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Gut Dysbiosis during COVID-19 and Potential Effect of Probiotics

Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan 700, Taiwan
Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan 704, Taiwan
Clinical Medicine Research Center, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan 705, Taiwan
Graduate Institute of Medical Sciences, College of Health Sciences, Chang Jung Christian University, Tainan 711, Taiwan
Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 705, Taiwan
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 705, Taiwan
Department of Pathology, National Cheng Kung University Hospital, Tainan 705, Taiwan
Department of Medicine, College of Medicine, National Cheng Kung University, Tainan 705, Taiwan
Author to whom correspondence should be addressed.
These authors contribute equally.
Microorganisms 2021, 9(8), 1605;
Submission received: 11 July 2021 / Revised: 23 July 2021 / Accepted: 26 July 2021 / Published: 28 July 2021
(This article belongs to the Special Issue Probiotics and Antimicrobial Effect)


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus of the family Coronaviridae, causes coronavirus disease 2019 (COVID-19), an influenza-like disease that chiefly infects the lungs through respiratory transmission. The spike protein of SARS-CoV-2, a transmembrane protein in its outer portion, targets angiotensin-converting enzyme 2 (ACE2) as the binding receptor for the cell entry. As ACE2 is highly expressed in the gut and pulmonary tissues, SARS-CoV-2 infections frequently result in gastrointestinal inflammation, with presentations ordinarily ranging from intestinal cramps to complications with intestinal perforations. However, the evidence detailing successful therapy for gastrointestinal involvement in COVID-19 patients is currently limited. A significant change in fecal microbiomes, namely dysbiosis, was characterized by the enrichment of opportunistic pathogens and the depletion of beneficial commensals and their crucial association to COVID-19 severity has been evidenced. Oral probiotics had been evidenced to improve gut health in achieving homeostasis by exhibiting their antiviral effects via the gut–lung axis. Although numerous commercial probiotics have been effective against coronavirus, their efficacies in treating COVID-19 patients remain debated. In, 19 clinical trials regarding the dietary supplement of probiotics, in terms of Lactobacillus and mixtures of Bifidobacteria and Lactobacillus, for treating COVID-19 cases are ongoing. Accordingly, the preventive or therapeutic role of probiotics for COVID-19 patients can be elucidated in the near future.

1. Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new RNA virus of the family Coronaviridae, can cause coronavirus disease 2019 (COVID-19), majorly affecting pulmonary tissues by respiratory transmission [1,2]. Clinical presentations of COVID-19 vary greatly, ranging from no or mild symptoms often in young patients without comorbidities, moderate diseases with pneumonia, to severe diseases complicated by hypoxia, respiratory or multi-organ failure, and even death [2]. SARS-CoV-2 is composed of four structure proteins, including spike glycoproteins (S), small envelope glycoproteins (E), glycoproteins membrane (M), nucleocapsid (N), and other accessory proteins [3]. The spike protein of SARS-CoV-2, a transmembrane protein, uses angiotensin-converting enzyme 2 (ACE2) as the receptor of the cell entry [3,4]. In addition to extensive existence in pulmonary tissue, ACE2 is highly expressed in the gut [3,4]; therefore, in the human small intestinal organoids model, enterocytes are easily infected by SARS-CoV-2, as demonstrated by confocal and electron microscopy [1,5]. In the gut, ACE2 is not only a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis [6], but also is linked to the activation of intestinal inflammation [6]. Accordingly, SARS-CoV-2 infections frequently result in gastrointestinal inflammation, with clinical presentations ranging from intestinal cramps and diarrhea to intestinal perforations (Figure 1) [7,8]. Additionally, its abdominal presentation was more frequent in critically ill patients requiring intensive care than those who did not require intensive care, and 10% of patients presented with diarrhea and nausea within 1–2 days before the development of fever and respiratory symptoms [9]. However, the evidence detailing successful therapy for gastrointestinal involvement in COVID-19 patients is currently limited.
One possible mechanism linked to gut presentations in COVID-19 is the downregulation of ACE2, followed by the decreased activation of mechanistic targets of rapamycin and increased autophagy, further leading to dysbiosis [7]. Another theory is that the blockage of ACE2 induces the increased levels of angiotensinogen by the hyperactivation of the renin–angiotensin system, resulting in the shutdown of the amino acid transporter BA0T1 and a lack of cellular tryptophan. These alterations cause the decreased secretion of antimicrobial peptides and disturbance in the gut microbiome [10]. Therefore, COVID-19 impacts the human gut microbiome, with a decline in microbial diversity and beneficial microbes [11].

