key: cord-0884689-83aiu6yw
authors: Kurian, Shilia Jacob; Unnikrishnan, Mazhuvancherry Kesavan; Miraj, Sonal Sekhar; Bagchi, Debasis; Banerjee, Mithu; Reddy, B Shrikar; Rodrigues, Gabriel Sunil; Manu, Mohan K; Saravu, Kavitha; Mukhopadhyay, Chiranjay; Rao, Mahadev
title: Probiotics in Prevention and Treatment of COVID-19: Current Perspective and Future Prospects
date: 2021-03-19
journal: Arch Med Res
DOI: 10.1016/j.arcmed.2021.03.002
sha: 14c1dd011421d0eee9aa4123057d80f1a8a2fbba
doc_id: 884689
cord_uid: 83aiu6yw

Saving lives and flattening the curve are the foremost priorities during the ongoing pandemic spread of SARS-CoV-2. Developing cutting-edge technology and collating available evidence would support frontline health teams. Nutritional adequacy improves general health and immunity to prevent and assuage infections. This review aims to outline the potential role of probiotics in fighting the COVID-19 by covering recent evidence on the association between microbiota, probiotics, and COVID-19, the role of probiotics as an immune-modulator and antiviral agent. The high basic reproduction number (R0) of SARS-CoV-2, absence of conclusive remedies, and the pleiotropic effect of probiotics in fighting influenza and other coronaviruses together favour probiotics supplements. However, further support from preclinical and clinical studies and reviews outlining the role of probiotics in COVID-19 are critical. Results are awaited from many ongoing clinical trials investigating the benefits of probiotics in COVID-19.

The novel coronavirus pandemic of 2019 (COVID-19) (1), an emerging infectious disease (EID) caused by multiple strains of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has spread to 216 countries and territories, with catastrophic impact on global health and economy. As of 12 th August 2020, there are 20.4 million cumulative confirmed cases of COVID-19, including 0.74 million deaths, with a case-fatality rate (CFR) of 3.6%

(2). Among WHO regions, the Americas and Europe have the highest confirmed cases. Ten most affected countries are the United States of America (USA), Brazil, India, Russia, South Africa, Mexico, Peru, Colombia, Chile, and Iran (3).

COVID-19 mortality rates vary significantly across different countries. Currently, CFR has been higher in the United Kingdom (14.8%), Italy (14.0%), France (12.4%), Mexico (10.9%), Spain (8.7%) than in Brazil (3.3%), USA (3.2%), India (2.0%), South Africa (1.9%) and

Russia (1.7%) (2) , but the reasons for this variation remain ambiguous. Differences in virus strains, rate of COVID-19 testing, quality, and access to the healthcare system, and preventive strategies are among the listed reasons (4, 5) . Demographic characteristics such as the proportion of elderly, dietary and lifestyle patterns, comorbidities, and socioeconomic status, also influence the susceptibility, severity, and fatality of COVID-19 (5) .

Most COVID-19 cases are mild to moderate with self-limiting respiratory illness. Geriatrics and individuals with hypertension, diabetes, cardiac diseases, pulmonary diseases, and cancer are extremely vulnerable to severe COVID-19 (1) . A meta-analysis with more than 50000 COVID-19 cases found a pooled incidence of 20.2% severity and 3.1% mortality (6) .

Inflammatory markers like c-reactive protein (CRP) and lymphocytopenia are significantly correlated with severity. The immune status of certain individuals seems to fight COVID-19 better than others (4) . Most trials repurposing antivirals have not proven effective so far.

