Probiotics in prevention and treatment of COVID-19: a systematic review of current evidence

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Introduction

The coronavirus disease

The coronavirus disease 2019 (COVID-19) has rapidly spread from China around the world and is considered a global pandemic. As of early December 2021, 263 000 000 people across five continents have been infected by COVID-19 [

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Supplementing with non-pharmacological substances such as probiotics and nutraceuticals has been suggested as a potential therapeutic option for COVID-19, due to evidence of an interference effect on the SARS-CoV-2 pathway [25]. Specifically, probiotics with anti-inflammatory or immunomodulatory properties may be the most effective for prevention or alleviation of COVID-19 symptoms [8]. In early February 2020, China’s National Health Commission and National Administration (version 5) recommended the use of probiotics and gut microecological modulators in COVID-19 patients to maintain the balance of intestinal microecology [67].

Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit to the host [1]. Probiotics exert their beneficial effects through various mechanisms including manipulation and restoration of gut microbiota, enhancement of intestinal barrier function, and competition with pathogens for adhesion to gut epithelium and nutrition, and suppression of opportunistic pathogens. Other potential mechanisms explaining how probiotics may promote beneficial effects include the production of antimicrobial substances, decrease in translocation of opportunistic organisms, activation of mucosal immunity, and modulation of the innate and adaptive immune response [66].

Although the rationale for using probiotics to treat COVID-19 comes from indirect evidence, it is mechanistically plausible that probiotics may help in the prevention of and/or alleviation of COVID-19 related symptoms and complications. Moreover, probiotics are readily available, easy to administer (oral administration), relatively safe and economical compared with antiviral drugs, immunomodulators or other strategies tested in COVID-19 [4]. There is clinical evidence showing that certain probiotics may help treat and prevent viral infections [67]. However, the role of probiotics in alleviation of the novel COVID-19 has not been established. The aim of this systematic review was to assess the role of probiotics in the prevention and treatment of COVID-19.

Materials and methods

Study objective and search strategy. An extensive search of four electronic databases was performed which included Embase, Scopus, Web of Science, and PubMed from November 2019 to June 2022. After reviewing the references list of related articles additional studies were identified. A multiple combination of keywords validated by MESH was used as the search strategy. Only English and Persian studies were included in the search. The search strategy is presented in Table 1. This systematic review was conducted according to the recommendations outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [41].

Table 1. Search strategy keywords

Inclusion/exclusion criteria. Articles were eligible for inclusion if they met the following criteria: (1) randomized controlled trials, cross sectional, case series, case reports, and cohort studies; (2) examined the effect of a probiotic on outcomes related to immunity, immunological responses, or signs/symptoms/severity of COVID-19; (3) involved adult humans that were 18 years old or older; (4) experiment was conducted either in vivo or in vitro, and (5) published in English and Persian. Articles were excluded if they were non-original, review papers, commentaries, or editorials.

Screening and selection. A two-step method was performed to improve the study selection process. After removing duplicate articles, step-one was performed which involved screening of titles and abstracts of retrieved. For step-two the full-text of articles that were potentially eligible were assessed by two reviewers to confirm eligibility. Articles were compiled in an Endnote X9© (Thomson Reuters) file.

Data extraction. A standardised template was used by the researchers to complete data extraction. The information extracted included the first authors’ name, type of study, date of study, study population, characteristics of participants, probiotic type, doses of probiotic, comparator group, effects of probiotic on cytokines and serum ingredients, and other relevant outcomes. Two independent researchers extracted and entered the information into the template.

Results

The database search yielded 690 potential studies (after 649 duplicates were removed), and following the screening, a total of 23 studies met the eligibility criteria (Fig.). The description of the studies included is detailed in Table 2. Six articles were conducted in vitro while the remaining studies were conducted in the human population (in vivo). The type of probiotic was defined in eighteen studies. There were two studies that used supplements (vitamins, herbals, minerals, etc.) in addition to probiotics. The largest sample size was 445 850 participants which were from a study that used an application-based survey [34]. The smallest sample size of the included studies was 30 participants [59].

Figure. PRISMA flow diagram of study retrieval process

Most studies (n = 20) confirmed that probiotics were effective in COVID-19 illness. Ten studies found that consumption of probiotics led to early remission of COVID-19 symptoms and a shorter duration of sickness. Meskina et al. stated that probiotics helped patients’ COVID-19 symptoms resolve faster [38]. In three studies, lower mortality was seen in patients who consumed probiotics.

Three studies reported that patients taking probiotics had decreased hospitalization and length of stay [9, 38, 67]. Two studies claimed that probiotic consumption is linked to earlier lung CT scan resolution in patients [31, 38]. According to Bozkurt et al., probiotic use is associated with lower mortality and earlier lung CT scan resolution [14] and other studies found probiotics helpful to resolve diarrhea.