2. The Interaction between Respiratory Tract Diseases and Gut Microbiota

A crucial association between a modified gut microbiome and the immune response to respiratory viral infections is evidenced. Taking respiratory syncytial virus and influenza as examples, gut microbiota was significantly altered by viral infections itself and multifactorial variables, such as inflammation-induced tumor necrosis factor-alpha (TNF-α) [12]. Intact microbiota provides signals leading to inflammasome activation, expression of pro-interleukin (IL)-1β and pro-IL-18, and the migration of dendritic cells (DCs) from the lung to the draining lymph node and T-cells, which are critical for protective immunity following influenza virus infection [13]. Disturbed gut microbiota directly or indirectly affects innate and adaptive immune signals and cells in the pulmonary tissue, such as the increased susceptibility to asthma, pulmonary allergic diseases, and chronic obstructive pulmonary diseases [14,15,16,17]. More importantly, the severity of influenza infections has been vastly related to the heterogeneous responses of the gut microbiota, as noted by the finding that Bifidobacterium species in the gut can expand to enhance host resistance to influenza [18].
In addition, gut microorganisms regulate innate memory by eliciting pattern recognition receptors (PRRs) on monocytes/macrophages and natural killer cells to recognize microbe- or pathogen-associated molecular patterns on microbes [19]. Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors, recognizable on the host’s cells through PRRs, evoke different immunological reactions depending on the types of cells, ligands, or receptors [20]. The fine alteration of the regulatory balance of pro-inflammatory responses and inflammatory regulatory T cells (Tregs) ultimately controlled by the commensal microorganisms is critical in coordinating gut immune homeostasis [20,21]. For example, polysaccharide A, an immunomodulatory molecule, secreted by Bacteroides fragilis, can mediate the conversion of CD4+ T cells into IL-10-producing Foxp3(+) Treg cells, and may be considered for the prevention and treatment of experimental colitis in mice [21].

3. Gut Dysbiosis during COVID-19

Patients with COVID-19 had significant changes in fecal microbiomes, characterized by the enrichment of opportunistic pathogens and the depletion of beneficial commensals [22]. Dysbiosis has been vastly associated with COVID-19 severity [22,23,24,25], because the microbial diversity is regarded as a critical determinant of microbial ecosystem stability [26]. Among short-chain fatty acids (SCFAs), butyrate is not only responsible for energy requirements of the colonic epithelium, but also preserves tissues by mitigating chronic inflammatory responses through the regulation of pro- and anti-inflammatory cytokines [27]. Accordingly, decreases in the abundance of butyrate-producing bacteria (such as Faecalibacterium prausnitzii and Clostridium species), and the subsequent decline in SCFA availability have been correlated with severe COVID-19 [22,23,24,25,28,29]. Additionally, an increase in common pathogens in gut microbiota, such as Prevotella, Enterococcus, Enterobacteriaceae, or Campylobacter, were consistently associated with high infectivity, disease deterioration, or poor prognosis in COVID-19 patients [23,24,25,28]. The Prevotella species, for example, is associated with augmented T helper type 17 (Th17)-mediated mucosal inflammation, including activating TLR2 and Th17-polarizing cytokine production (such as IL-23 and IL-1), stimulating epithelial cells to produce IL-8, IL-6, and CCL20, and thus promoting neutrophil recruitment and inflammation [30]. The deterioration of the clinical course of patients with COVID-19 infection might be in part due to the activation of severe inflammation through disruption in gut microbiota and the out-growth of pathogenic bacteria.
Patients with COVID-19 also had the increased proportion of opportunistic fungal pathogens, such as Aspergillus flavus and Aspergillus niger, detected in fecal samples [31]. In metagenomic sequencing analyses of fecal samples from COVID-19 patients, the baseline abundance of Coprobacillus, Clostridium ramosum, and Clostridium hathewayi was correlated with disease severity, and an inverse correlation between abundance of F. prausnitzii (an anti-inflammatory bacterium) and disease severity was disclosed [22]. Furthermore, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides massiliensis, and Bacteroides ovatus, which downregulated the expression of ACE2 in the gut, were correlated inversely with SARS-CoV-2 load [22]. The same study team also indicated that, in the cases of active SARS-CoV-2 infections, the gut microbiota presented a higher abundance of opportunistic pathogens, while increased nucleotide and amino acid biosynthesis, as well as carbohydrate metabolism, were evidenced [24]. In summary, these findings reasonably suggest that the development of therapeutic agents able to neutralize the SARS-CoV-2 activity in the gut, as well as to restore the physiological gut microbiota composition, may be warranted.
A crucial association between the predominance of opportunistic pathogens in gut microbiomes and unfavorable outcomes of COVID-19 patients has been comprehensively reported [23]. In a Chinese cohort of COVID-19 patients with different disease severity, the abundance of butyrate-producing bacteria decreased significantly, which may help discriminate critically ill patients from general and severe patients. The increased proportion of opportunistic pathogens, such as Enterococcus and Enterobacteriaceae, in critically ill patients might be associated with a poor prognosis [23]. In another study, a higher abundance of opportunistic pathogens, such as Streptococcus, Rothia, Veillonella, and Actinomyces species, and a lower abundance of beneficial symbionts, could be noted in the gut microbiota of COVID-19 patients [25]. In the American cohort, the specific alteration in the gut microbiome, particularly Peptoniphilus, Corynebacterium, and Campylobacter, was also noticed [28]. Nevertheless, opportunistic pathogens were prevalent in the COVID-19 cases, particularly among critically individuals, but the causal effect of the predominance of opportunistic pathogens, and a grave outcome remains to be determined.
The recovery of dysbiosis after active SARS-CoV-2 infections exhibited geographical and demographic differences [22,28,32]. After the clearance of SARS-CoV-2 and resolution of respiratory symptoms, depleted symbionts and gut dysbiosis were usually persistent among recovered COVID-19 patients, because microbiota richness did not yield to normal levels after 6-month recovery [22]. In contrast, in an American cohort including recovered COVID-19 cases, the dysbiosis could rapidly recover with a return of the human gut microbiota to an uninfected status [28]. Although the great diversity in the ability of the microbiota return was disclosed, it was evident that the recovery of gut microbiota could be regarded as an indicator of the favorable prognosis among patients with COVID-19.