Moreover, a subset of patients develops a potentially life-threatening hyperinflammatory state called cytokine storm, accompanied by multi-organ dysfunction, respiratory failure, and a clinically distinct hypercoagulable state of the pulmonary vasculature. COVID-19 requires a multidimensional therapeutic approach, ranging from virus-targeted interventions in the early stages to immunomodulation in late stages (7) . While dexamethasone reduces the mortality rate in severe COVID-19 patients, it has limited value in mild disease (8) . Besides, WHO and many countries have advised caution in implementing steroid therapy in COVID-19 patients with co-morbidities such as diabetes and hypertension (9) . Suppressing the exaggerated immune response can protect the lungs, but containing the infection needs a fully functional immune system. Therefore, fine-tuning the host-microbiota balance could be useful in COVID-19, especially with co-morbidities. Considering the immunomodulatory (10), antiinflammatory (11) , antioxidant (12) , and antiviral (13) actions of probiotics, we hypothesize that a pleiotropic mechanism could be a preventive /curative option for COVID-19 ( Figure   1 ).

Microbiotas constitute the entire spectrum of microbial communities residing in the host, such as bacteria, viruses, fungi, and protozoans. The human body has more microbes than human cells, occupying mucosal membranes, and the skin. The human microbiota's role in shaping the immunity and preserving homeostasis has been extensively studied, particularly in the gut, where microbes are most abundant (14) . Germ-free mice have demonstrated the protective effects of the microbiota in pathological conditions, including infections, inflammatory and metabolic disorders of multiple body parts, including lungs (15, 16) . The host-microbiota symbiosis is sensitive to genetic makeup, antibiotic use, dietary pattern, allergens, and infective agents, all of which can alter the microbiota composition.

'Dysbiosis', resulting from the host-microbiome maladjustment, can increase susceptibility or severity of diseases and multiple health issues concerning the gastrointestinal (GI) and distal sites such as lungs, brain, vagina, liver, etc. Alteration of the microbiota in gut and lung has been observed in metabolic and respiratory illnesses (14) , such as inflammatory bowel diseases (IBD), obesity, type 2 diabetes, cardiovascular disease, Alzheimer's disease, and depression (17) (18) (19) (20) (21) (22) . Disturbance in lung microbiota in chronic obstructive airway disease, asthma, tuberculosis, cystic fibrosis, etc. implies the influence of the lung microbiota in pulmonary health and illnesses (23) (24) (25) (26) . Dysbiosis also creates an imbalance in the degree of activation of leucocytes, leading to lung injury. Gut microbiota modulates the immunity of the lung via the gut-lung axis, implying crosstalk between different mucosal sites of the human body (27) . Likewise, the gut-brain axis presents a bidirectional exchange through neural, humoral, endocrine, and immune connections, presumed to be mediated by bacterial metabolites such as short-chain fatty acids (SCFAs) (28) . SCFAs modify neuronal excitability, like the many microbiota-derived neuroactive substances (histamine, acetylcholine, γ -aminobutyric acid, dopamine, and tryptophan, a precursor in serotonin biosynthesis). Thus, gut microbiota intervenes in the crosstalk between the central nervous system (CNS) and the enteric nervous system (ENS), thereby linking brain centers with peripheral intestinal functions for emotional as well as cognitive functions (28) . The role of the gut-brain axis is exemplified by the dysbiosis associated with CNS diseases and functional GI disorders.

Gut microbiota is also involved in the pathogenesis of sepsis and ARDS (29) . Depletion of gut microbial diversity can cause dysbiosis, which is therefore attributed to several pathologies. Geriatrics have reduced the diversity of gut microbiota, including beneficial microbes such as Bifidobacteria species (30) suggesting microbiotal interaction with the gutlung axis. Thus, modulating the microbiome could demonstrate antiviral effects.

Host-microbiota interactions are bidirectional, complex, and potentially modulates the development and function of innate and adaptive immune systems (31, 32) . Commensals maintain homeostasis by releasing antimicrobial peptides (AMPs) and compete with pathogens for nutrition and space at the site of infection (33) , demonstrating a mutual relationship between gut microbiota and immune homeostasis, to be exploited in the current pandemic. Signals by gut microbiota can tune the immune-mediated cells for proinflammatory (helper T cells type 17; Th17) and anti-inflammatory (regulatory T cells;

Tregs) responses, determining susceptibility to different illnesses (34) . Coronavirus infections can be countered by healthy gut microbiota that protects the lungs and vital organs from an exaggerated immunological response.

