinical symptoms with HSV virus to provide protection in experimental animals against HSV1&2 etc. [84].The earlier studies have shown that BCG activates DCs & myeloid cells to increase I-III IFN and IL-28/29 production, and reduce the IFN-α and IFN-β production giving a strategy for establishing immunity against SARSCoV-2 [85].The coronavirus associated gastroenteritis is controlled by Enterococcus faecium in piglets.The increased production of nitric oxide in the cells treated with E. faecium expressed IL-6 and IL-8 results in stimulating the cellular immunity to fight against TGEV infection [25].
TLRs/or PRRs and NOD-like receptors on DCs provide active protection via.adjuvanted GM.TLR-5 mediated signals yield effective Abs response against influenza vaccine [10].Trimix, with CD70 and CD40 ligands and activated TLR4 (immune activator proteins) are recognized as effective adjuvant for mRNA to be encoded with similar sequences.The SCFAs induce higher Ab response via.effective stimulation of B-cells.Therefore, Bifidobacterium adolescentis was linked with higher NAbs titre in subjects who received CoronaVac to overcome the waning immunity of inactivated vaccines.

Conclusion
It has been revealed that L. rhamnosus GG can prevent viral associated pneumonia (VAP) in high-risk ICU population [23].More peer reviewed information is required to validate the efficacy of L. rhamnosus GG.Some studies, nonetheless, also suggest using probiotics could restrain other coronavirus associated gastroenteritis.The restoration of commensals may also revert the impaired antibodies response.The earlier studies have shown that BCG activates DCs & myeloid cells to increase IFN I-III and IL-28/29 production, and reduce the excessiveness of IFN-α and IFN-β giving a strategy for establishing immunity against SARSCoV-2 [85].IFNs induce the STAT and JAK pathway to control viral infection in vitro.The open reading frames, ORF3b &ORF6, are antagonists to IFNs harbouring the diagnostic significance to inform disease prognosis, treatment options and animal model developments [79].
Megamonas funiformis and Megamonas hypermegale have been explored to sustain metabolic and T17 helper cells' regulation [72].Similarly, L. plantarum was reported to enhance influenza IgA and IgG.
The combinational therapy with pre and probiotics followed by vaccinations could have adjuvant effects in controlling the waning NAb titres.It is hypothesized that the future microbiota interventions may significantly improve the response to vaccines.Bifidobacterium adolescentis was linked with higher NAbs titre in subjects received CoronaVac to overcome the waning immunity of inactivated vaccines.
BNT162b2 vaccine elicited improved NAb response correlated to microbiota abundance with Bifidobacterium and Roseburia spp.[70].Therefore, it is imperative the optimize involved therapies, while detecting microbial abundance.Probiotics and prebiotics supplements restore the diversity of gut microbiota, to regulate TLRs balancing the induction of pro-inflammatory and immune-regulatory cytokines conferring the viral clearance from lungs and gut to reduce the local and systemic pathogenicity.Hence, protect the body organs from permanent damage (Fig. 2) [20].
European food safety authority has already developed guidance in 2012 for safer use of E. faecium and implemented the viability assays revealing the complete protection against enteropathogenic coronavirus transmissible gastroenteritis virus (TGEV), in a dose-dependent rescue process [25].Therefore, exploitation of these microbes offers the strategies to combat the viral gastroenteritis or IBD in humans.
Corticosteroids, vaccines, anti-sera, interferon therapies along with necessary nutraceutical supplements can enhance the protective immune response.Probiotic interventions at optimal dose level could minimize the debilitated effects in patients with improved symptomatic outcomes, therefore, shorten the stay in hospitals.
Some challenges are yet to be resolved e.g., over dose of probiotics can cause nausea and bloating.The comorbid status of patients should also be taken under consideration while using probiotics.The cohort study models should be designed to assess the errored immune signals, especially with people from underlying/comorbid conditions.Using risk free nutraceuticals trials irrespective of other medications' regimens would certainly deliver various clues for personalized treatments to restore and sustain health.On the other hand, probiotics can also contribute to the antibiotic resistant genes, which may exchange thoroughly among commensals.This also provides clues to establishing strategies as how the health is impacted in clinic/hospital environment than at home.More research could be executed to study the impact of active foods on antibiotic susceptibility.A synergistic relationship among bacteriophages, essential probiotics, other commensals and how these implicate the immune cells modulation, including the environments contributing to the antibiotic resistance.Efficacies of ω-PUFA, other vitamins and dietary fibres along with probiotics is yet to be determined among different group of patients at different severity levels from asymptomatic to symptomatic.Last but not least, would probiotics really improve the potency of molecular vaccines to combat the problems of waning immunity, is yet to be revealed?