4. Therapeutic Effects of Dietary Supplement of Probiotics for COVID-19

Oral probiotics had been proven to exhibit antiviral effects and thereby to improve gut health for achieving homeostasis [33,34]. To take the influenza infection as an example, Lactococcus lactis JCM 5805 demonstrated the activity against influenza virus through the activation of anti-viral immunity [34]. The oral administration of Bacteroides breve YIT4064 can enhance antigen-specific IgG against influenza virus [33]. Moreover, a meta-analysis report indicated the administration of these probiotics significantly reduced the incidence of ventilator-associated pneumonia, possibly through reducing the overgrowth of potentially opportunistic pathogens and stimulating immune responses [35]. However, such a promotion of oral probiotics in treating critically ill patients experiencing COVID-19 should be further explored.
In COVID-19 patients, the excessive production of pro-inflammatory cytokines, a so-called “cytokine storm”, is pathologically related to acute respiratory distress syndrome and extensive tissue injury, multi-organ failure, or eventually death [36]. With COVID-19 progression, critically ill patients had higher plasma levels of many cytokines, in terms of IL-2, IL-7, IL-10, granulocyte colony-stimulating factor, IFN-γ-inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1A, and TNF-α [37]. Therefore, therapeutic targeting on cytokines in COVID-19 treatment was evidenced to increase survival [36]. Fecal levels of IL-8 and IL-23 and intestinal specific IgA responses were vastly associated with severe COVID-19 disease, which indicated the co-existence of systemic and local intestine inflammation in critically ill patients [38]. One of the commercial probiotics, Lactobacillus rhamnosus HDB1258, might be effective in treating COVID-19 by modulating both microbiota-mediated immunity in gut and systemic inflammation induced by lipopolysaccharide [39]. Accordingly, concomitant targeting on local and systemic inflammatory responses by probiotics is reasonably believed to be valuable to counteract COVID-19-related gut and systemic inflammation.
Numerous probiotics and by-probiotic products exhibiting direct and indirect antiviral effects have been reported in the scientific literature. Lactic acid-producing bacteria such as lactobacilli can exert their antiviral activity by direct probiotic–virus interaction, the production of antiviral inhibitory metabolites, preventing secondary infection, and eliciting anti-viral immunity [40,41,42,43,44,45,46,47]. Nisin, one of the well-characterized bacteriocins from probiotics, contributes to probiotic antiviral effects against influenza A virus and other respiratory viruses [41,43]. A peptide, P18, produced by the probiotic Bacillus subtilis strain, was regarded as an antiviral compound against influenza virus [42]. Probiotics capsules containing live B. subtilis and E. faecalis (Medilac-S) can lower the acquisition of the gut colonization of potentially pathogenic microorganisms [44]. L. rhamnosus GG have been reported to prevent ventilator-associated pneumonia [45]. The heat-killed L. casei DK128 strain has been active against different subtypes of influenza viruses by an increasing proportion of alveolar macrophages in lungs and airways, the early induction of virus-specific antibodies, and reduced levels of pro-inflammatory cytokines and innate immune cells [46]. S. salivarius 24SMB and S. oralis 89a were able to inhibit the biofilm formation capacity of airway bacterial pathogens and even to disperse their pre-formed biofilms [47]. The S. salivarius strain K12 may stimulate IFN-γ release and suppress bronchial inflammation, and its colonization in the oral cavity and upper respiratory tract will actively interfere with the growth of pathogenic microbes [48]. Although these probiotics and their products provide the favorable antiviral interaction with immune composition in the gut, the feasibility and health effect of dietary probiotics to improve the dysbiosis in COVID-19 patients remains to be studied.
Numerous probiotics had been proposed to be beneficial in coronaviral infections, but the evidence detailing their efficacies in treating COVID-19 infection is limited [49]. L. plantarum Probio-38 and L. salivarius Probio-37 could inhibit transmissible gastroenteritis coronavirus [50]. The probiotic, E. faecium NCIMB 10415, has been approved as a feed additive for young piglets in the European Union for treating the transmissible coronavirus gastroenteritis [51]. The recombinant IFN-λ3-anchored L. plantarum can in vitro inhibit porcine gastroenteritis caused by coronavirus [52]. However, the clinical utility of probiotics in human infections caused by SARS-CoV-2 warrants further evaluations [53,54,55,56,57].
Another important issue regarding probiotics for COVID-19 cases is the patient safety. For an example, B. longum bacteremia had been reported in preterm infants receiving probiotics [58,59]. Since gastrointestinal SARS-CoV-2 involvement has been reported, the possibility of increased intestinal permeability should be expected and the risk of secondary bacterial infections in the gut is substantial if high-dosage steroid and other immunomodulation agents are administrated to treat the cytokine storm associated with COVID-19 [60,61]. The oral formulation Sivomixx®, which was a mixture of probiotics, was independently associated with a reduced risk for death in a retrospective, observational cohort study that included 200 adults with severe COVID-19 pneumonia [62]. In another study, nearly all COVID-19 patients treated with Sivomixx® showed remission of diarrhea and other symptoms within 72 h, in contrast to less than half in the control group [63]. However, the clinical application of probiotics in COVID-19 patients requires more evidence.
In, 22 trials of probiotics for the prevention or adjuvant therapy of COVID-19 were registered since April 2020, including one aiming to study the effect of oxygen-ozone therapy, one studying intranasal probiotics, and the other using throat spray-containing probiotic [64]. Of the remaining 19 trials, 8 common probiotic strains include Lactobacillus (7 trials), a mixture of Bifidobacteria and Lactobacillus (5), and Saccharomyces species (2) (Table 1). The major outcome was greatly diverse in these trials, including disease prevention, symptom relief, antibody titers, disease progression, changes of viral load, microbiome effects, and mortality. Based on these trials, the role of dietary supplement probiotics for COVID-19 can be more evident in the near future.
There are microbiome-targeting agents other than oral probiotics for patients with COVID-19 infection. A clinical trial of oral prebiotics, KB109, a novel synthetic glycan to modulate gut microbiome composition and to increase SCFA production in the gut, is ongoing (NCT04414124) [64]. Throat spray containing three Lactobacillus strains was implemented in a clinical trial to change the severity of COVID-19 and prevent transmission of SARS-COV-2 virus to household members (NCT04793997) [64]. Moreover, there are several next-generation probiotics identified by metagenomic approaches, such as F. prausnitzii and Akkermansia muciniphila, which can generate diffusible metabolites, including butyrate, desaminotyrosine, and SCFAs, and may improve pulmonary immunity and prevent viral respiratory infections [65]. It can be expected, in the future, microbiome-targeting therapy may decrease disease severity, relief symptoms, or prevent viral transmission, and play a role in the treatment of patients with COVID-19 infection