Pattern recognition receptors (PRRs) on host cells can recognize microbe-associated molecular patterns (MAMPs) and pathogen-associated molecular patterns (PAMPs) (34, 35) , possibly generating memory response at primary exposure. PRRs primarily comprises of the families of toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and RIG-I-like receptors (RLRs).

TLRs recognize the MAMPS and PAMPs and induce immunological reactions based on cell type, ligand, or receptor (35) . TLR stimulation by cell wall components and flagellin of gut microbiota is necessary for mounting the immune responses towards influenza. In contrast, oral SCFA-induced anti-inflammatory actions are attributed to decreased pulmonary pathology following bacterial and viral infections in mice (36) . Effectively engaging PRRs expressing innate cells with gut-or non-microbial ligands is essential for the protective mechanism, independent of adaptive immunity during exposure to a pathogen or secondary infection. The gut microbiota secretes SCFA metabolites (e.g., acetate, butyrate, and propionate and secondary bile acids) that generate immunomodulatory signals. Commensals such as Lactobacillus, Bacteroides, and Bifidobacteria bind receptors in dendritic cells (DCs) and macrophages, subsequently regulating their metabolism and immune response functions (37) . More importantly, probiotics like Bifidobacterium lactis increased mononuclear leukocytes and antitumour action of NK (natural killer) cells in healthy geriatric volunteers (38) . Balanced gut microbiota composition significantly impacts the efficiency of the lung immunity of the host (14) . Moreover, germ-free mice (GF mice) have been found to suffer from impaired pathogen clearance in their lungs (15) . Interestingly, lung infection with influenza virus (IFV) in mice enriches Enterobacteriaceae and depletes Lactobacilli and Lactococci in the gut microbiota (39) .

A pilot study with sequencing faecal samples of 15 patients showed that COVID-19

infections significantly altered faecal microbiomes characterized by a decline in beneficial commensals and enrichment of opportunistic pathogens (40) . The baseline abundance of Many COVID-19 patients present with GI symptoms and have sepsis that may originate in the gut (43) . GI symptoms correlate with profound disease severity. Moreover, angiotensinconverting enzyme 2 (ACE 2) and virus nucleocapsid protein have been detected in GI epithelial cells, and virus particles have been isolated from faeces. Once the virus enters the epithelial cells of GIT and faeces, COVID-19 patients become highly infectious (44) . Since SARS-CoV-2 binds ACE 2 receptor for its entry into human cells (45) , the high expression of angiotensin II receptor type 2 (AT2) cells of the lung, stratified epithelial cells of the esophagus, and absorptive enterocytes of ileum and colon are critical for infectivity.

Bioinformatics data indicate that, like the respiratory system, the GI system is an important route for SARS-CoV-2 infection (46) . ACE 2 is an essential regulator of intestinal inflammation (46) and significantly influences the composition of gut microbiota, thereby affecting cardiopulmonary diseases (47) . Pneumonia and subsequent acute respiratory distress syndrome (ARDS) are critical clinical manifestations of COVID-19, particularly in geriatric and immuno-compromised patients (48) . Gou W, et al. suggest that the gut microbiome of healthy non-infected individuals is highly predictive of the blood proteomic biomarkers of COVID-19 severity (49) . Disruption of the healthy gut microbiome potentially predisposes healthy individuals to abnormal inflammatory states, possibly accounting for COVID-19 susceptibility and severity.

Restoration of commensal probiotic strains may enhance the recovery of the lung and the gut via host-derived cytokines and chemokines in addition to microbiota-derived SCFAs (14) .