Fig. 2
Fig. 2 Properties of Nutraceuticals and Pharmacological interventions to regulate the protective immune activities in alveolar and gut cell linings.A probable modulatory effect of probiotics with supplements to build ILC 3 homeostasis in gut and the functional integrity of the other body organs[2,20,[29][30][31][32]36]

Table 1
Immunomodulatory and pathological implications to fight against diseases using favourable microbes and nutraceuticals (dietary fibres, vitamins, polyunsaturated fatty acids and flavonoids)

Table 1 (continued) Relevant features Modulatory/pathological factors References
Heteropolymersxanthan, gellan, galactan, kefiran are produced by Lactococcus lactis, Lactobacillus spp.,Streptococcus thermophilus, Weissella confusa, Leuconostoc spp., and Pediococcus spp.Modulate CD8+ and Tc17 cells and↑ anti-inflammatory properties Enzymes (oxidoreductase, transferases, hydrolases, lyases, isomerases, ligases) secretion from Bacillus subtilis, Bacillus licheniformis, Aspergillus niger, Aspergillus oryzea and Lactobacillus lactis Immunomodulatory, antitumor, antimutagenic, anti-oxidant, anti-inflammatory, antihypertensive, antibacterial and antiviral, cholesterol lowering, anti-IBD properties Cell wall components (Peptidoglycan-Teichoic acid and Lipoteichoic acid) especially from gram+ ve bacteria e.g., Lactobacillus spp.Promote physiological, biochemical and regulatory properties Cell Free supernatant and bacterial lysate from Lactobacillus spp.and Bifidobacteriums pp.Immunostimulatory and safe to human health except biogenic amino acids and d-lactis acid Vitamins Vitamin C (l-ascorbic acid-2-glucoside) Neutralise the oxidative stress, apoptotic response, decrease the cellular viability in H. pylori Also inhibit HSV, polio, and influenza [5, 40, 42-46] Vitamin D&E Bifidobacterium, Lactobacillus, Akkermansia, Roseburia to get modulated.Could reduce Firmicutes/Bacteroides (F/B) ratio, if used inappropriately Vitamin E with Selenium and retinoic acid Ameliorate mucosal inflammation, ↑ Bacteroidetes and ↓ Firmicutes (mice model).Inhibit Norovirus replication, but ↑ Lactobacillus spp.abundance Vitamin A exhibits adjuvant properties Retinoic acid vit A can cause the hepatotoxicity, if used inappropriately Vitamin D Immunomodulatory/and anti-inflammatory effects on immune cells ↓ hospitalization potentially while maintaining the adequate level (> 20 to < 50 ug/ml).Administered at higher doses can reduce ICU admissions Vitamin K deficiency Poor prognosis of COVID-19.Moderate level of Vit K suppresses the co-infections with COVID-19 with increased use of antibiotics Table 1 (continued) Relevant features Modulatory/pathological factors References Essential trace minerals-selenium & zinc Selenium increases the beneficial microbes such as, Akkermansia, Lactobacillus, and Faecalbacterium and depletes the deleterious microbes like Dorea and Mucispirillum Gut microbiota to secrete SCFAs to control the inflammatory bowel disease (IBD) and colitis, by decreasing the GM impairment Regulates the redox state

Table 3
The interventional studies are being carried out using probiotics in COVID-19 individuals with expected outcome (ClinicalTrials.gov-U.S.National Library of Medicine)