5. Conclusions

Patients with COVID-19 had significant changes in fecal microbiomes, characterized by the enrichment of opportunistic pathogens and the depletion of beneficial commensals, which is vastly associated with disease severity. Besides anti-viral agents or supportive treatment, microbiome-targeting therapy may provide an alternative to prevent COVID-19 deterioration. Oral probiotics may have antiviral effects via the gut–lung axis and improve gut health for achieving homeostasis. Although some commercial probiotics have been effective against coronavirus, the evidence detailing their efficacies in treating COVID-19 patients is limited. Registered clinical trials of probiotics in COVID-19, mainly Lactobacillus and mixtures of Bifidobacteria and Lactobacillus, are ongoing and thus the preventive or therapeutic role of probiotics for such patients can be elucidated in the near future.

Author Contributions

Y.-P.H., P.-J.T. and W.-C.K. designed the experiments, performed the experiments, analyzed the data, and participated in the writing of the manuscript. Y.-P.H., J.-C.L., C.-C.L., P.-J.T. and W.-C.K. All authors have read and agreed to the published version of the manuscript.


The present study was supported by research grants from the Ministry of Health and Welfare (MOHW105-CDC-C-114-122113), and the Ministry of Science and Technology (MOST 108-2321-B-006-004, 108-2320-B-006-043-MY3, 109-2314-B-006-089-MY3, 110-2314-B-675-001).

Institutional Review Board Statement

Not applicable for our review study.

Informed Consent Statement

Not applicable for our review study.

Data Availability Statement

Data available in a publicly accessible repository.

Conflicts of Interest

All authors report no conflicts of interest relevant to this article.


