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Probiotics: A gut response to the COVID-19 pandemic but what does the evidence show?

sciencedirect.com · added Dec 2023

Keywords
1. SARS-CoV-2 2. COVID-19 3. Gut microbiome 4. Lung microbiome 5. Probiotics
Practices
Microbiome balancing
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Summary

Probiotics have been suggested as potential prophylactics and therapeutics for COVID-19, but the current evidence is limited and inconclusive regarding their effectiveness in preventing or treating the disease.

Key points

  • Probiotic supplements may not be universally effective and safe.
  • The gut microbiome may play a role in the COVID-19 pandemic.
  • Circadian rhythms can affect gut microbiota and overall health.
  • Bacterial transmission from probiotic capsules to blood has been observed in ICU patients.
  • There is a potential link between gut microbiota and metabolic and gastrointestinal pathology.
  • The interaction between drugs and the gut microbiome is an important consideration.
  • The gut microbiome can affect drug metabolism.
  • The gut microbiome is involved in maintaining barrier integrity in the colon.
  • Saccharomyces cerevisiae var. boulardii fungemia has been reported following probiotic treatment.
  • Bacteremia from probiotics has been observed in some cases.

Summary

Since the global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), research has focused on understanding the etiology of coronavirus disease 2019 (COVID-19). Identifying and developing prophylactic and therapeutics strategies to manage the pandemic is still of critical importance. Among potential targets, the role of the gut and lung microbiomes in COVID-19 has been questioned. Consequently, probiotics were touted as potential prophylactics and therapeutics for COVID-19. In this review we highlight the role of the gut and lung microbiome in COVID-19 and potential mechanisms of action of probiotics. We also discuss the progress of ongoing clinical trials for COVID-19 that aim to modulate the microbiome using probiotics in an effort to develop prophylactic and therapeutic strategies. To date, despite the large interest in this area of research, there is promising but limited evidence to suggest that probiotics are an effective prophylactic or treatment strategy for COVID-19. However, the role of the microbiome in pathogenesis and as a potential target for therapeutics of COVID-19 cannot be discounted.

**Keywords: **SARS-CoV-2COVID-19Gut microbiomeLung microbiomeProbioticsRespiratory tract infectionsSupplements

1. Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first identified in the city of Wuhan, China, in November 2019 is responsible for the coronavirus disease 2019 (COVID-19) that has resulted in almost 6.5 million deaths and over 600 million confirmed cases across the globe [1]. While vaccines have lowered the risk of death, hospitalization, and to some extent infection, the hunt for additional prophylactics and therapeutics is still ongoing. Among these, probiotics were deemed of interest due to their potential immunomodulatory and anti-inflammatory effects, as well as their putative protective effects against viral diseases [2,3]. Probiotics are generally defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit to the host” [4], although it should be noted that multiple definitions exist that are interpreted in various ways [5]. These discrepancies have contributed to differing regulation regarding probiotics in Europe and North America [6]. Despite these regulatory issues, interest surrounding probiotics and their potential benefits have not waned and probiotics are among the main products intentionally consumed by humans to beneficially affect the gut microbiome to improve health [7,8]. Research has continued to grow over the last decade with a fivefold increase in the number of publications published between 2010 and 2021 in PubMed alone relating to “probiotics”. Indeed, over 300 manuscripts have been published on COVID-19 and probiotics alone since the emergence of the pandemic [9]. Among the areas of research being investigated, probiotics administration and their potential effects on the gut microbiome and subsequent health and protection against respiratory infections has been explored.

The human microbiome is the sum of all microbiotas present in our tissues and fluids. The microbiome is composed of diverse bacteria (bacteriome), fungi (mycobiome), protozoa, and even viruses (virome). The human gut microbiome alone accounts for a collection of between 100 million to 100 trillion commensal microorganisms [10], which feed on fiber, a crucial dietary component that has the potential to influence host immune health [[11], [12], [13]]. Exploration of the human microbiome has led to important discoveries in brain and neurological diseases, mood, depression [14,15] and various noncommunicable diseases. The microbiome provides a unique highway of communication between the gut and the lungs via the circulatory system [[16], [17], [18], [19]], whereby the gut-lung axis has been linked to asthma [20] and various respiratory diseases [21,22]. Indeed, COVID-19 has also been linked to the gut-lung axis [23].

Coronaviruses that affect humans are generally associated with respiratory infections, and occasionally the gastrointestinal tract [24]. Angiotensin-converting enzyme 2 (ACE2) is the cellular gateway of the SARS-CoV-2 spike protein [24]. A recent study by Xu et al. conducted retrospective analysis of bulk tissue RNA of the digestive tract organs and lungs from a public database and observed that the digestive tract had higher ACE2 expression levels compared to the lung, and the expression of ACE2 in the lung increased with age [25]. In the gut, SARS-CoV-2 targets both the proximal and distal enterocytes [26] and there is evidence that SARS-CoV-2 can be prevalent in the mucous membranes of the oesophagus, stomach, and tissues of the small and large intestines [27,28]. Therefore, it is not surprising that SARS-CoV-2 infection induces gastrointestinal symptoms in adults and children [29,30]. Factors that affect gut health may also have negative consequences for a patient's nutritional status, which is now under investigation in relation to COVID-19 [31]. Indeed, many host factors can affect the microbiome including one's health, diet, exercise, and lifestyle choices [32,33].

SARS-CoV-2 enters the host via the respiratory system, which may implicate the lung microbiome in the etiology of COVID-19 [34]. Indeed, this has led researchers to question the role of the gut-lung axis and how its modulation may affect COVID-19 outcomes [35]. The aim of this review is to provide an update and cast a critical eye on the current state of research regarding the gut-lung axis in relation to the microbiome, probiotics, nutritional status, and their interactions in relation to COVID-19. Additionally, we discuss the current state of clinical trials investigating the modulation of the gut and lung microbiome via probiotics administration in humans. We highlight the need for a greater understanding of how probiotics affect the gut microbiome and immune function in response to viral infections.

2. The gut-lung microbiome axis and COVID-19

Attenuating the gut and/or lung microbiome is a strategy that has been previously explored for viral infections. Research has shown that lactic acid bacteria (LAB) can be used to treat oral [36], vaginal [37,38], and gastrointestinal infections [39] in animal and human studies. Probiotics have also been shown to be effective against respiratory infections. Administration of Lactobacillus gasseri to mice reduced respiratory syncytial virus (RSV) viral titers, increased interferon I and II, and decreased cytokines in the lung [40]. The latter findings are in agreement with other studies that suggest nasal and oral administration of LAB may exert anti-inflammatory effects against RSV in mice [41,42].

Considering nasal and oral routes of probiotic administration may be beneficial against viral infection in vivo, some speculate a mechanistic role for the gut-lung axis in amelioration of respiratory viral infections. As alluded to, microbial metabolites can affect host health on a system level by producing vital metabolic byproducts from dietary components [43,44]. One of the most studied of these microbiome-derived metabolites for their potential human health benefits are short chain fatty acids (SCFA), such as acetic acid, butyric acid, and propionic acid. SCFA act as the main sources of energy for intestinal epithelial cells and thereby help to strengthen the immune system through Toll-like receptor (TLR) expression, differentiation of T cells including CD4+ T cells, and antibody expression [16]. Butyrate has been touted as a potential therapy to prevent the development of ARDS and the cytokine storm via immune response modulation and potentially proresolving factors [45]. In accordance, depletion of butyrate-producing microbiota may also be linked to a potential increased risk of COVID-19 in hypertension patients via down regulating pathways integral to SARS-CoV-2 infection, upregulating antiviral and TLR related genes, and modulating Ace2 and Tmprss2 gene expression as demonstrated in a gut epithelium organoid model [46]. Although these findings have not been validated in human studies, there is evidence that the gut microbiome of COVID-19 patients have impaired capacity to produce SCFA, which persists into recovery and correlates with host immune responses [47]. Contrariwise, some in vitro evidence casts doubt on the benefits of SCFA in the prevention of SARS-CoV-2 infection in gut tissue [48]. Though promising, alteration of the gut microbiome to favor synthesis of SCFA requires further research.

Because alterations to the gut microbiome have been previously implicated in the outcomes of patients with viral infections [[49], [50], [51]], the scientific community speculates that there could be a strong link associated with the risk factors for COVID-19 driven by poor diet consisting of high saturated fat, high sugar, refined carbohydrates and lesser amounts of fibers, unsaturated fat, and polyphenols, leading to a dysbiosis in gut microbial community [[52], [53], [54]]. Dysbiosis is a mechanism whereby an imbalance of the microbiome occurs because of disruption of the microbiota homeostasis. Many factors including host genetics, diet, supplementation, stress, infection, and/or medical interventions (such as antibiotics) influence the microbial community at compositional and functional levels [55]. The gut microbiome affects pulmonary health through a crosstalk via the gut-lung axis [[56], [57], [58], [59]]. Consequently, the role of the gut and lung microbiomes in SARS-CoV-2 infection susceptibility and COVID-19 severity and their modulation by probiotics are under investigation.

A systematic review of COVID-19 and the microbiome determined that the human fecal microbiomes were altered by COVID-19, which was characterized by a greater prevalence of opportunistic pathogens [34]. The presence of such pathogens is a concern due to the potential for further dysbiosis or nosocomial infections. These findings are important, because it is known that the commensal microbiota can modulate virus-specific adaptive immune responses. Several studies have shown that germ free mice or mice orally treated with antibiotics have impaired responses to systemic and respiratory infections [[60], [61], [62], [63]]. Numerous mechanisms have been proposed for how the microbiome may prime the lungs to control respiratory infections including production of type I interferons (IFNs) [[64], [65], [66]] or modulation of adaptive immune responses via activation of CD4+ and CD8+ T cells [67].