Since human microbiota plays a vital role in immunomodulation, it can impact SARS-CoV-2 infection. Current evidence supports the potential role of microbiota in the susceptibility, progression, and severity of COVID-19. Five studies directly connect microbiota with COVID-19, supporting the presumptive role of probiotics in both prevention and treatment of COVID-19 (40) (41) (42) 49, 50) (Table 1) . The introduction of probiotics prevents cytokine-induced epithelial damage, which is also attributed to mucosal barrier reinforcement. Besides, probiotics enhance mucous secretion, improve barrier function, and pathogen exclusion. Probiotics also prevent pathogen binding by promoting qualitative alterations in intestinal mucins (53, 54) . Interestingly, the bacterial component is also degraded into an AMP, which lends anti-pathogenic properties to the host. This constitutes an example for an evolutionarily beneficial pleiotropic effect of large surface proteins. Besides, probiotics also induce the release of defensins from epithelia, the small peptides active against bacteria, fungi, and viruses. Additionally, these peptides steady the barrier function of the gut. Probiotics inhibit the binding of the pathogen via steric hindrance at pathogen receptors of the enterocyte. Specific metabolites of probiotics modulate signalling and metabolic pathways in different cells. Diverse components of the probiotic metabolome (e.g., hydrogen peroxide, amines, organic acids, and bacteriocins) interact with multiple targets in host metabolic pathways that regulate inflammation, angiogenesis, metastasis and cellular proliferation, differentiation, and apoptosis (54) . Probiotics stimulate the immune system, thereby increasing Igs generation, enhancing macrophages and lymphocytes activity, and interferon (IFN)-ɤ stimulation (10) . Probiotics may also inhibit the immune system, primarily embodied in their anti-inflammatory response. (55, 61) . Vitamin D can also alleviate severe complications and mortality related to COVID-19 and inhibit cytokine storm by simultaneously boosting the innate immunity and evading the exaggeration of the adaptive immunity (4). Interestingly, current findings also associate VDD to common comorbidities that increase the severity of COVID-19 such as certain cancers, autoimmune disorders, diabetes, and cardiovascular diseases. A well-designed multicentric randomized controlled trial (RCT) with Lactobacillus reuteri NCIMB 30242 probiotics strain (for nine weeks) increased serum vitamin D level by 25% (62) . Increased vitamin D levels may be attributed to the probiotic secreting lactic acid and lowering intestinal pH (Figure 2 ). When a probiotic was combined with a vitamin D supplement, vitamin D absorption improved further.

Probiotics Lactobacillus plantarum and Lactobacillus rhamnosus enhanced the expression of vitamin D receptor (VDR) protein and its transcriptional activity, increasing the expression of an AMP, viz. cathelicidin (63) . Probiotics-induced signalling modulation has been demonstrated in VDR knock-out mice in a salmonella-induced colitis model (64) . Probiotics confer both physiological as well as histological protection in VDR+/+ mice, but not in VDR-/-mice, suggesting that the probiotic protection in colitis depends on the VDR pathway. Probiotic supplementation also increases Paneth cells, thereby enhancing host defense by secreting AMPs. Elucidating the probiotics' mechanism in enhancing VDR signalling and inhibiting inflammation, makes them an attractive agent for preventing and treating COVID-19 related chronic inflammation (55, 61) .

As discussed earlier, protection by probiotics includes synthesis of antimicrobial agents, immune-modulatory responses, and enhancement of innate host defense. Certain probiotics also have anti-viral effects, including against coronavirus (65) . LGG's protective effect is mediated via a myeloid differentiation factor (MyD)88-dependent mechanism, specifically via TLR 4. LGG can provide early control of IFV and improve transcriptional responsiveness, acting as a simple and safe strategy to protect neonates.