  1. Lamers, M.M.; Beumer, J.; van der Vaart, J.; Knoops, K.; Puschhof, J.; Breugem, T.I.; Ravelli, R.B.G.; van Schayck, J.P.; Mykytyn, A.Z.; Duimel, H.Q.; et al. SARS-CoV-2 productively infects human gut enterocytes. Science 2020, 369, 50–54. [Google Scholar] [CrossRef]
  2. Wu, F.; Zhao, S.; Yu, B.; Chen, Y.M.; Wang, W.; Song, Z.G.; Hu, Y.; Tao, Z.W.; Tian, J.H.; Pei, Y.Y.; et al. A new coronavirus associated with human respiratory disease In China. Nature 2020, 579, 265–269. [Google Scholar] [CrossRef] [Green Version]
  3. Suryana, K.D.; Simadibrata, M.; Renaldi, K. Impact of COVID-19 on the Gut: A review of the manifestations, pathology, management, and challenges. Acta Med. Indones. 2021, 53, 96–104. [Google Scholar]
  4. Letko, M.; Marzi, A.; Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B Betacoronaviruses. Nat. Microbiol. 2020, 5, 562–569. [Google Scholar] [CrossRef] [Green Version]
  5. Zhou, J.; Li, C.; Liu, X.; Chiu, M.C.; Zhao, X.; Wang, D.; Wei, Y.; Lee, A.; Zhang, A.J.; Chu, H.; et al. Infection of bat and human intestinal organoids by SARS-CoV-2. Nat. Med. 2020, 26, 1077–1083. [Google Scholar] [CrossRef] [PubMed]
  6. Hashimoto, T.; Perlot, T.; Rehman, A.; Trichereau, J.; Ishiguro, H.; Paolino, M.; Sigl, V.; Hanada, T.; Hanada, R.; Lipinski, S.; et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 2012, 487, 477–481. [Google Scholar] [CrossRef]
  7. de Oliveira, A.P.; Lopes, A.L.F.; Pacheco, G.; de Sa Guimaraes Noleto, I.R.; Nicolau, L.A.D.; Medeiros, J.V.R. Premises among SARS-CoV-2, dysbiosis and diarrhea: Walking through the ACE2/mTOR/autophagy route. Med. Hypotheses 2020, 144, 110243. [Google Scholar] [CrossRef] [PubMed]
  8. Bas, S.; Zarbaliyev, E. The role of dual-energy computed tomography in locating gastrointestinal tract perforations. Cureus 2021, 13, e15265. [Google Scholar]
  9. Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020, 323, 1061–1069. [Google Scholar] [CrossRef]
  10. Monkemuller, K.; Fry, L.C.; Rickes, S. Systemic inflammatory response and thrombosis due to alterations in the gut microbiota in COVID-19. Rev. Esp. Enferm. Dig. 2020, 112, 584–585. [Google Scholar] [PubMed]
  11. Finlay, B.B.; Amato, K.R.; Azad, M.; Blaser, M.J.; Bosch, T.C.G.; Chu, H.; Dominguez-Bello, M.G.; Ehrlich, S.D.; Elinav, E.; Geva-Zatorsky, N.; et al. The hygiene hypothesis, the COVID pandemic, and consequences for the human microbiome. Proc. Natl. Acad. Sci. USA 2021, 118, e2010217118. [Google Scholar] [CrossRef]
  12. Groves, H.T.; Higham, S.L.; Moffatt, M.F.; Cox, M.J.; Tregoning, J.S. Respiratory viral infection alters the gut microbiota by inducing inappetence. Mbio 2020, 11, e03236-19. [Google Scholar] [CrossRef] [Green Version]
  13. Ichinohe, T.; Pang, I.K.; Kumamoto, Y.; Peaper, D.R.; Ho, J.H.; Murray, T.S.; Iwasaki, A. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl. Acad. Sci. USA 2011, 108, 5354–5359. [Google Scholar] [CrossRef] [Green Version]
  14. Enaud, R.; Prevel, R.; Ciarlo, E.; Beaufils, F.; Wieers, G.; Guery, B.; Delhaes, L. The gut-lung axis in health and respiratory diseases: A place for inter-organ and inter-kingdom crosstalks. Front. Cell Infect. Microbiol. 2020, 10, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Dang, A.T.; Marsland, B.J. Microbes, metabolites, and the gut-lung axis. Mucosal Immunol. 2019, 12, 843–850. [Google Scholar] [CrossRef] [Green Version]
  16. Kuss, S.K.; Best, G.T.; Etheredge, C.A.; Pruijssers, A.J.; Frierson, J.M.; Hooper, L.V.; Dermody, T.S.; Pfeiffer, J.K. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science 2011, 334, 249–252. [Google Scholar] [CrossRef] [Green Version]
  17. Wilks, J.; Golovkina, T. Influence of microbiota on viral infections. PLoS Pathog. 2012, 8, e1002681. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Zhang, Q.; Hu, J.; Feng, J.W.; Hu, X.T.; Wang, T.; Gong, W.X.; Huang, K.; Guo, Y.X.; Zou, Z.; Lin, X.; et al. Influenza infection elicits an expansion of gut population of endogenous Bifidobacterium animalis which protects mice against infection. Genome Biol. 2020, 21, 99. [Google Scholar] [CrossRef] [PubMed]
  19. Negi, S.; Das, D.K.; Pahari, S.; Nadeem, S.; Agrewala, J.N. Potential role of gut microbiota in induction and regulation of innate immune memory. Front. Immunol. 2019, 10, 2441. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Dhar, D.; Mohanty, A. Gut microbiota and Covid-19- possible link and implications. Virus Res. 2020, 285, 198018. [Google Scholar] [CrossRef]
  21. Round, J.L.; Mazmanian, S.K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl. Acad. Sci. USA 2010, 107, 12204–12209. [Google Scholar] [CrossRef] [Green Version]
  22. Zuo, T.; Zhang, F.; Lui, G.C.Y.; Yeoh, Y.K.; Li, A.Y.L.; Zhan, H.; Wan, Y.; Chung, A.C.K.; Cheung, C.P.; Chen, N.; et al. Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology 2020, 159, 944–955.e8. [Google Scholar] [CrossRef]