3. Targeting the gut-lung microbiome axis and its clinical significance

The oropharynx and gastrointestinal tract are physiologically interlinked and share similar microbial compositions, albeit the lung microbiota has a significantly lower biomass than the gut microbiota whose diversity depends on the conditions in the entire respiratory tract [19,68]. There has been no shortage of studies demonstrating a link between lung health and the lung and gut microbiomes [19,[68], [69], [70], [71]]. As discussed, the microbiota and their metabolites play an important role in the development of the immune system both locally and systemically. However, alterations to the gut microbiome by diet, medical interventions or disease has been shown to alter immune responses to the respiratory system [72]. It is irrefutable that an individual's diet and lifestyle contributes to a person's risk of non-communicable diseases [[73], [74], [75]]. The same is true of how nutritional status contributes to one's susceptibility to acute illnesses such as infectious diseases [76,77] as nutritional status is interlinked with immune function [78]. Indeed, deficiency of a single nutrient may weaken immune function [79]. There is already emerging evidence that a patient's nutritional status is an important factor in COVID-19 [31,[80], [81], [82]]. A bidirectional relationship exists, whereby the gut microbiome affects nutritional status and vice versa [83,84], which likely affects COVID-19 risk [85]. These links are mediated by metabolites generated by gut microbiota in response to factors such as nutrition or drug intake. These metabolites can act locally and systemically to affect multiple systems, including the respiratory system [72]. Therefore, the maintenance of the gut microbiome prior to, during, and post COVID-19 through appropriate dietary and therapeutic measures is critical for positive patient outcomes and recovery [51,86]. As a consequence, several guidelines have been devised to promote COVID-19 patient recovery [87].

In COVID-19 patients, several studies show that the lung [23,88,89] and gut microbiota [30,50] composition is altered versus non-COVID-19 patients, which in the case of the gut at least seems to stratify according to disease severity [51]. Depletion of the gut microbiome is associated with immune modulation and can remain low for up to 30 days [51]. In some cases, gut dysbiosis can persist six-months post infection [90]. This is important as gut dysbiosis has been linked to dysbiosis in the lung microbiome, both in animal studies and in humans and may potentially have long-term gut and lung health implications [21,[91], [92], [93]].

A systematic review highlighted that the majority of existing studies have determined that both the upper and lower respiratory tract microbiome is altered by COVID-19. These alterations are characterized by a greater prevalence of opportunistic pathogens [22]. Therefore, it is no surprise that studies have shown that respiratory tract co-infections are common among COVID-19 patients [[94], [95], [96]]. In the upper respiratory tract, it has been reported that pathogenic Candida albicans, human alpha-herpesvirus, RSV, and influenza were in abundance [94]. Other studies have also confirmed the presence of RSV and influenza A/B, along with rhinoviruses and enteroviruses in abundance [95]. These findings also highlight that fungal dysbiosis is prevalent in COVID-19 patients. Indeed, this is important considering the emerging role of the mycobiome and fungal dysbiosis as a contributor to immune dysregulation in infectious diseases [97] immune system development [98].

Host transcriptomics show that severe COVID-19 patients that develop secondary bacterial infections such as ventilator-associated pneumonia (VAP) may have respiratory microbiome disturbances and impaired antibacterial immune defenses before infection onset. Which begs the question whether point-of-care prognostic tools may be developed to predict VAP prior to occurrence [99]. Indeed, one study has shown sampling on arrival to either the Emergency Department or COVID-19 unit of one hospital was predictive of the need for respiratory support. An oropharyngeal microbiome denoted by a reduced abundance of Prevotella* salivae* and metabolic pathways associated with mycolic acid and liposaccharide biosynthesis appeared to be of prognostic value [100]. Severe COVID-19 patients also experience acute respiratory distress syndrome (ARDS) [101], which induces the production of pro-inflammatory cytokines such as TNF-a, IL-10, IL-7, IL-2, MCP1 and others that can cause extensive organ damage [102]. Studies prior to the pandemic have shown that certain gut microbiome colonization patterns are associated with these same inflammatory markers [103] indicating a potential role of the gut microbiome in ARDS.

Gut dysbiosis appears to be a common clinical feature of COVID-19 patients [104] and has been correlated with IL-18 detection in fecal material, which is unique to COVID-19 patients [105]. COVID-19 patients also have 3-fold increase in fungal diversity and pathogens from the genus Aspergillus in the gut*.* More severe COVID-19 symptoms were associated with patients who had high abundance of more than two Aspergillus pathogens. Despite nasopharyngeal clearance of SARS-CoV-2 these fungi were found to be present in the feces, hinting to persistent colonization of fungal pathogens and a potential threat to the host in the longer term [106]. The same study found that there was an increase in the opportunistic pathogens over beneficial commensals, which is in accordance with previous studies [34].

It is also important to recognize that pre-existing conditions play a role in COVID-19 outcomes [24]. Inflammatory diseases such as inflammatory bowel disease (IBD), colon cancer, and even diseases such as rheumatoid arthritis and liver cirrhosis have been associated with microbial translocation along the oral–gut axis [107]. This implies that microbes from either the gut or lung may have the capacity to translocate to each other or different organs that may affect COVID-19 outcomes and may have long-term health implications.

4. Investigation of probiotics for COVID-19 mitigation in clinical trials

The popularity of probiotics has increased over the last two decades, and they have been investigated during the pandemic due to the putative health benefits [108,109]. Several authors have speculated that prebiotics/probiotics may prevent and/or treat COVID-19 [16,86,[110], [111], [112], [113], [114], [115]] via modulation of the gut microbiota and the gut-lung axis. Previous studies have shown a beneficial effect of probiotic intake against some respiratory infections [[116], [117], [118]], potentially through immunomodulatory effects [2,3] and anti-inflammatory effects [119,120]. Probiotics may even enhance the antibody response generated by immunization [[121], [122], [123], [124]]. To date, there have been few clinical trials published (Table 1) investigating the potential therapeutic role of probiotics in relation to COVID-19. However, there are over 25 registered clinical trials that aim to investigate the biological and therapeutic roles of probiotic administration on COVID-19 management (Table 2).

Table 1. Published studies investigating the administration of probiotics and their effects on SARS-CoV-2 transmission, infection, COVID-19, and related post sequelae.

Abbreviations: ICU = Intensive care unit; SOC = Standard of care.

Table 2. A summary of some of the randomized controlled trials registered in ClinicalTrials.gov underway or recruiting that are investigating the application of probiotics for the prevention and/or treatment of COVID-19.

Various individual species and formulations of probiotics are thought to affect immune function [120,125], which may also affect COVID-19 outcomes, which is reflected in the combinations of probiotics administered to patients in both Table 1 and in Table 2. In general, the majority of probiotics utilized consist of lactic acid bacteria (LAB) including Lactobacillus and Bifidobacterium. LAB have long been touted as potential immune modulators and as such are the obvious choice to investigate.

Of the limited published trials to date (Table 1), the main findings as a result of probiotic administration appears to be a more rapid improvement of symptoms, reduced fatigue, and potentially resolution of gastrointestinal issues. Gutiérrez-Castrellón, Gandara-Martí [126] observed more rapid recovery (p < 0.0001) and shortening of symptom duration following administration of a probiotic (n = 147; Lactiplantibacillus plantarum KABP022, KABP023, and KAPB033, and Pediococcus acidilactici KABP021) versus placebo (n = 146) in a 30-day intervention in a blinded, randomized, placebo-controlled trial. Zhang, Han (129) retrospectively analyzed the efficacy of a probiotic (Bifidobacterium, Lactobacillus, and Enterococcus - detailed breakdown unavailable) administered to 196 COVID-19 patients receiving standard of care (SOC) versus a matched cohort of patients receiving SOC alone (n = 179). They noted an improved time to clinical improvement (p < 0.022), reduced hospital stay length (p = 0.009), and shorter time to RNA clearance measured via throat swabs (p < 0.001) in the treatment group. In accordance with these findings, Li, Cheng (130) reported a moderate reduction of in-patients days (p < 0.001) and shorter time to viral RNA clearance in throat swabs (p < 0.001) in COVID-19 patients receiving various probiotic formulations (n = 123) versus SOC (n = 188) in another retrospective study. In a preprint, Rathi, Jadhav [127] also reported improvements in patients receiving probiotics and an enzyme supplement. Indeed, 91/100 COVID-19 patients that received a probiotic (Bacillus coagulans, Bacillus subtilis, and Bacillus clausii) reported less physical and mental fatigue versus 15/100 placebo patients by day 14 of treatment (p < 0.001). However, it is not known whether these effects are a result of the probiotic or enzyme treatment or a combination of both. These studies together indicate that there may be a modest benefit of probiotic supplementation on time to patient recovery. However, blinded, randomized, placebo-controlled clinical trials are required to confirm these findings. In another trial that have been published (Table 1) [131], gastrointestinal symptoms appeared to improve (p < 0.049) and less frequent hospital-acquired diarrhea occurred (p < 0.023) in COVID-19 patients that received a probiotic (n = 99) versus those that received a placebo (n = 101) in a randomized, placebo-controlled trial. However, the aforementioned study by Li, Cheng (130) found that those who had received a probiotic (albeit a different formulation) required a longer duration of antibiotic treatment to recover from diarrhea.