LGG also protected mice from infection with IFV by stimulating respiratory cellmediated immunity following up-regulation of lung NK cell activation (71) . In the LGG- patients (43, 44) . Indeed, the intestinal epithelial cells, predominantly the small intestinal enterocytes, also express ACE 2 receptors that are critically involved in cardiovascular physiology, pathology, and acute lung injury, including ARDS. ACE 2 is an important regulator of intestinal inflammation. Moreover, there is a wide disparity in COVID susceptibility and disease progression. Gou W, et al. suggest that susceptibility among diverse cohorts might be related to composition of microbiota (49) . The faecal metabolites suggest that an amino acid-related pathway may provide the key link between the core gut microbiota, inflammation, and COVID-19 susceptibility. The core gut microbial features and related metabolites may serve as potential preventive/ treatment targets for intervention, especially among susceptible populations (34) .

A report from China suggests that COVID-19 patients suffer microbial dysbiosis with depleted Lactobacillus and Bifidobacterium, with over 60% of patients expressing GI symptoms such as diarrhoea, nausea, and vomiting (81) . GI symptoms also imply greater severity. Around 58-71% of COVID-19 patients were administered antibiotics in China, and diarrhoea was reported in 2-36% of them. Reinforcement of colonic microflora using probiotics diminishes secondary infection and diarrhoea in patients receiving antibiotics. (84) . 'Cytokine storm' or the excessive release of inflammatory cytokines is the reason for severity and death of COVID-19 patients (4). Therefore, anti-cytokine therapy for the suppression of the hyperinflammatory states is a recommended strategy to treat severe COVID-19. So far, many preclinical studies with probiotics have focused on influenza and pneumonia, demonstrating benefits from oral or nasal administration of probiotics, which prolonged survival, reduced weight loss, diminished viral loads in the lung, and minimized bronchial epithelial damage (70) (71) (72) (73) . Protection was mediated by immune regulation, distinguished by potent viricidal properties by early recruitment of innate immune system through alveolar macrophages, NK lymphocytes and heightened proinflammatory cytokines such as TNF-α and IL-6, etc. This inflammatory boost is followed by a rapid decline, attributed to enhanced anti-inflammatory mediators like Treg cells and IL-10 in the lungs, diminishing lung injuries (14) . Moreover, probiotics' ability to modulate vitamin D/VDR and balancing the composition and growth of gut microbiota (34) , together suggest the immunomodulatory potential in ameliorating the cytokine storm. Therefore, the use of probiotics with anti-inflammatory effects could maintain the equilibrium of intestinal microecology and prevent secondary infection in COVID-19.

Most importantly, the current pandemic is particularly severe, with higher case fatality in individuals with non-communicable diseases (NCDs). 20-51% of COVID-19 patients suffered at least one comorbidity, like diabetes (10-20%), hypertension (10-15%), and cardio-and cerebrovascular diseases (7-40%) (85) . Many studies and anecdotal reports suggest obesity as a notable risk factor for COVID-19, primarily in younger patients (86) .

Moreover, people with diabetes need a balanced diet to control glycemia and maintain immune function. However, hypo-nutrition aggravates impaired immunity in COVID-19 (87) . On the other hand, probiotics may reduce cardiovascular and diabetes risk factors such as elevated blood pressure, serum cholesterol, obesity, and insulin resistance. Growing evidence reveals that probiotics can lower elevated blood pressure, glycemia, low-density lipoproteins (LDL)-cholesterol, LDL/high-density lipoproteins (HDL) ratio, inflammatory mediators, and body mass index (88) . Modulating the gut microbiota composition by probiotics modify central energy metabolism and alter satiety hormone levels, exerting antiobesity effects. A study in mice demonstrated that a carboxypeptidase derived from Remarkably, the patient data showed cerebrovascular event (77;62%) including ischaemic strokes (57;46%), intracerebral haemorrhages (9;7%), CNS vasculitis (1;<1%), and other cerebrovascular events (10;8%). The significant role of probiotics in the prevention and treatment of neurologic disorders involves multiple pathways such as neural, immunological, and metabolic via the brain-gut axis. Preclinical evidence shows probiotics have neuroprotective effects against ischemic/reperfusion injury, possibly via antioxidant and antiapoptotic effects, anxiolytic effects, improved cognition, attenuation of inflammatory response and elevated serotoninergic precursors and antidepressant effects (95) . Indeed, in an RCT, the oral administration of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175, for one month, decreased psychological distress and depression in healthy volunteers (96) . Likewise, in another RCT, fermented milk with Bifidobacterium animalis subsp. lactis, Streptococcus thermophiles, Lactobacillus bulgaricus and Lactococcus lactis subsp. lactis affected regions of the brain that regulate the central processing of emotion and sensation in healthy women (97) . Similarly, oral administration of Lactobacillus casei strain Shirota for two months in chronic fatigue syndrome reduced anxiety significantly more than controls.