  23. Tang, L.; Gu, S.; Gong, Y.; Li, B.; Lu, H.; Li, Q.; Zhang, R.; Gao, X.; Wu, Z.; Zhang, J.; et al. Clinical significance of the correlation between changes in the major intestinal bacteria species and COVID-19 severity. Eng. Beijing 2020, 6, 1178–1184. [Google Scholar] [CrossRef] [PubMed]
  24. Zuo, T.; Liu, Q.; Zhang, F.; Lui, G.C.; Tso, E.Y.; Yeoh, Y.K.; Chen, Z.; Boon, S.S.; Chan, F.K.; Chan, P.K.; et al. Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut 2021, 70, 276–284. [Google Scholar] [CrossRef]
  25. Gu, S.; Chen, Y.; Wu, Z.; Chen, Y.; Gao, H.; Lv, L.; Guo, F.; Zhang, X.; Luo, R.; Huang, C.; et al. Alterations of the gut microbiota in patients with coronavirus disease 2019 or H1N1 influenza. Clin. Infect. Dis. 2020, 71, 2669–2678. [Google Scholar] [CrossRef]
  26. Lahti, L.; Salojarvi, J.; Salonen, A.; Scheffer, M.; de Vos, W.M. Tipping elements in the human intestinal ecosystem. Nat. Commun. 2014, 5, 4344. [Google Scholar] [CrossRef] [Green Version]
  27. McNabney, S.M.; Henagan, T.M. Short chain fatty acids in the colon and peripheral tissues: A focus on butyrate, colon cancer, obesity and insulin resistance. Nutrients 2017, 9, 1348. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Newsome, R.C.; Gauthier, J.; Hernandez, M.C.; Abraham, G.E.; Robinson, T.O.; Williams, H.B.; Sloan, M.; Owings, A.; Laird, H.; Christian, T.; et al. The gut microbiome of COVID-19 recovered patients returns to uninfected status in a minority-dominated United States cohort. Gut Microbes 2021, 13, 1–15. [Google Scholar] [CrossRef] [PubMed]
  29. Xu, K.; Cai, H.; Shen, Y.; Ni, Q.; Chen, Y.; Hu, S.; Li, J.; Wang, H.; Yu, L.; Huang, H.; et al. Management of corona virus disease-19 (COVID-19): The Zhejiang experience. Zhejiang Exp. J. Zhejiang Univ. Med. Sci. 2020, 49, 147–157. [Google Scholar]
  30. Larsen, J.M. The immune response to Prevotella bacteria in chronic inflammatory disease. Immunology 2017, 151, 363–374. [Google Scholar] [CrossRef] [Green Version]
  31. Zuo, T.; Zhan, H.; Zhang, F.; Liu, Q.; Tso, E.Y.K.; Lui, G.C.Y.; Chen, N.; Li, A.; Lu, W.; Chan, F.K.L.; et al. Alterations in fecal fungal microbiome of patients with COVID-19 during time of hospitalization until discharge. Gastroenterology 2020, 159, 1302–1310. [Google Scholar] [CrossRef]
  32. Chen, Y.; Gu, S.; Chen, Y.; Lu, H.; Shi, D.; Guo, J.; Wu, W.R.; Yang, Y.; Li, Y.; Xu, K.J.; et al. Six-month follow-up of gut microbiota richness in patients with COVID-19. Gut 2021. [Google Scholar] [CrossRef]
  33. Yasui, H.; Kiyoshima, J.; Hori, T.; Shida, K. Protection against influenza virus infection of mice fed Bifidobacterium breve YIT4064. Clin. Diagn. Lab. Immunol. 1999, 6, 186–192. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Xia, Y.; Cao, J.; Wang, M.; Lu, M.; Chen, G.; Gao, F.; Liu, Z.; Zhang, D.; Ke, X.; Yi, M. Effects of Lactococcus lactis subsp. lactis JCM5805 on colonization dynamics of gut microbiota and regulation of immunity in early ontogenetic stages of tilapia. Fish Shellfish Immunol. 2019, 86, 53–63. [Google Scholar] [CrossRef]
  35. Su, M.; Jia, Y.; Li, Y.; Zhou, D.; Jia, J. Probiotics for the prevention of ventilator-associated pneumonia: A meta-analysis of randomized controlled trials. Respir. Care 2020, 65, 673–685. [Google Scholar] [CrossRef] [PubMed]
  36. Ragab, D.; Salah Eldin, H.; Taeimah, M.; Khattab, R.; Salem, R. The COVID-19 cytokine storm; what we know so far. Front. Immunol. 2020, 11, 1446. [Google Scholar] [CrossRef] [PubMed]
  37. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef] [Green Version]
  38. Britton, G.J.; Chen-Liaw, A.; Cossarini, F.; Livanos, A.E.; Spindler, M.P.; Plitt, T.; Eggers, J.; Mogno, I.; Gonzalez-Reiche, A.; Siu, S.; et al. SARS-CoV-2-specific IgA and limited inflammatory cytokines are present in the stool of select patients with acute COVID-19. MedRxiv 2020. [Google Scholar] [CrossRef]
  39. Han, S.K.; Shin, Y.J.; Lee, D.Y.; Kim, K.M.; Yang, S.J.; Kim, D.S.; Choi, J.W.; Lee, S.; Kim, D.H. Lactobacillus rhamnosus HDB1258 modulates gut microbiota-mediated immune response in mice with or without lipopolysaccharide-induced systemic inflammation. BMC Microbiol. 2021, 21, 146. [Google Scholar] [CrossRef]
  40. Al Kassaa, I.; Hober, D.; Hamze, M.; Chihib, N.E.; Drider, D. Antiviral potential of lactic acid bacteria and their bacteriocins. Probiotics Antimicrob. Proteins 2014, 6, 177–185. [Google Scholar] [CrossRef]
  41. Baindara, P.; Chakraborty, R.; Holliday, Z.M.; Mandal, S.M.; Schrum, A.G. Oral probiotics in coronavirus disease 2019: Connecting the gut-lung axis to viral pathogenesis, inflammation, secondary infection and clinical trials. New Microbes New Infect. 2021, 40, 100837. [Google Scholar] [CrossRef] [PubMed]
  42. Starosila, D.; Rybalko, S.; Varbanetz, L.; Ivanskaya, N.; Sorokulova, I. Anti-influenza activity of a Bacillus subtilis probiotic strain. Antimicrob. Agents Chemother. 2017, 61, e00539-17. [Google Scholar] [CrossRef] [Green Version]