5. Proposed mechanisms of action for probiotics in COVID-19

The studies discussed in this review indicate that there may be some benefits to probiotic administration but considering the current pandemic and the progress made on existing therapeutics [132] it is not known whether probiotics may impact patient outcomes. Despite the many potential mechanisms already discussed in this review, a clearer understanding of the implicated mechanisms of action of probiotics to alleviate COVID-19 symptoms are not yet studied in detail. However, a few published studies speculate and/or provide insight into the role of bioactive compounds produced by probiotic bacteria in COVID-19 management as depicted in Fig. 1. Apart from the mechanisms of anti-inflammatory action, immune modulation, and modulation of the microbiome previously discussed, probiotics may also inhibit the binding of SARS-CoV-2 to its receptor via bacteriocins. Bacteriocins are antimicrobial peptides or proteins synthesized by Gram-positive and Gram-negative bacteria commonly found in fermented foods and currently under investigation as potential food additives and antimicrobial therapeutic agents [133,134]. An in-silico study by Anwar et al. [135] used protein modeling to propose a mechanism of action for metabolic products of Lactobacillus plantarum in COVID-19 management. Using a molecular dynamics simulation model, the study suggested that Plantaricin (Pln) W, D, and JLA-9- compounds inhibit the entry of SARS-CoV-2 by blocking ACE2 receptors and virus transcription by targeting the S protein and blocking RNA polymerase (RdRp). Additionally, in vitro study by Rather, Choi (136) showed reduction in SARS CoV-2 viral titers post treatment with cell free supernatant from L. plantarum- Probio-88. Furthermore, molecular docking by Rather et al. predicted that PlnE and PlnF from L. plantarum could inhibit the SARS CoV-2 replication by binding at either ssRNA or ATP binding sites of helicase. Molecular docking studies have also indicated the potential of pediocin PA-1, salivaricin P, and salivaricin B to bind with the SARS-CoV-2 spike protein receptor-binding domain, thereby inhibiting viral entry into host cells [137]. Considering endogenous microbial peptides such as cathelicidin are under investigation for their effects on SARS-CoV-2 infection [82], further studies of administration of antimicrobial peptides or probiotics are warranted.

  1. Download : Download high-res image (677KB)
  2. Download : Download full-size image Fig. 1. Bacteriocins such as plantaricin secreted by probiotic bacteria such as L. plantarum are predicted to be involved in inhibiting SARS-CoV-2 entry and replication. Molecular docking studies have projected that the plantaricin construct may obstruct the entry of the virus by targeting S protein or bind to the RNA-dependent RNA polymerases (RdRP) thereby impeding transcription of the genome.

6. Future perspectives on probiotics and COVID-19

Moving forward, there are several factors trialists should consider in relation to the gut microbiome, probiotics, COVID-19. For instance, it is important to consider the intervention duration while studying the effects of dietary strategies, treatments or interventions on the gut microbiota because the gut microbiota responds rapidly to short-term dietary alterations, however, long-term dietary interventions may only maintain microbiota changes if the intervention becomes habitual, due to the fact that ceasing the intervention can cause the microbiota composition to revert back to pre-intervention composition [138]. This concept explains the “responder/non-responder” phenomenon, which is based on the changes of an individual's gut microbiota in response to prebiotic interventions [139,140].

The utility of prebiotics and synbiotics has also largely been neglected. Prebiotics are fibers including various oligosaccharides provided by foods or supplements that promote the growth or activity of healthy microorganisms in the gut. On the other hand, synbiotics are a mixture of both probiotics and prebiotics that can be ingested via foods or supplements with intended health benefits [141]. To date, the beneficial effects of prebiotic, probiotic, and synbiotics on the host's antiviral response have mostly focused on the intestinal tract with limited evidence on their ability to modulate responses in distant respiratory mucosal sites.

Another notable issue is that the ongoing clinical trials have used bacterial formulations capable of eliciting specific anti-inflammatory and antiviral activities [142,143]. However, studies have shown that not all probiotics are created equal, nor do they elicit the same immune benefits. For example, L. plantarum CRL1506 stimulates antiviral intestinal immunity, however, is incapable of modulating respiratory antiviral immune response [144,145]. Therefore, results between trials are not always directly transferable or interpretable to other bacterial preparations and there may be considerable heterogeneity between trial outcomes. Depending on the delivery mechanisms, which is generally oral consumption, some probiotics may be prone to degradation by the digestive system, hence why novel methods of probiotic delivery are being assessed [146]. Indeed, next-generation probiotics, which are probiotic formulations more akin to pharmaceutical-grade supplements, are also being investigated for various conditions, but have yet to be fully explored for COVID-19 [86,146].

Additionally, while inferring the results of clinical trials (Table 1, Table 2) it is important to be aware of confounding factors such as various age groups with different immune system statuses, the season of the year, doses of probiotics, nutritional status, other supplements being consumed, etc. Therefore, a more targeted approach may be warranted, whereby a patients gut microbiota profile is sequenced at a bacterial strain level to fully address the role of the microbiota and their interactions between diet and extrinsic stressors against SARS-CoV-2 infection. This level of diagnostic capacity could potentially lead to personalized treatments or formulations of probiotics or next-generation probiotics in the future.

An important question is if these probiotics, probiotics, and synbiotics can be used for preventive or therapeutic interventions? None of the published studies have reported using these immunobiotics for the management of COVID-19. Considering the fact that people with co-morbidities are at higher risk of worse outcomes post SARS-CoV-2 exposure, these bacterial formulations should be considered to strengthen the immune response of healthy and at-risk populations rather than a therapeutic measure. People with comorbidities, old age, nightshift, and jetlag are more susceptible to disease progression owing to disrupted circadian rhythms and vice-versa [[147], [148], [149]]. Recent studies have shown that host circadian rhythms influence the outcomes of respiratory infections [150,151]. One cannot ignore a tripartite crosstalk between circadian rhythm, commensals and viral infections while considering microbial formulations as a supplement for COVID-19 management [152], especially since patients in intensive care units suffer from circadian rest/activity misalignment [153], which may affect the microbiome and lead to severe disease outcomes.

Probiotics are not a panacea for the treatment of COVID-19, but their potential modulation of the gut microbiome may beneficially or negatively affect the efficacy and bioavailability of some drugs, including those that were on trial for treatment of COVID-19. It is important to consider the role of the microbiome and its interactions with drug metabolism and pharmacokinetics [154,155]. Some drugs are metabolized by the microbiome and therefore their efficacy and bioavailability may be affected [156]. Some drugs negatively affect the microbiome [157]. For example, tocilizumab, an anti-IL-6 monoclonal antibody used to treat ARDS in COVID-19 that may affect the microbiome. Individuals with diverticular disease, a disease known to alter the gut microbiome, are at higher risk of lower intestinal perforation when medicated with tocilizumab [158]. Indeed, IL-6 deficient mice also have thinning of the mucus layers and impaired gut-epithelial barrier function [159]. This indicates that COVID-19 patients treated with tocilizumab may impair gut-epithelial barrier function via IL-6 depletion. Therefore, these patients may be candidates to receive probiotic treatments to ameliorate dysbiosis induced by both COVID-19 and resulting treatments. In fact, it is largely unknown what effects other medications targeting COVID-19 may have on microbiota, thus further research is required.

The efficacy and the safety of probiotics has been contentious in the literature. For example, a case report on a immunocompromised patient showed development of fungemia as a result of treatment of antibiotic-associated pseudomembranous colitis with the probiotic Saccharomyces cerevisiae var. Boulardii [160]. Another report presented a clinically significant bacteremia in immunocompromised patients who received Bacillus clausii [161]. A clinical study conducted at Boston Hospital showed alarming results of developing Lactobacillus bacteremia in ICU patients who received Lactobacillus rhamnosus strain GG (LGG) probiotics [162]. Moreover, Kothari et al. have written an exhaustive review on deleterious effects of administration of probiotics that were not only limited to localized and opportunistic infections but also resulted in sepsis, ischemia, infective endocarditis, and horizontal transfer of antibiotic resistant genes [163]. At the time of writing, there is no direct evidence that probiotics or their metabolites or bioactive compounds attenuate the complex symptoms related to COVID-19.

Probiotics also come in various compositions and so it is likely that multiple mechanisms contribute to some of the observed benefits of their administration against respiratory infections and COVID-19. However, determining the most effective composition and concentration will be important if probiotics are to be used in COVID-19 treatment. Formulations may also need to be adjusted depending on the symptoms. Indeed, a formulation that may be beneficial for one patient could be detrimental to another. Therefore, considerably more research is required.

Among the limited studies published to date, there appears to be some promising but mixed results for the use of probiotics in hospitalized COVID-19 patients. Indeed, many of the trials that have been registered (Table 2) are further investigating the potential therapeutic benefits of co-administering probiotics with SOC. Until these findings have been published, it is not possible to provide evidence-based recommendations for the administration of probiotics to patients and therefore, we conclude that probiotics have not yet been shown to be substantially effective against COVID-19 to warrant inclusion in COVID-19 treatment plans. However, complementary use of probiotics as an adjuvant treatment may be used cautiously for the enhancement of antiviral defenses and prevention of secondary microbial infections as was previously proposed by the Chinese health authorities [164]. Further research is required to discern the role of the microbiome in the gut-lung axis and the role of probiotics in the prevention and treatment of SARS-CoV-2 and COVID-19 and the modulation of the gut and lung microbiomes.

Author contributions

Conceptualization, R.L.; writing—original draft preparation, S.B., A.N., and R.L.; writing—review and editing, S.B., A.B., and R.L.; Visualization, A.N; project administration and supervision, R.L. All authors have read and agreed to the published version of the manuscript.

Declaration of Competing Interest

The authors have no conflicts of interest to declare. This study did not receive funding.

Acknowledgments

A.N. and R.L. would like to thank the Children's Hospital of Philadelphia, the Institute for Translational Medicine and Therapeutics, and the Perelman School of Medicine for their continued support. Figure created using Biorender.