Probiotic metabolites can interact with and play a role in behaviour. Dinan TG, et al. (98) showed that physical or psychological stress is directly associated with the microbiota-braingut axis imbalance. Moreover, probiotics also diminish the frequency and severity of migraine headache attacks (99) .

We found 14 RCTs and one prospective observational study with probiotics registered in clinical trial registries around the world (Supplementary Table1).

Differences persist in the physiology and metabolism among probiotic strains of various species, and consequently, their effects are different on the human body. Even different strains of the same species may have different health effects (100) . The dose also matters, and a probiotic consumed at a higher dose may not be as good as a lower dose. Similarly, different doses of the same probiotic strain can produce diverse effects. Besides, the same probiotic strain can function differently in different hosts. Hence, the functions of probiotics should be proved at the strain level to confirm efficacy. Therefore, probiotics should be cautiously selected for optimal benefit.

There have been adverse reports of probiotics. According to Single-cell RNA sequencing (scRNA-Seq) analysis, Feng Z, et al. (101) demonstrated the ACE2, SARS-Cov-2 receptor, could be elevated in the presence of both invasive bacteria Salmonella enterica and its counterpart, Segmented Filamentous Bacteria as probiotics in the mouse small intestine (102) and human enterocytes (101) . In another study, both Lactobacillus acidophilus and Bacillus clausii also failed to decrease the expression of coronavirus receptors compared to control after Salmonella infection in the murine intestine (103) . The efficacy, as well as the safety of probiotics, have been contentious. Although adverse effects of probiotics appear to be mild (mainly digestive belching or bloating), severe consequences have been noticed in individuals with underlying health issues. There are reports of fungaemia (104) and bacteraemia (105) following probiotic administration. A Salmonella-colitis mice model has demonstrated that probiotic therapy in the absence of VDR expression produce severe infection (106) . The dependence of probiotic function on VDR status, may explain the disparity in the clinical response of some IBD patients. The rationale for introducing probiotics for COVID-19 comes from indirect evidence (107) . Therefore, blindly using conventional probiotics is not warranted until we clearly understand SARS-CoV-2 pathogenesis, its effect on gut microbiota, and vice-versa.

Evidence supports probiotics' role in regulating the immune system, suggesting a definitive role for probiotics in viral infections. Probiotics supplementation could reduce the severity of COVID-19 morbidity and mortality. Probiotics can inhibit cytokine storm by simultaneously boosting the innate immunity and evading the exaggeration of adaptive immunity, which is challenged to respond quickly to the viral onslaught. Probiotics-induced suppression of the inflammatory cytokine response may prevent both the severity and the occurrence of ARDS, making probiotics an attractive adjunct. Inventing effective therapy will transform the impact of the pandemic on lives as well as economies across the globe. Therefore, supplementation of probiotics in high risk and severely ill patients, and frontline health workers, might limit Dysbiosis (an altered gut microbial flora) predisposes the individual to abnormal inflammatory status and increases the susceptibility to the disease. Probiotic supplementation helps to maintain symbiosis in the GIT and thereby modulate the immune system. The symbiotic state also helps to control the severity of the disease via, the gut-lung and gut-brain axes. 

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The authors express their gratitude to Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal for the support and facilities.

The authors report no conflicts of interest Source of Financial Support None