  43. Malaczewska, J.; Kaczorek-Lukowska, E.; Wojcik, R.; Siwicki, A.K. Antiviral effects of nisin, lysozyme, lactoferrin and their mixtures against bovine viral diarrhoea virus. BMC Vet. Res. 2019, 15, 318. [Google Scholar] [CrossRef] [Green Version]
  44. Zeng, J.; Wang, C.T.; Zhang, F.S.; Qi, F.; Wang, S.F.; Ma, S.; Wu, T.J.; Tian, H.; Tian, Z.T.; Zhang, S.L.; et al. Effect of probiotics on the incidence of ventilator-associated pneumonia in critically ill patients: A randomized controlled multicenter trial. Intensive Care Med. 2016, 42, 1018–1028. [Google Scholar] [CrossRef]
  45. Morrow, L.E.; Kollef, M.H.; Casale, T.B. Probiotic prophylaxis of ventilator-associated pneumonia: A blinded, randomized, controlled trial. Am. J. Respir. Crit. Care Med. 2010, 182, 1058–1064. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Jung, Y.J.; Lee, Y.T.; Ngo, V.L.; Cho, Y.H.; Ko, E.J.; Hong, S.M.; Kim, K.H.; Jang, J.H.; Oh, J.S.; Park, M.K.; et al. Heat-killed Lactobacillus casei confers broad protection against influenza A virus primary infection and develops heterosubtypic immunity against future secondary infection. Sci. Rep. 2017, 7, 17360. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Bidossi, A.; De Grandi, R.; Toscano, M.; Bottagisio, M.; De Vecchi, E.; Gelardi, M.; Drago, L. Probiotics Streptococcus salivarius 24SMB and Streptococcus oralis 89a interfere with biofilm formation of pathogens of the upper respiratory tract. BMC Infect. Dis. 2018, 18, 653. [Google Scholar] [CrossRef] [PubMed]
  48. Di Pierro, F. A possible probiotic (S. salivarius K12) approach to improve oral and lung microbiotas and raise defenses against SAR S-CoV-2. Minerva Med. 2020, 111, 281–283. [Google Scholar] [CrossRef] [PubMed]
  49. Bottari, B.; Castellone, V.; Neviani, E. Probiotics and COVID-19. Int. J. Food Sci. Nutr. 2021, 72, 293–299. [Google Scholar] [CrossRef]
  50. Kumar, R.; Seo, B.J.; Mun, M.R.; Kim, C.J.; Lee, I.; Kim, H.; Park, Y.H. Putative probiotic Lactobacillus spp. from porcine gastrointestinal tract inhibit transmissible gastroenteritis coronavirus and enteric bacterial pathogens. Trop. Anim. Health Prod. 2010, 42, 1855–1860. [Google Scholar]
  51. Chai, W.; Burwinkel, M.; Wang, Z.; Palissa, C.; Esch, B.; Twardziok, S.; Rieger, J.; Wrede, P.; Schmidt, M.F. Antiviral effects of a probiotic Enterococcus faecium strain against transmissible gastroenteritis coronavirus. Arch. Virol. 2013, 158, 799–807. [Google Scholar] [CrossRef] [Green Version]
  52. Liu, Y.S.; Liu, Q.; Jiang, Y.L.; Yang, W.T.; Huang, H.B.; Shi, C.W.; Yang, G.L.; Wang, C.F. Surface-displayed porcine IFN-lambda3 in Lactobacillus plantarum inhibits porcine enteric coronavirus infection of porcine intestinal epithelial cells. J. Microbiol. Biotechnol. 2020, 30, 515–525. [Google Scholar] [CrossRef] [PubMed]
  53. Mak, J.W.Y.; Chan, F.K.L.; Ng, S.C. Probiotics and COVID-19: One size does not fit all. Lancet Gastroenterol. Hepatol. 2020, 5, 644–645. [Google Scholar] [CrossRef]
  54. Kurian, S.J.; Unnikrishnan, M.K.; Miraj, S.S.; Bagchi, D.; Banerjee, M.; Reddy, B.S.; Rodrigues, G.S.; Manu, M.K.; Saravu, K.; Mukhopadhyay, C.; et al. Probiotics in prevention and treatment of COVID-19: Current perspective and future prospects. Arch. Med. Res. 2021. [Google Scholar] [CrossRef] [PubMed]
  55. Peng, J.; Zhang, M.; Yao, G.; Kwok, L.Y.; Zhang, W. Probiotics as adjunctive treatment for patients contracted COVID-19: Current understanding and future needs. Front. Nutr. 2021, 8, 669808. [Google Scholar] [CrossRef]
  56. Sundararaman, A.; Ray, M.; Ravindra, P.V.; Halami, P.M. Role of probiotics to combat viral infections with emphasis on COVID-19. Appl. Microbiol. Biotechnol. 2020, 104, 8089–8104. [Google Scholar] [CrossRef] [PubMed]
  57. Khaled, J.M.A. Probiotics, prebiotics, and COVID-19 infection: A review article. Saudi J. Biol. Sci. 2021, 28, 865–869. [Google Scholar] [CrossRef]
  58. Esaiassen, E.; Cavanagh, P.; Hjerde, E.; Simonsen, G.S.; Stoen, R.; Klingenberg, C. Bifidobacterium longum subspecies infantis bacteremia in 3 extremely preterm infants receiving probiotics. Emerg. Infect. Dis. 2016, 22, 1664–1666. [Google Scholar] [CrossRef] [Green Version]
  59. Bertelli, C.; Pillonel, T.; Torregrossa, A.; Prod’hom, G.; Fischer, C.J.; Greub, G.; Giannoni, E. Bifidobacterium longum bacteremia in preterm infants receiving probiotics. Clin. Infect. Dis. 2015, 60, 924–927. [Google Scholar] [CrossRef] [Green Version]
  60. Alataby, H.; Atemnkeng, F.; Bains, S.S.; Kenne, F.M.; Diaz, K.; Nfonoyim, J. A COVID-19 case complicated by Candida dubliniensis and Klebsiella pneumoniae-carbapenem-resistant Enterobacteriaceae. J. Med. Cases 2020, 11, 403–406. [Google Scholar] [CrossRef]