References

  1. [1]John Hopkins UniversityJohn Hopkins University & Medicine: Coronavirus Resource Center(2020)Available from:https://coronavirus.jhu.edu/map.htmlGoogle Scholar
  2. [2]E.-J. Kang, S.Y. Kim, I.-H. Hwang, Y.-J. JiThe effect of probiotics on prevention of common cold: a meta-analysis of randomized controlled trial studiesKorean J Fam Med, 34 (1) (2013), pp. 2-10View article CrossRefView in ScopusGoogle Scholar631430
  3. [3]O. Kanauchi, A. Andoh, S. AbuBakar, N. YamamotoProbiotics and paraprobiotics in viral infection: clinical application and effects on the innate and acquired immune systemsCurr Pharmaceut Des, 24 (6) (2018), pp. 710-717View article CrossRefView in ScopusGoogle Scholar13601140
  4. [4]C. Hill, F. Guarner, G. Reid, G.R. Gibson, D.J. Merenstein, B. Pot, *et al.*Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probioticNat Rev Gastroenterol Hepatol, 11 (8) (2014), pp. 506-514 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar5,590173,3722
  5. [5]G. ReidProbiotics: definition, scope and mechanisms of actionBest Pract Res Clin Gastroenterol, 30 (1) (2016), pp. 17-25View PDFView articleView in ScopusGoogle Scholar
  6. [6]G.T. Rijkers, W.M. de Vos, R.-J. Brummer, L. Morelli, G. Corthier, P. MarteauHealth benefits and health claims of probiotics: bridging science and marketingBr J Nutr, 106 (9) (2011), pp. 1291-1296View in ScopusGoogle Scholar
  7. [7]M.E. Sanders, F. Guarner, R. Guerrant, P.R. Holt, E.M. Quigley, R.B. Sartor, *et al.*An update on the use and investigation of probiotics in health and diseaseGut, 62 (5) (2013), pp. 787-796View article CrossRefView in ScopusGoogle Scholar41502680
  8. [8]B. Sánchez, S. Delgado, A. Blanco-Míguez, A. Lourenço, M. Gueimonde, A. MargollesProbiotics, gut microbiota, and their influence on host health and diseaseMol Nutr Food Res, 61 (1) (2017), Article 1600240View in ScopusGoogle Scholar
  9. [9]NIH. PubMed 2022 [Available from: https://pubmed.ncbi.nlm.nih.gov.Google Scholar
  10. [10]J.K. Nicholson, E. Holmes, J. Kinross, R. Burcelin, G. Gibson, W. Jia, *et al.*Host-gut microbiota metabolic interactionsScience, 336 (6086) (2012), pp. 1262-1267View article CrossRefView in ScopusGoogle Scholar3,512412,6103
  11. [11]L.K. Ursell, J.L. Metcalf, L.W. Parfrey, R. KnightDefining the human microbiomeNutr Rev, 70 (Suppl 1) (2012), pp. S38-S44 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar75825310
  12. [12]E. Thursby, N. JugeIntroduction to the human gut microbiotaBiochem J, 474 (11) (2017), pp. 1823-1836View in ScopusGoogle Scholar
  13. [13]A.R. Hoffmann, L.M. Proctor, M.G. Surette, J.S. SuchodolskiThe microbiome:the trillions of microorganisms that maintain health and cause disease in humans and companion animalsVet Pathol, 53 (1) (2016), pp. 10-21 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar740200
  14. [14]L. Klingelhoefer, H. ReichmannPathogenesis of Parkinson disease—the gut–brain axis and environmental factorsNat Rev Neurol, 11 (11) (2015), pp. 625-636View article CrossRefView in ScopusGoogle Scholar45982861
  15. [15]J.F. Cryan, K.J. O'Riordan, C.S.M. Cowan, K.V. Sandhu, T.F.S. Bastiaanssen, M. Boehme, *et al.*The microbiota-gut-brain AxisPhysiol Rev, 99 (4) (2019), pp. 1877-2013 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar2,05891,5310
  16. [16]L. Conte, D.M. ToraldoTargeting the gut–lung microbiota axis by means of a high-fibre diet and probiotics may have anti-inflammatory effects in COVID-19 infectionTher Adv Respir Dis, 14 (2020), Article 1753466620937170Google Scholar
  17. [17]B. Aktas, B. AslimGut-lung axis and dysbiosis in COVID-19Turk J Biol, 44 (3) (2020), pp. 265-272View article CrossRefView in ScopusGoogle Scholar10711110
  18. [18]D. Dhar, A. MohantyGut microbiota and Covid-19- possible link and implicationsVirus Res, 285 (2020), Article 198018View PDFView articleView in ScopusGoogle Scholar
  19. [19]R. Enaud, R. Prevel, E. Ciarlo, F. Beaufils, G. Wieërs, B. Guery, *et al.*The gut-lung Axis in health and respiratory diseases: a place for inter-organ and inter-kingdom crosstalksFront Cell Infect Microbiol, 10 (9) (2020)Google Scholar
  20. [20]W. Barcik, R.C.T. Boutin, M. Sokolowska, B.B. FinlayThe role of lung and gut microbiota in the pathology of asthmaImmunity, 52 (2) (2020), pp. 241-255View PDFView articleView in ScopusGoogle Scholar
  21. [21]A. Dumas, L. Bernard, Y. Poquet, G. Lugo-Villarino, O. NeyrollesThe role of the lung microbiota and the gut–lung axis in respiratory infectious diseasesCell Microbiol, 20 (12) (2018), Article e12966View article CrossRefView in ScopusGoogle Scholar28982340
  22. [22]K.F. Budden, S.L. Gellatly, D.L.A. Wood, M.A. Cooper, M. Morrison, P. Hugenholtz, *et al.*Emerging pathogenic links between microbiota and the gut–lung axisNat Rev Microbiol, 15 (1) (2017), pp. 55-63 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar88878380
  23. [23]G.L.V. de Oliveira, C.N.S. Oliveira, C.F. Pinzan, L.V.V. de Salis, CRdB. CardosoMicrobiota modulation of the gut-lung Axis in COVID-19Front Immunol, 12 (2021)Google Scholar
  24. [24]H.M. Rando, A.L. MacLean, A.J. Lee, R. Lordan, S. Ray, V. Bansal, *et al.*Pathogenesis, symptomatology, and transmission of SARS-CoV-2 through analysis of viral genomics and structuremSystems, 6 (5) (2021), p. e0009521Google Scholar
  25. [25]J. Xu, M. Chu, F. Zhong, X. Tan, G. Tang, J. Mai, *et al.*Digestive symptoms of COVID-19 and expression of ACE2 in digestive tract organsCell Death Dis, 6 (2020), p. 76View article CrossRefGoogle Scholar2000
  26. [26]W. Liang, Z. Feng, S. Rao, C. Xiao, X. Xue, Z. Lin, *et al.*Diarrhoea may be underestimated: a missing link in 2019 novel coronavirusGut, 69 (6) (2020), pp. 1141-1143View article CrossRefView in ScopusGoogle Scholar33763133
  27. [27]K.S. Cheung, I.F.N. Hung, P.P.Y. Chan, K.C. Lung, E. Tso, R. Liu, *et al.*Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong cohort: systematic review and meta-analysisGastroenterology, 159 (1) (2020), pp. 81-95View PDFView articleView in ScopusGoogle Scholar
  28. [28]L. Lin, X. Jiang, Z. Zhang, S. Huang, Z. Zhang, Z. Fang, *et al.*Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infectionGut, 69 (6) (2020), pp. 997-1001View article CrossRefView in ScopusGoogle Scholar758217952
  29. [29]A. Pizuorno, H. Brim, H. AshktorabGastrointestinal manifestations and SARS-CoV-2 infectionCurr Opin Pharmacol, 61 (2021), pp. 114-119View PDFView articleView in ScopusGoogle Scholar0000
  30. [30]S. VillapolGastrointestinal symptoms associated with COVID-19: impact on the gut microbiomeTransl Res, 226 (2020), pp. 57-69View PDFView articleView in ScopusGoogle Scholar
  31. [31]D.P. Richardson, J.A. LovegroveNutritional status of micronutrients as a possible and modifiable risk factor for COVID-19: a UK perspectiveBr J Nutr, 125 (6) (2021), pp. 678-684View article CrossRefView in ScopusGoogle Scholar780621
  32. [32]A. Kurilshikov, C. Medina-Gomez, R. Bacigalupe, D. Radjabzadeh, J. Wang, A. Demirkan, *et al.*Large-scale association analyses identify host factors influencing human gut microbiome compositionNat Genet, 53 (2) (2021), pp. 156-165View article CrossRefView in ScopusGoogle Scholar473143140
  33. [33]J.M. Allen, L.J. Mailing, G.M. Niemiro, R. Moore, M.D. Cook, B.A. White, *et al.*Exercise alters gut microbiota composition and function in lean and obese humansMed Sci Sports Exerc, 50 (4) (2018), pp. 747-757View article CrossRefView in ScopusGoogle Scholar457244533
  34. [34]S. Yamamoto, M. Saito, A. Tamura, D. Prawisuda, T. Mizutani, H. YotsuyanagiThe human microbiome and COVID-19: a systematic reviewPLoS One, 16 (6) (2021), Article e0253293View article CrossRefView in ScopusGoogle Scholar9510770
  35. [35]O. Spagnolello, C. Pinacchio, L. Santinelli, P. Vassalini, G.P. Innocenti, G. De Girolamo, *et al.*Targeting microbiome: an alternative strategy for fighting SARS-CoV-2 infectionChemotherapy, 66 (1–2) (2021), pp. 24-32 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar220120