Wang et al. reported that for COVID-19 patients that began taking probiotics, their COVID-19 test results became negative faster and diarrhea resolved sooner compared to patients that did not consume probiotics [62]. Six in vitro studies found some probiotics to be beneficial against SARS-CoV-2 through antiviral effects, preventing its replication or modulating ACE2 and inflammatory cytokines. Rather et al., reported that L. plantarum had a meaningfully beneficial effect on preventing SARS-CoV-2 replication [47]. Potentially this ability may be caused by plantarcin E and F. There were two studies that discussed COVID-19 reinfection. Li et al. claimed that probiotics can decrease secondary infection through immunity moderation [32]. The other study by Veterini et al. reported that two individuals in a non-probiotic group experienced reinfection, while no reinfection was seen in a group that consumed probiotics [59].

Table 2. Description of the findings reported in eligible studies

In contrast to the positive findings reported on consumption of probiotics, there were some studies which demonstrated that probiotics were ineffective or even had negative effects on the course of COVID-19 infection. According to Hegazy et al., probiotic yoghurt consumption in the 12 months preceding COVID-19 infection was linked to more severe disease [24]. Ivashkin et al. reported that the studied probiotic had no meaningful effect on the COVID-19 severity [21, 32]. Finally, Li et al. claimed that consumption of probiotics did not decrease IL-6 and length of hospitalization was higher in probiotic group [26].

Discussion

The aim of this systematic review was to investigate the effect of probiotics on COVID-19. The results of this review are based on 23 studies that used various study designs. The findings suggest that the greatest impact of probiotics on COVID-19 is related to controlling inflammation, reducing mortality and morbidity by strengthening and regulating the immune system. Additionally, some probiotics may play an effective role in controlling the symptoms and severity of COVID-19, which will be detailed below.

Previous studies have demonstrated that generally probiotics are complementary options for the treatment and prevention of viral and bacterial infections. Probiotics have also been shown to exert anti-viral effects via diverse mechanisms such as: regulation and modulation of innate and adaptive immune system, maintaining gut and lung mucosal integrity, as well as inhibiting and binding to opportunistic pathogens [27, 50, 61]. Regarding upper respiratory tract infections (URTIs), one meta-analysis of RCTs with 3720 cases showed that patients undergoing probiotics treatment had two-times lower odds of developing URTIs [23]. Regarding lower RTIs, another meta-analyses of RCTs with 2000 patients showed that probiotic use can significantly decrease the ventilator-associated pneumonia incidence [13, 57]. Further, a large meta-analysis of 52 articles stated that probiotics were strongly efficient in the prevention or treatment of acute RTIs [33].

Regarding the effects of probiotics on COVID-19, many studies have shown gut dysbiosis among COVID-19 patients such as alterations in Bifidobacterium and Lactobacillus. Therefore, probiotic implementation, specifically with these strains, may lead to beneficial outcomes when managing this disease [18]. In one systematic review, probiotic use was suggested to improve host immune response against COVID-19 by three possible mechanisms. These include altering the level of interleukins (IL), virus titers reduction, and interferon and antibody production [39]. Moreover, a review by Batista et al. proposed that probiotic consumption can ameliorate COVID-19 symptoms via regulating, and boosting an individuals’ immune response, and improving their gut microbiota in favor of protective microflora [10]. Authors from another review suggested that immune system improvement against COVID-19 can be achieved via intestinal microbiota profile enhancement by probiotic use [2]. Similarly, a study that included a large online cohort of 445 850 individuals, documented that women who consumed probiotics, Omega-3 or Vitamin-D were less infected by SARS-CoV-2, although this was not the case among males [34].