  36. [36]M.L. CrossMicrobes versus microbes: immune signals generated by probiotic lactobacilli and their role in protection against microbial pathogensFEMS Immunol Med Microbiol, 34 (4) (2002), pp. 245-253View PDFView articleView in ScopusGoogle Scholar
  37. [37]R. Zabihollahi, E. Motevaseli, S.M. Sadat, A.R. Azizi-Saraji, S. Asaadi-Dalaie, M.H. ModarressiInhibition of HIV and HSV infection by vaginal lactobacilli in vitro and in vivoDaru, 20 (1) (2012), p. 53 View PDF  This article is free to access.View in ScopusGoogle Scholar
  38. [38]C. Conti, C. Malacrino, P. MastromarinoInhibition of herpes simplex virus type 2 by vaginal lactobacilliJ Physiol Pharmacol, 60 (Suppl 6) (2009), pp. 19-26View in ScopusGoogle Scholar
  39. [39]P. Baindara, R. Chakraborty, Z.M. Holliday, S.M. Mandal, A.G. SchrumOral probiotics in coronavirus disease 2019: connecting the gut–lung axis to viral pathogenesis, inflammation, secondary infection and clinical trialsNew Microb and New Infect, 40 (2021), Article 100837View PDFView articleView in ScopusGoogle Scholar0000
  40. [40]K. Eguchi, N. Fujitani, H. Nakagawa, T. MiyazakiPrevention of respiratory syncytial virus infection with probiotic lactic acid bacterium Lactobacillus gasseri SBT2055Sci Rep, 9 (1) (2019), p. 4812 View PDF  This article is free to access.View in ScopusGoogle Scholar
  41. [41]Y. Tomosada, E. Chiba, H. Zelaya, T. Takahashi, K. Tsukida, H. Kitazawa, *et al.*Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infectionBMC Immunol, 14 (1) (2013), p. 40 View PDF  This article is free to access.View in ScopusGoogle Scholar
  42. [42]J. Villena, E. Chiba, Y. Tomosada, S. Salva, G. Marranzino, H. Kitazawa, *et al.*Orally administered Lactobacillus rhamnosus modulates the respiratory immune response triggered by the viral pathogen-associated molecular pattern poly(I:C)BMC Immunol, 13 (1) (2012), p. 53Google Scholar
  43. [43]R.K. Singh, H.-W. Chang, D. Yan, K.M. Lee, D. Ucmak, K. Wong, *et al.*Influence of diet on the gut microbiome and implications for human healthJ Transl Med, 15 (1) (2017), p. 73Google Scholar
  44. [44]S. Brahma, I. Martínez, J. Walter, J. Clarke, T. Gonzalez, R. Menon, *et al.*Impact of dietary pattern of the fecal donor on in vitro fermentation properties of whole grains and bransJ Funct Foods, 29 (2017), pp. 281-289View PDFView articleView in ScopusGoogle Scholar
  45. [45]M. Jardou, R. LawsonSupportive therapy during COVID-19: the proposed mechanism of short-chain fatty acids to prevent cytokine storm and multi-organ failureMed Hypotheses, 154 (2021), Article 110661View PDFView articleView in ScopusGoogle Scholar0000
  46. [46]J. Li, E.M. Richards, E.M. Handberg, C.J. Pepine, M.K. RaizadaButyrate regulates COVID-19–relevant genes in gut epithelial organoids from normotensive ratsHypertension, 77 (2) (2021), pp. e13-e16View in ScopusGoogle Scholar
  47. [47]F. Zhang, Y. Wan, T. Zuo, Y.K. Yeoh, Q. Liu, L. Zhang, *et al.*Prolonged impairment of short-chain fatty acid and L-isoleucine biosynthesis in gut microbiome in patients with COVID-19Gastroenterology, 162 (2) (2022), pp. 548-561e4Google Scholar
  48. [48]L.B. Pascoal, P.B. Rodrigues, L.M. Genaro, ABdSP. Gomes, D.A. Toledo-Teixeira, P.L. Parise, *et al.*Microbiota-derived short-chain fatty acids do not interfere with SARS-CoV-2 infection of human colonic samplesGut Microb, 13 (1) (2021), pp. 1-9 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar373270
  49. [49]N. Li, W.-T. Ma, M. Pang, Q.-L. Fan, J.-L. HuaThe commensal microbiota and viral infection: a comprehensive reviewFront Immunol, 10 (1551) (2019)Google Scholar
  50. [50]T. Zuo, F. Zhang, G.C.Y. Lui, Y.K. Yeoh, A.Y.L. Li, H. Zhan, *et al.*Alterations in gut microbiota of patients with COVID-19 during time of hospitalizationGastroenterology, 159 (3) (2020), pp. 944-955e8 View PDF  This article is free to access.View in ScopusGoogle Scholar
  51. [51]Y.K. Yeoh, T. Zuo, G.C.-Y. Lui, F. Zhang, Q. Liu, A.Y. Li, *et al.*Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19Gut, 70 (4) (2021), pp. 698-706View article CrossRefView in ScopusGoogle Scholar780699385
  52. [52]G.G.F. Alberca, R.L. Solis-Castro, M.E. Solis-Castro, R.W. AlbercaCoronavirus disease-2019 and the intestinal tract: an overviewWorld J Gastroenterol, 27 (13) (2021), pp. 1255-1266View article CrossRefView in ScopusGoogle Scholar210200
  53. [53]M.J. Butler, R.M. BarrientosThe impact of nutrition on COVID-19 susceptibility and long-term consequencesBrain Behav Immun, 87 (2020), pp. 53-54View PDFView articleView in ScopusGoogle Scholar
  54. [54]S. Lobionda, P. Sittipo, H.Y. Kwon, Y.K. LeeThe role of gut microbiota in intestinal inflammation with respect to diet and extrinsic stressorsMicroorganisms, 7 (8) (2019)Google Scholar
  55. [55]S. Carding, K. Verbeke, D.T. Vipond, B.M. Corfe, L.J. OwenDysbiosis of the gut microbiota in diseaseMicrob Ecol Health Dis, 26 (2015), Article 26191Google Scholar
  56. [56]D. Baud, V. Dimopoulou Agri, G.R. Gibson, G. Reid, E. GiannoniUsing probiotics to flatten the curve of coronavirus disease COVID-2019 pandemicFront Public Health, 8 (186) (2020)Google Scholar
  57. [57]S. Keely, N.J. Talley, P.M. HansbroPulmonary-intestinal cross-talk in mucosal inflammatory diseaseMucosal Immunol, 5 (1) (2012), pp. 7-18View PDFView articleCrossRefView in ScopusGoogle Scholar27432480
  58. [58]R. Bingula, M. Filaire, N. Radosevic-Robin, M. Bey, J.-Y. Berthon, A. Bernalier-Donadille, *et al.*Desired turbulence? Gut-lung Axis, immunity, and lung cancerJ Oncol, 2017 (2017), Article 5035371View in ScopusGoogle Scholar
  59. [59]V. Fanos, M.C. Pintus, R. Pintus, M.A. MarcialisLung microbiota in the acute respiratory disease: from coronavirus to metabolomicsJ Pediat and Neonatal Individualized Med (JPNIM), 9 (1) (2020), Article e090139View in ScopusGoogle Scholar
  60. [60]C. Abt Michael, C. Osborne Lisa, A. Monticelli Laurel, A. Doering Travis, T. Alenghat, F. Sonnenberg Gregory, *et al.*Commensal bacteria calibrate the activation threshold of innate antiviral immunityImmunity, 37 (1) (2012), pp. 158-170Google Scholar
  61. [61]R.L. Brown, R.P. Sequeira, T.B. ClarkeThe microbiota protects against respiratory infection via GM-CSF signalingNat Commun, 8 (1) (2017), p. 1512 View PDF  This article is free to access.View in ScopusGoogle Scholar
  62. [62]T.B. ClarkeMicrobial programming of systemic innate immunity and resistance to infectionPLoS Pathog, 10 (12) (2014), Article e1004506View article CrossRefGoogle Scholar342420
  63. [63]C.T. Fagundes, F.A. Amaral, A.T. Vieira, A.C. Soares, V. Pinho, J.R. Nicoli, *et al.*Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree miceJ Immunol, 188 (3) (2012), pp. 1411-1420View article CrossRefView in ScopusGoogle Scholar18981490
  64. [64]K.H. Antunes, J.L. Fachi, R. de Paula, E.F. da Silva, L.P. Pral, A. Dos Santos, *et al.*Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon responseNat Commun, 10 (1) (2019), p. 3273 View PDF  This article is free to access.View in ScopusGoogle Scholar
  65. [65]K.C. Bradley, K. Finsterbusch, D. Schnepf, S. Crotta, M. Llorian, S. Davidson, *et al.*Microbiota-driven tonic interferon signals in lung stromal cells protect from influenza virus infectionCell Rep, 28 (1) (2019), pp. 245-256e4 View PDF  This article is free to access.View in ScopusGoogle Scholar
  66. [66]A.L. Steed, G.P. Christophi, G.E. Kaiko, L. Sun, V.M. Goodwin, U. Jain, *et al.*The microbial metabolite desaminotyrosine protects from influenza through type I interferonScience, 357 (6350) (2017), pp. 498-502 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar36273262
  67. [67]T. Ichinohe, I.K. Pang, Y. Kumamoto, D.R. Peaper, J.H. Ho, T.S. Murray, *et al.*Microbiota regulates immune defense against respiratory tract influenza A virus infectionProc Natl Acad Sci USA, 108 (13) (2011), pp. 5354-5359View article CrossRefView in ScopusGoogle Scholar1,190311,1956
  68. [68]M.A. Sze, P.A. Dimitriu, S. Hayashi, W.M. Elliott, J.E. McDonough, J.V. Gosselink, *et al.*The lung tissue microbiome in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med, 185 (10) (2012), pp. 1073-1080View in ScopusGoogle Scholar