Seven studies included in the present review mentioned Bifidobacterium solely or in combination with other bacteria as the studied probiotic [38, 67, 14, 26, 53, 55, 62]. Two studies reported shorter hospitalization periods in the Bifidobacterium-receiving group [14, 67]. Bozkurt et al. investigated mild to moderate COVID-19 cases and found that chest CT scan resolved faster, and lower mortalities occurred among patients receiving Bifidobacterium compared to patients treated with anti-ILs or antibiotics [14]. They also stated that probiotics use decreased IL-6 levels [14]. Moreover, Zhang et al. in their study among mild, moderate, and severe cases of COVID-19 found that consumption of probiotics composed of Lactobacillus, Entrococcus, and Bifidobacterium genera was associated with reduced length of hospitalization, virus shedding, and fever duration [67]. Previous studies have demonstrated that loss of Bifidobacterium in the elderly is associated with chronic diseases [29]. In addition, one review investigated the possible effects of probiotics, and signified that Bifidobacterium longum MM-2, Bifidobacterium longum BB536, Bifidobacterium animalis ssp. lactis (BB-12®), Bifidobacterium longum SPM1205, and SPM1206, and Bifidobacterium longum SP 07/3 and B. bifidum MF 20/5 are among probiotics strains that possess anti-viral features. These results were found in both in vitro, and in vivo studies as follows, suppressing uncontrolled inflammatory response, reducing virus proliferation in the lungs, increasing adaptive immune response to vaccines, and reducing episodes and severity of URTIs. In addition, many studies on Bifidobacterium indicate that this strain may be considered as a complementary therapeutic agent in suppressing cytokine storm, and uncontrolled inflammatory response in COVID-19 patients [12, 19, 42]. Therefore, Bifidobacterium appears to be helpful in combating COVID-19 infection via numerous mechanisms.

In terms of signs and symptoms of COVID-19, four studies reported that probiotics use was efficient in relieving diarrhea, cough, anosmia, weakness, preventing nosocomial diarrhea, and decreasing secondary infection [26, 38, 53, 62]. Ivashkin et al. in their RCT reported that despite relieving GI symptoms, probiotics had no meaningful effect on COVID-19 severity. Other similar studies have also reported consistent results, and reported that probiotics use is a beneficial tool for treating gut dysbiosis and improvement of GI symptoms [52]. One study reported that by using a combination of Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus tablets, a better immune function and reduced secondary bacterial or fungal infection can be achieved [32]. Moreover, one large systematic review among COVID-19 patients indicated that consumption of probiotics, prebiotics, and synbiotics, via gut/lung microbiome modulation, can shorten disease duration, and decrease its severity of symptoms including fatigue, anosmia, dyspnea, nausea, vomiting and other GI symptoms [65].

With the renowned systemic inflammatory response triggered by SARS-CoV-2, the physiological balance of the gut-brain, gut-heart, and gut-lung axis gets disrupted [11]. Thus, adequate metabolic modulation and preservation of the microbial diversity may be an additional tool to enhance innate immunity and positively modulate the inflammatory response. In a recently published review [56], Spagnolello et al., elegantly summarized the existing evidence around the onset of microbial intestinal dysbiosis in patients with COVID-19, linking the disruption in the normal intestinal flora to a dysregulated immune response [46]. Indeed, the COVID-19 infection was proven to last for a longer period of time in patients with a history of various gastrointestinal diseases [44]. Although the exact pathophysiology of this process remains unknown, potential explanatory models have been recently illustrated [60]. The process may lay in its foundation on the activation of the ACE2 receptors on the intestinal mucosa, which induces enteritis, alteration in the local T cells and B cells response, and eventually inflammatory diarrhea.

Various in vitro studies have tried to probe the positive effects of probiotics in normalizing or attenuating inflammatory responses [17, 45, 47, 48, 49]. Ezzat et al. [17] showed that a combination of Bacillus subtilis, Pseudomonas aeruginosa, and Enterococcus faecalis have meaningful antiviral effects on SARS-CoV-2. This highlights the positive effect of this probiotic polysaccharide made of D-fructose units in COVID-19 modulation, in addition to its renown roles [51]. Similarly, another in vitro study [45] showed that non-fermented milk subsequently fermented with the probiotic L. paracasei could significantly decrease the number of human enteric cells infected by the SARS-CoV-2 virus and led to lower levels of IL-1-beta, IL-6, IL-15, and Vascular Endothelial Growth Factor (VEGF) beta. Three additional in vitro studies [47, 48, 49] elucidated a similar role of other Lactobacillus species. Specifically, Lactobacillus plantarum was proven to have a meaningful effect on preventing the replication of the SARS-CoV-2 virus, probably by the means of plantarcin E and plantarcin F [47], while Lactobacillus crispatus (i.e., DSM25988) was proven to have a beneficial effect on human cells in the process of eliminating the SARS-CoV-2 virus [48]. Finally, Lactobacillus paracasei was shown to have strong antiviral effects on the SARS-CoV-2 virus by decreasing the replication of the virus per se and by enhancing the antiviral effect of lactoferrin [49]. Analogous positive effects have also been conceptually confirmed by an in silico study by Alam et al. showing that bacterial compounds extracted from Bacillus species may represent a potential source of SARS-CoV-2 protease inhibitors [3]. In vitro and in silico studies are therefore providing an increasing body of molecular evidence in support of the role of probiotics in both counteracting the life cycle of SARS-CoV-2 and modulating the relatedinflammatory response [43].