  69. [69]L.D.N. Nguyen, E. Viscogliosi, L. DelhaesThe lung mycobiome: an emerging field of the human respiratory microbiomeFront Microbiol, 6 (89) (2015)Google Scholar
  70. [70]X. Zhang, D. Zhang, H. Jia, Q. Feng, D. Wang, D. Liang, *et al.*The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatmentNat Med, 21 (8) (2015), pp. 895-905View article CrossRefView in ScopusGoogle Scholar1,182631,09512
  71. [71]C.P. Bradley, F. Teng, K.M. Felix, T. Sano, D. Naskar, K.E. Block, *et al.*Segmented filamentous bacteria provoke lung autoimmunity by inducing gut-lung Axis Th17 cells expressing dual TCRsCell Host Microbe, 22 (5) (2017), pp. 697-704e4 View PDF  This article is free to access.View in ScopusGoogle Scholar
  72. [72]A.T. Dang, B.J. MarslandMicrobes, metabolites, and the gut–lung axisMucosal Immunol, 12 (4) (2019), pp. 843-850View PDFView articleCrossRefView in ScopusGoogle Scholar50044160
  73. [73]E. Yu, V.S. Malik, F.B. HuCardiovascular disease prevention by diet modification: JACC Health Promotion SeriesJ Am Coll Cardiol, 72 (8) (2018), pp. 914-926View PDFView articleView in ScopusGoogle Scholar0000
  74. [74]K.-H. Wagner, H. BrathA global view on the development of non communicable diseasesPrev Med, 54 (2012), pp. S38-S41View PDFView articleView in ScopusGoogle Scholar0000
  75. [75]R. Lordan, I. ZabetakisInvited review: the anti-inflammatory properties of dairy lipidsJ Dairy Sci, 100 (6) (2017), pp. 4197-4212View PDFView articleCrossRefView in ScopusGoogle Scholar11301000
  76. [76]N.T.H. Trang, N.P. Long, T.T.M. Hue, L.P. Hung, T.D. Trung, D.N. Dinh, *et al.*Association between nutritional status and dengue infection: a systematic review and meta-analysisBMC Infect Dis, 16 (1) (2016), p. 172 View PDF  This article is free to access.View in ScopusGoogle Scholar
  77. [77]P.C. Calder, A.C. Carr, A.F. Gombart, M. EggersdorferOptimal nutritional status for a well-functioning immune system is an important factor to protect against viral infectionsNutrients, 12 (4) (2020), p. 1181View article CrossRefView in ScopusGoogle Scholar63796930
  78. [78]Y. Alwarawrah, K. Kiernan, N.J. MacIverChanges in nutritional status impact immune cell metabolism and functionFront Immunol, 9 (2018)Google Scholar
  79. [79]L. Barrea, G. Muscogiuri, E. Frias-Toral, D. Laudisio, G. Pugliese, B. Castellucci, *et al.*Nutrition and immune system: from the Mediterranean diet to dietary supplementary through the microbiotaCrit Rev Food Sci Nutr, 61 (18) (2021), pp. 3066-3090View article CrossRefGoogle Scholar900480
  80. [80]M. Deschasaux-Tanguy, B. Srour, L. Bourhis, N. Arnault, N. Druesne-Pecollo, Y. Esseddik, *et al.*Nutritional risk factors for SARS-CoV-2 infection: a prospective study within the NutriNet-Santé cohortBMC Med, 19 (1) (2021), p. 290 View PDF  This article is free to access.View in ScopusGoogle Scholar
  81. [81]I. Zabetakis, R. Lordan, C. Norton, A. TsouprasCOVID-19: the inflammation link and the role of nutrition in potential mitigationNutrients, 12 (5) (2020), p. 1466View article CrossRefView in ScopusGoogle Scholar40344801
  82. [82]R. LordanNotable developments for vitamin D amid the COVID-19 pandemic, but caution warranted overall: a narrative reviewNutrients, 13 (3) (2021), p. 740View article CrossRefGoogle Scholar280210
  83. [83]E.M. O'ConnorThe role of gut microbiota in nutritional statusCurr Opin Clin Nutr Metab Care, 16 (5) (2013), pp. 509-516View in ScopusGoogle Scholar
  84. [84]R.M. Golonka, X. Xiao, A.A. Abokor, B. Joe, M. Vijay-KumarAltered nutrient status reprograms host inflammation and metabolic health via gut microbiotaJ Nutr Biochem, 80 (2020), Article 108360View PDFView articleView in ScopusGoogle Scholar
  85. [85]L. Daoust, G. Pilon, A. MarettePerspective: nutritional strategies targeting the gut microbiome to mitigate COVID-19 outcomesAdv Nutr, 12 (4) (2021), pp. 1074-1086View PDFView articleCrossRefView in ScopusGoogle Scholar14080
  86. [86]R. Lordan, H.M. Rando, COVID-19 review Consortium, C.S. GreeneDietary supplements and nutraceuticals under investigation for COVID-19 prevention and treatmentmSystems, 6 (3) (2021), p. e0012221Google Scholar
  87. [87]A.L. Cawood, E.R. Walters, T.R. Smith, R.H. Sipaul, R.J. StrattonA review of nutrition support guidelines for individuals with or recovering from COVID-19 in the communityNutrients, 12 (11) (2020), p. 3230View article CrossRefGoogle Scholar430520
  88. [88]E. Viciani, P. Gaibani, A. Castagnetti, A. Liberatore, M. Bartoletti, P. Viale, *et al.*Critically ill patients with COVID-19 show lung fungal dysbiosis with reduced microbial diversity in patients colonized with Candida sppInt J Infect Dis, 117 (2022), pp. 233-240View PDFView articleView in ScopusGoogle Scholar
  89. [89]P. Gaibani, E. Viciani, M. Bartoletti, R.E. Lewis, T. Tonetti, D. Lombardo, *et al.*The lower respiratory tract microbiome of critically ill patients with COVID-19Sci Rep, 11 (1) (2021), Article 10103 View PDF  This article is free to access.View in ScopusGoogle Scholar
  90. [90]Y. Chen, S. Gu, Y. Chen, H. Lu, D. Shi, J. Guo, *et al.*Six-month follow-up of gut microbiota richness in patients with COVID-19Gut, 71 (1) (2022), pp. 222-225View article CrossRefGoogle Scholar12281280
  91. [91]K. Hufnagl, I. Pali-Schöll, F. Roth-Walter, E. Jensen-JarolimDysbiosis of the gut and lung microbiome has a role in asthmaSemin Immunopathol, 42 (1) (2020), pp. 75-93 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar18471600
  92. [92]K.A. Willis, J.D. Stewart, N. AmbalavananRecent advances in understanding the ecology of the lung microbiota and deciphering the gut-lung axisAm J Physiol Lung Cell Mol Physiol, 319 (4) (2020), pp. L710-L716 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar260100
  93. [93]J.E. Martínez, A. Vargas, T. Pérez-Sánchez, I.J. Encío, M. Cabello-Olmo, M. BarajasHuman microbiota network: unveiling potential crosstalk between the different microbiota ecosystems and their role in health and diseaseNutrients, 13 (9) (2021), p. 2905View article CrossRefView in ScopusGoogle Scholar240170
  94. [94]H. Zhang, J.-W. Ai, W. Yang, X. Zhou, F. He, S. Xie, *et al.*Metatranscriptomic characterization of coronavirus disease 2019 identified a host transcriptional classifier associated with immune signalingClin Infect Dis, 73 (3) (2020), pp. 376-385View in ScopusGoogle Scholar
  95. [95]J.-W. Ai, H.-C. Zhang, T. Xu, J. Wu, M. Zhu, Y.-Q. Yu, *et al.*Optimizing diagnostic strategy for novel coronavirus pneumonia, a multi-center study in Eastern ChinamedRxiv (2020)2020.02.13.20022673Google Scholar
  96. [96]A. Budding, E. Sieswerda, B. Wintermans, M. BosAn age dependent pharyngeal microbiota signature associated with SARS-CoV-2 infection(2020)Available at: SSRN 3582780Google Scholar
  97. [97]M.W. Gutierrez, E. van Tilburg Bernardes, D. Changirwa, B. McDonald, M.-C. Arrieta“Molding” immunity—modulation of mucosal and systemic immunity by the intestinal mycobiome in health and diseaseMucosal Immunol, 15 (2022), pp. 573-583View PDFView articleCrossRefView in ScopusGoogle Scholar80602
  98. [98]E. van Tilburg Bernardes, V.K. Pettersen, M.W. Gutierrez, I. Laforest-Lapointe, N.G. Jendzjowsky, J.B. Cavin, *et al.*Intestinal fungi are causally implicated in microbiome assembly and immune development in miceNat Commun, 11 (1) (2020), p. 2577 View PDF  This article is free to access.View in ScopusGoogle Scholar
  99. [99]A. Tsitsiklis, B.S. Zha, A. Byrne, C. DeVoe, E. Rackaityte, S. Levan, *et al.*Impaired immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19medRxiv (2021)2021.03.23.21253487Google Scholar
  100. [100]E.S. Bradley, A.L. Zeamer, V. Bucci, L. Cincotta, M.-C. Salive, P. Dutta, *et al.*Oropharyngeal microbiome profiled at admission is predictive of the need for respiratory support among COVID-19 patientsmedRxiv (2022)2022.02.28.22271627Google Scholar
  101. [101]P.G. Gibson, L. Qin, S.H. PuahCOVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDSMed J Aust, 213 (2) (2020), pp. 54-56e1 View PDF  This article is free to access.CrossRefGoogle Scholar43642410
  102. [102]C. Huang, Y. Wang, X. Li, L. Ren, J. Zhao, Y. Hu, *et al.*Clinical features of patients infected with 2019 novel coronavirus in Wuhan, ChinaLancet, 395 (10223) (2020), pp. 497-506View PDFView articleGoogle Scholar
  103. [103]M. Schirmer, S.P. Smeekens, H. Vlamakis, M. Jaeger, M. Oosting, E.A. Franzosa, *et al.*Linking the human gut microbiome to inflammatory cytokine production capacityCell, 167 (4) (2016), pp. 1125-1136e8 View PDF  This article is free to access.View in ScopusGoogle Scholar
  104. [104]T. Zuo, Q. Liu, F. Zhang, G.C.-Y. Lui, E.Y. Tso, Y.K. Yeoh, *et al.*Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19Gut, 70 (2) (2021), pp. 276-284View in ScopusGoogle Scholar
  105. [105]W. Tao, G. Zhang, X. Wang, M. Guo, W. Zeng, Z. Xu, *et al.*Analysis of the intestinal microbiota in COVID-19 patients and its correlation with the inflammatory factor IL-18Med Microecol, 5 (2020), Article 100023View PDFView articleView in ScopusGoogle Scholar
  106. [106]T. Zuo, H. Zhan, F. Zhang, Q. Liu, E.Y.K. Tso, G.C.Y. Lui, *et al.*Alterations in fecal fungal microbiome of patients with COVID-19 during time of hospitalization until dischargeGastroenterology, 159 (4) (2020), pp. 1302-1310e5 View PDF  This article is free to access.View in ScopusGoogle Scholar
  107. [107]S. Jin, D. Wetzel, M. SchirmerDeciphering mechanisms and implications of bacterial translocation in human health and diseaseCurr Opin Microbiol, 67 (2022), Article 102147View PDFView articleView in ScopusGoogle Scholar
  108. [108]A.S. Chopra, R. Lordan, O.K. Horbańczuk, A.G. Atanasov, I. Chopra, J.O. Horbańczuk, *et al.*The current use and evolving landscape of nutraceuticalsPharmacol Res, 175 (2022), Article 106001View PDFView articleView in ScopusGoogle Scholar0000
  109. [109]R. LordanDietary supplements and nutraceuticals market growth during the coronavirus pandemic – implications for consumers and regulatory oversightPharm Nutr, 18 (2021), Article 100282View PDFView articleView in ScopusGoogle Scholar0000
  110. [110]A.N. Olaimat, I. Aolymat, M. Al-Holy, M. Ayyash, M. Abu Ghoush, A.A. Al-Nabulsi, *et al.*The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19npj Science of Food, 4 (1) (2020), p. 17 View PDF  This article is free to access.View in ScopusGoogle Scholar
  111. [111]F. Infusino, M. Marazzato, M. Mancone, F. Fedele, C.M. Mastroianni, P. Severino, *et al.*Diet supplementation, probiotics, and nutraceuticals in SARS-CoV-2 infection: a scoping reviewNutr, 12 (6) (2020), p. 1718View article CrossRefGoogle Scholar16901580
  112. [112]A.E.C. Antunes, G. Vinderola, D. Xavier-Santos, K. SivieriPotential contribution of beneficial microbes to face the COVID-19 pandemicFood Res Int, 136 (2020), Article 109577View PDFView articleView in ScopusGoogle Scholar
  113. [113]S.K. Angurana, A. BansalProbiotics and Coronavirus disease 2019: think about the linkBr J Nutr, 126 (10) (2021), pp. 1564-1570View article CrossRefView in ScopusGoogle Scholar230210
  114. [114]G.E. Walton, G.R. Gibson, K.A. HunterMechanisms linking the human gut microbiome to prophylactic and treatment strategies for COVID-19Br J Nutr, 126 (2) (2021), pp. 219-227View article CrossRefView in ScopusGoogle Scholar531641
  115. [115]B. Bottari, V. Castellone, E. NevianiProbiotics and covid-19Int J Food Sci Nutr, 72 (3) (2021), pp. 293-299View article CrossRefView in ScopusGoogle Scholar800560
  116. [116]S. Enani, A. Przemska-Kosicka, C.E. Childs, C. Maidens, H. Dong, L. Conterno, *et al.*Impact of ageing and a synbiotic on the immune response to seasonal influenza vaccination; a randomised controlled trialClin Nutr, 37 (2) (2018), pp. 443-451View PDFView articleView in ScopusGoogle Scholar
  117. [117]J. Fonollá, C. Gracián, J.A. Maldonado-Lobón, C. Romero, A. Bédmar, J.C. Carrillo, *et al.*Effects of Lactobacillus coryniformis K8 CECT5711 on the immune response to influenza vaccination and the assessment of common respiratory symptoms in elderly subjects: a randomized controlled trialEur J Nutr, 58 (1) (2019), pp. 83-90 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar335250
  118. [118]R. Shahbazi, H. Yasavoli-Sharahi, N. Alsadi, N. Ismail, C. MatarProbiotics in treatment of viral respiratory infections and neuroinflammatory disordersMolecules, 25 (21) (2020), p. 4891View article CrossRefGoogle Scholar490290
  119. [119]P.W. O'Toole, J.R. Marchesi, C. HillNext-generation probiotics: the spectrum from probiotics to live biotherapeuticsNature Microbiol, 2 (5) (2017), Article 17057View in ScopusGoogle Scholar
  120. [120]J. Plaza-Diaz, F.J. Ruiz-Ojeda, M. Gil-Campos, A. GilMechanisms of action of probioticsAdv Nutr, 10 (suppl_1) (2019), pp. S49-S66View PDFView articleCrossRefView in ScopusGoogle Scholar627238401
  121. [121]W.-T. Lei, P.-C. Shih, S.-J. Liu, C.-Y. Lin, T.-L. YehEffect of probiotics and prebiotics on immune response to influenza vaccination in adults: a systematic review and meta-analysis of randomized controlled trialsNutrients, 9 (11) (2017), p. 1175View article CrossRefView in ScopusGoogle Scholar902691
  122. [122]C. Maidens, C. Childs, A. Przemska, I.B. Dayel, P. YaqoobModulation of vaccine response by concomitant probiotic administrationBr J Clin Pharmacol, 75 (3) (2013), pp. 663-670 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar500550
  123. [123]T.L. Yeh, P.C. Shih, S.J. Liu, C.H. Lin, J.M. Liu, W.T. Lei, *et al.*The influence of prebiotic or probiotic supplementation on antibody titers after influenza vaccination: a systematic review and meta-analysis of randomized controlled trialsDrug Des Dev Ther, 12 (2018), pp. 217-230View article CrossRefView in ScopusGoogle Scholar680590
  124. [124]P. Zimmermann, N. CurtisThe influence of probiotics on vaccine responses – a systematic reviewVaccine, 36 (2) (2018), pp. 207-213View PDFView articleView in ScopusGoogle Scholar0000
  125. [125]C. Maldonado Galdeano, S.I. Cazorla, J.M. Lemme Dumit, E. Vélez, G. PerdigónBeneficial effects of probiotic consumption on the immune systemAnn Nutr Metabol, 74 (2) (2019), pp. 115-124 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar39231620
  126. [126]P. Gutiérrez-Castrellón, T. Gandara-Martí, A.T. Abreu, C.D. Nieto-Rufino, E. López-Orduña, I. Jiménez-Escobar, *et al.*Efficacy and safety of novel probiotic formulation in adult Covid19 outpatients: a randomized, placebo-controlled clinical trialmedRxiv (2021)2021.05.20.21256954Google Scholar
  127. [127]A. Rathi, S.B. Jadhav, N. ShahA randomized controlled trial of the efficacy of systemic enzymes and probiotics in the resolution of post-COVID fatigueMedicine (Baltim), 8 (9) (2021), p. 47View article CrossRefGoogle Scholar190230
  128. [128]M. Dehghan, A. Mente, X. Zhang, S. Swaminathan, W. Li, V. Mohan, *et al.*Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort studyLancet, 390 (10107) (2017), pp. 2050-2062View PDFView articleView in ScopusGoogle Scholar
  129. [129]L. Zhang, H. Han, X. Li, C. Chen, X. Xie, G. Su, *et al.*Probiotics use is associated with improved clinical outcomes among hospitalized patients with COVID-19Therap Adv Gastroenterol, 14 (2021), Article 17562848211035670Google Scholar
  130. [130]Q. Li, F. Cheng, Q. Xu, Y. Su, X. Cai, F. Zeng, *et al.*The role of probiotics in coronavirus disease-19 infection in Wuhan: a retrospective study of 311 severe patientsInt Immunopharm, 95 (2021), Article 107531View PDFView articleView in ScopusGoogle Scholar0000
  131. [131]V. Ivashkin, V. Fomin, S. Moiseev, M. Brovko, R. Maslennikov, A. Ulyanin, *et al.*Efficacy of a probiotic consisting of lacticaseibacillus rhamnosus PDV 1705, Bifidobacterium bifidum PDV 0903, Bifidobacterium longum subsp. infantis PDV 1911, and Bifidobacterium longum subsp. longum PDV 2301 in the treatment of hospitalized patients with COVID-19: a randomized controlled trialProbiotics and Antimicrobial Proteins (2021), 10.1007/s12602-021-09858-5 View PDF  This article is free to access.Google Scholar292210
  132. [132]H.M. Rando, N. Wellhausen, S. Ghosh, A.J. Lee, A.A. Dattoli, F. Hu, *et al.*Identification and development of therapeutics for COVID-19mSystems, 6 (6) (2021), pp. e0023321-eGoogle Scholar