When moving from the bench to the bedside, a handful of RCTs have recently investigated the effects of certain probiotics on COVID-19 infections [16, 21, 22, 31, 63, 64]. While a variety of different probiotic types and dosages were used, thus hindering any chances of drawing meta-analytic comparisons, few considerations can be made from their results, leveraging the rigorous methodology of clinical trials. Gutierrez-Castrellon et al. [21] enrolled 300 patients with mild to moderate COVID-19 infection and supplemented them with a mix of probiotics (e.g., Pediococcus acidi lacti, Lactiplanti bacills plantarum, etc.). When compared to placebo, they reported that probiotics could shorten the duration of COVID-19-related symptoms in enrolled patients, as well as decrease the radiologic burden of disease when assessed by CT imaging. The authors speculated an association between their clinical findings and the detection of higher levels of virus-specific IgM and IgG, lower levels of high-sensitivity C-reactive protein, and overall lower levels of nasopharyngeal viral load, which are renown proxy of inflammatory response and burden of disease in COVID-19 patients [58].

Another RCT reported significantly higher remission rates among a probiotic group compared to a placebo group (53.1% vs 28.1%). [20] The results from this RCT also found that treatment was linked to lower nasopharyngeal viral load, pulmonary infiltrations, and shortened duration of symptoms, compared to a control group [20]. Another RCT demonstrated that probiotics were able to modulate the immune performance, and decrease secondary infection [32]. Moreover, in terms of COVID-19 prevention, many studies have shown that probiotics can block the Angiotensin-Converting Enzyme (ACE) receptor by binding to active sites, and thus act as a possible preventive measure against SARS-CoV-2. Also, probiotics in foods, such as dairy products can exert a potentially efficient impact to prevent COVID-19. Extensive research among infants, children, adults, and people of older age have shown that probiotic-containing fermented milk significantly reduces the incidence of URTIs [35, 37].

Analogously, Wischmeyer et al. investigated the protective role of Lactobacillus rhamnosus [64]. They enrolled 182 individuals who were self-identified as close contacts of SARS-CoV-2-positive patients. The researchers found that those who received Lactobacillus and eventually contracted COVID-19 had a prolonged latency for symptoms onset and milder symptoms compared to the placebo group. This allowed the research group to add to the existing literature on the topic [30] by hypothesizing an effective role of probiotics in the early phases of the COVID-19 infection, from the first contact to onset of typical symptoms. Interestingly, a similar clinical trial has been tailored to healthcare providers and first responders, who are at close contact with COVID-19 patients. Wang et al. [63] showed that the administration of one tablet of S. thermophiles (ENT-K12) daily for a 30-day timespan was associated with an effective prophylaxis, leading to a lower rate of respiratory tract infections, lower number of prescribed medications in the patients who eventually became infected, as well as a shorter recovery.

There is a growing body of clinical studies and RCTs supporting consumption of probiotics for the prevention and supportive treatment of patients with the SARS-CoV-2 infection. The pleiotropism of available probiotics may enhance the process of strengthening biological barriers in the gastro-intestinal tract and facilitate the homeostasis within the normal flora. In spite of the enthusiasm that surrounds the adoption of probiotics in this setting, a word of caution is warranted. Specifically, three adverse reports have been recently published showing that the efficacy and safety of certain probiotics (e.g., Salmonella enterica, Lactobacillus acidophilus, and Bacillus clausii) in this setting is contentious [30].

Conclusion

To date, the fight against COVID-19 causes and requires more interventions to manage it. Related interventions and prevention of new cases places large economic burdens on governments, and effective interventions can make disease control possible. Therefore, probiotics intake could be a complementary strategy to effectively control the disease along with the vaccines, due to their antiviral properties and their metabolites. Probiotics are considered an anti-COVID-19 strategy because of its effect on ameliorating gut microbiota and boosting response of immune host. Additionally, probiotics reduce the risk of secondary infection by making immune function moderate. Available evidence on probiotics can be utilize as a valuable source for investigating the antiviral role of probiotics in related research studies. In this review, the antiviral potential of Lactobacillus paracasei metabolite PlnE and PlnF against SARS-CoV-2 was found. Other and new types of probiotics may be considered for health promotion, disease prevention, and treatment of various diseases. More studies are needed to investigate the relationship between probiotics and the management of COVID-19.

Declarations

Ethics approval and consent to participate. Not applicable.

Consent to publication. Not applicable.

Availability of data and material. The authors stated that all information provided in this article could be shared.

Competing interests. The authors declare that there is no conflict of interest regarding the publication of this manuscript.

Funding. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgments. The present study was conducted in collaboration with Khalkhal University of Medical Sciences, Iranian Research Center for HIV/AIDS, Tehran University of Medical Sciences, and the University of Sydney.