  133. [133]S. Soltani, R. Hammami, P.D. Cotter, S. Rebuffat, L.B. Said, H. Gaudreau, *et al.*Bacteriocins as a new generation of antimicrobials: toxicity aspects and regulationsFEMS (Fed Eur Microbiol Soc) Microbiol Rev, 45 (1) (2020)Google Scholar
  134. [134]R. Lordan, A. Walsh, F. Crispie, L. Finnegan, M. Demuru, A. Tsoupras, *et al.*Caprine milk fermentation enhances the antithrombotic properties of cheese polar lipidsJ Funct Foods, 61 (103507) (2019)Google Scholar
  135. [135]F. Anwar, H.N. Altayb, F.A. Al-Abbasi, A.L. Al-Malki, M.A. Kamal, V. KumarAntiviral effects of probiotic metabolites on COVID-19J Biomol Struct Dyn, 39 (11) (2021), pp. 4175-4184View article CrossRefView in ScopusGoogle Scholar880850
  136. [136]I.A. Rather, S.-B. Choi, M.R. Kamli, K.R. Hakeem, J.S.M. Sabir, Y.-H. Park, *et al.*Potential adjuvant therapeutic effect of Lactobacillus plantarum probio-88 postbiotics against SARS-COV-2Vaccines, 9 (10) (2021), p. 1067View article CrossRefView in ScopusGoogle Scholar281240
  137. [137]I. Erol, S.E. Kotil, O. Fidan, A.E. Yetiman, S. Durdagi, F. OrtakciIn Silico analysis of Bacteriocins from lactic acid bacteria against SARS-CoV-2Probiotics and Antimicrobial Proteins (2021), 10.1007/s12602-021-09879-0 View PDF  This article is free to access.Google Scholar15090
  138. [138]E.R. Leeming, A.J. Johnson, T.D. Spector, C.I. Le RoyEffect of diet on the gut microbiota: rethinking intervention durationNutr, 11 (12) (2019), p. 2862View article CrossRefView in ScopusGoogle Scholar40992551
  139. [139]K. Korpela, H.J. Flint, A.M. Johnstone, J. Lappi, K. Poutanen, E. Dewulf, *et al.*Gut microbiota signatures predict host and microbiota responses to dietary interventions in obese individualsPLoS One, 9 (3) (2014), Article e90702View article CrossRefView in ScopusGoogle Scholar16371200
  140. [140]J.L. Sonnenburg, F. BäckhedDiet-microbiota interactions as moderators of human metabolismNature, 535 (7610) (2016), pp. 56-64View article CrossRefView in ScopusGoogle Scholar1,526121,1332
  141. [141]K.S. Swanson, G.R. Gibson, R. Hutkins, R.A. Reimer, G. Reid, K. Verbeke, *et al.*The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of synbioticsNat Rev Gastroenterol Hepatol, 17 (11) (2020), pp. 687-701 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar80413210
  142. [142]A. Tada, H. Zelaya, P. Clua, S. Salva, S. Alvarez, H. Kitazawa, *et al.*Immunobiotic Lactobacillus strains reduce small intestinal injury induced by intraepithelial lymphocytes after Toll-like receptor 3 activationInflamm Res, 65 (10) (2016), pp. 771-783View article CrossRefView in ScopusGoogle Scholar357560
  143. [143]L. Albarracin, H. Kobayashi, H. Iida, N. Sato, T. Nochi, H. Aso, *et al.*Transcriptomic analysis of the innate antiviral immune response in porcine intestinal epithelial cells: influence of immunobiotic lactobacilliFront Immunol, 8 (57) (2017)Google Scholar
  144. [144]E. Chiba, Y. Tomosada, M.G. Vizoso-Pinto, S. Salva, T. Takahashi, K. Tsukida, *et al.*Immunobiotic Lactobacillus rhamnosus improves resistance of infant mice against respiratory syncytial virus infectionInt Immunopharm, 17 (2) (2013), pp. 373-382View PDFView articleView in ScopusGoogle Scholar
  145. [145]H. Zelaya, K. Tsukida, E. Chiba, G. Marranzino, S. Alvarez, H. Kitazawa, *et al.*Immunobiotic lactobacilli reduce viral-associated pulmonary damage through the modulation of inflammation-coagulation interactionsInt Immunopharm, 19 (1) (2014), pp. 161-173View PDFView articleView in ScopusGoogle Scholar
  146. [146]T. Gautier, S. David-Le Gall, A. Sweidan, Z. Tamanai-Shacoori, A. Jolivet-Gougeon, O. Loréal, *et al.*Next-generation probiotics and their metabolites in COVID-19Microorganisms, 9 (5) (2021), p. 941View article CrossRefView in ScopusGoogle Scholar310330
  147. [147]M.A. Salehinejad, A. Azarkolah, E. Ghanavati, M.A. NitscheCircadian disturbances, sleep difficulties and the COVID-19 pandemicSleep Med, 91 (2021), pp. 246-252Google Scholar
  148. [148]X. Zhuang, S. Tsukuda, F. Wrensch, P.A.C. Wing, M. Schilling, J.M. Harris, *et al.*The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cellsiScience, 24 (10) (2021), Article 103144View PDFView articleView in ScopusGoogle Scholar0000
  149. [149]H. Mortaş, S. Bilici, T. KarakanThe circadian disruption of night work alters gut microbiota consistent with elevated risk for future metabolic and gastrointestinal pathologyChronobiol Int, 37 (7) (2020), pp. 1067-1081View article CrossRefView in ScopusGoogle Scholar301190
  150. [150]S. Sengupta, T.G. Brooks, G.R. Grant, G.A. FitzGeraldAccounting for time: circadian rhythms in the time of COVID-19J Biol Rhythm, 36 (1) (2021), pp. 4-8 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar153120
  151. [151]A. Naik, K. Forrest, Y. Issah, U. Valekunja, A.B. Reddy, E. Hennessy, *et al.*Circadian regulation of lung repair and regenerationbioRxiv (2021)2021.11.20.469376Google Scholar
  152. [152]J.A. Pearson, A.C. Voisey, K. Boest-Bjerg, F.S. Wong, L. WenCircadian rhythm modulation of microbes during health and infectionFront Microbiol, 12 (2468) (2021)Google Scholar
  153. [153]P. Gupta, J.L. Martin, A. Malhotra, J. Bergstrom, M.A. Grandner, B.B. KamdarCircadian rest-activity misalignment in critically ill medical intensive care unit patientsJ Sleep Res (2022), Article e13587n/a(n/a)View in ScopusGoogle Scholar
  154. [154]R.K. Weersma, A. Zhernakova, J. FuInteraction between drugs and the gut microbiomeGut, 69 (8) (2020), pp. 1510-1519View article CrossRefView in ScopusGoogle Scholar38122142
  155. [155]T.A. Clayton, D. Baker, J.C. Lindon, J.R. Everett, J.K. NicholsonPharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolismProc Natl Acad Sci USA, 106 (34) (2009), pp. 14728-14733View article CrossRefView in ScopusGoogle Scholar65785542
  156. [156]M. Zimmermann-Kogadeeva, M. Zimmermann, A.L. GoodmanInsights from pharmacokinetic models of host-microbiome drug metabolismGut Microb, 11 (3) (2020), pp. 587-596 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar220160
  157. [157]M. Zimmermann, K.R. Patil, A. Typas, L. MaierTowards a mechanistic understanding of reciprocal drug–microbiome interactionsMol Syst Biol, 17 (3) (2021), Article e10116 View PDF  This article is free to access.View in ScopusGoogle Scholar
  158. [158]J.P. Segal, J.W.Y. Mak, B.H. Mullish, J.L. Alexander, S.C. Ng, J.R. MarchesiThe gut microbiome: an under-recognised contributor to the COVID-19 pandemic?Therapeutic Advances in Gastroenterology, 13 (2020), Article 1756284820974914Google Scholar
  159. [159]K.A. Kuhn, H.M. Schulz, E.H. Regner, E.L. Severs, J.D. Hendrickson, G. Mehta, *et al.*Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrityMucosal Immunol, 11 (2) (2018), pp. 357-368View PDFView articleCrossRefView in ScopusGoogle Scholar1023741
  160. [160]M.C. Appel-da-Silva, G.A. Narvaez, L.R.R. Perez, L. Drehmer, J. LewgoySaccharomyces cerevisiae var. boulardii fungemia following probiotic treatmentMedical Mycology Case Reports, 18 (2017), pp. 15-17View PDFView articleView in ScopusGoogle Scholar
  161. [161]J.D. Gargar, R.M. DivinagraciaWhen good things go bad: a case series of bacteremia from probioticsChest, 155 (4) (2019), p. 92AView PDFView articleGoogle Scholar
  162. [162]I. Yelin, K.B. Flett, C. Merakou, P. Mehrotra, J. Stam, E. Snesrud, *et al.*Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patientsNat Med, 25 (11) (2019), pp. 1728-1732 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar17031210
  163. [163]D. Kothari, S. Patel, S.-K. KimProbiotic supplements might not be universally-effective and safe: a reviewBiomed Pharmacother, 111 (2019), pp. 537-547View PDFView articleView in ScopusGoogle Scholar
  164. [164]Q.Y. Gao, Y.X. Chen, J.Y. Fang2019 Novel coronavirus infection and gastrointestinal tractJ Dig Dis, 21 (3) (2020), pp. 125-126 View PDF  This article is free to access.CrossRefView in ScopusGoogle Scholar356334301

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