  61. Miao, Q.; Ma, Y.; Ling, Y.; Jin, W.; Su, Y.; Wang, Q.; Pan, J.; Zhang, Y.; Chen, H.; Yuan, J.; et al. Evaluation of superinfection, antimicrobial usage, and airway microbiome with metagenomic sequencing in COVID-19 patients: A cohort study in Shanghai. J. Microbiol. Immunol. Infect. 2021. [Google Scholar] [CrossRef] [PubMed]
  62. Ceccarelli, G.; Borrazzo, C.; Pinacchio, C.; Santinelli, L.; Innocenti, G.P.; Cavallari, E.N.; Celani, L.; Marazzato, M.; Alessandri, F.; Ruberto, F.; et al. Oral bacteriotherapy in patients with COVID-19: A retrospective cohort study. Front. Nutr. 2020, 7, 613928. [Google Scholar] [CrossRef]
  63. d’Ettorre, G.; Ceccarelli, G.; Marazzato, M.; Campagna, G.; Pinacchio, C.; Alessandri, F.; Ruberto, F.; Rossi, G.; Celani, L.; Scagnolari, C.; et al. Challenges in the management of SARS-CoV2 Infection: The role of oral bacteriotherapy as complementary therapeutic strategy to avoid the progression of COVID-19. Front. Med. 2020, 7, 389. [Google Scholar] [CrossRef] [PubMed]
  64. Available online: (accessed on 24 July 2021).
  65. Gautier, T.; Gall, S.D.L.; Sweidan, A.; Tamanai-Shacoori, Z.; Jolivet-Gougeon, A.; Loréal, O.; Bousarghin, L. Next-generation probiotics and their metabolites in COVID-19. Microorganisms 2021, 9, 941. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Gastrointestinal involvement and disturbance of gut microbiota during COVID-19 and recovery by dietary supplement of probiotics.
Figure 1. Gastrointestinal involvement and disturbance of gut microbiota during COVID-19 and recovery by dietary supplement of probiotics.
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Table 1. Nineteen clinical trials of dietary supplement of probiotics in coronavirus disease 2019 (COVID-19) registered at posted from April 2020 to June 2021.
Table 1. Nineteen clinical trials of dietary supplement of probiotics in coronavirus disease 2019 (COVID-19) registered at posted from April 2020 to June 2021. IdentifierStudy TitleFirst PostedStudy DesignProbiotic StrainLocationOutcome MeasuresStatus
NCT04366180Evaluation of probiotic Lactobacillus coryniformis K8 on COVID-19 prevention in healthcare workers28 April 2020RandomizedL. coryniformis K8Granada, SpainIncidence of COVID-19 infection in healthcare workersRecruiting
NCT04390477Study to evaluate the effect of a probiotic in COVID-1915 May 2020RandomizedNot revealedAlicante, SpainICU admission rateRecruiting
NCT04399252Effect of Lactobacillus on the microbiome of household contacts exposed to COVID-1922 May 2020RandomizedL. rhamnosus GGNorth Carolina, United StatesIncidence of symptoms of COVID-19Active, not recruiting
NCT04420676Synbiotic therapy of gastrointestinal symptoms during COVID-19 infection (SynCov)9 June 2020RandomizedOmni-Biotic® 10 AAD (chiefly Lactobacillus and Bifidobacterium)Graz, AustriaStool calprotectinRecruiting
NCT04462627Reduction of COVID 19 transmission to health care professionals8 July 2020Non-randomizedMetagenics Probactiol plus (chiefly Lactobacillus and Bifidobacterium)Brussels, BelgiumAntibody concentrationRecruiting
NCT04507867Effect of a NSS to reduce complications in patients with COVID-19 and comorbidities in stage III11 August 2020RandomizedSaccharomyces bourllardii with nutritional support system (NSS)MexicoOxygen saturationNot yet recruiting
NCT04517422Efficacy of L. plantarum and P. acidilactici in adults with SARS-CoV-2 and COVID-1918 August 2020RCTL. plantarum and P. acidilacticiMexico City, MexicoSeverity progression of COVID-19Completed
NCT04621071Efficacy of probiotics in reducing duration and symptoms of COVID-19 (PROVID-19)9 November 2020RCTNot revealedCanada, QuebecDuration of symptoms of the COVID-19Recruiting
NCT04666116Changes in viral load in COVID-19 after probiotics14 December 2020Randomized, single blindGASTEEL PLUS (mixture of Bifidobacteria and Lactobacillus)Valencia, SpainViral load in nasopharyngeal smearRecruiting
NCT04734886The effect of probiotic supplementation on SARS-CoV-2 antibody response after COVID-192 February 2021RandomizedL. reuteri DSM 17938 + vitamin DÖrebro Län, SwedenSARS-CoV-2 specific antibodiesRecruiting
NCT04756466Effect of the consumption of a Lactobacillus strain on the incidence of COVID-19 in the elderly16 February 2021RCTLactobacillus strainA Coruña, SpainIncidence of SARS CoV-2 infectionActive, not recruiting
NCT04798677Efficacy and tolerability of ABBC1 in volunteers receiving the influenza or COVID-19 Vaccine15 March 2021Non-randomizedS. cerevisiae, rich in selenium and zincBarcelona, SpainChange in acute immune response to influenza vaccine after supplementationRecruiting
NCT04813718Post COVID-19 syndrome and the gut-lung axis24 March 2021RandomizedOmni-Biotic Pro Vi 5 (chiefly Lactobacillus)Graz, AustriaMicrobiome compositionRecruiting
NCT04847349Live microbials to boost anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) immunity clinical trial19 April 2021RCTOL-1 (Content not revealed)New Jersey, United StatesChange in serum titer of anti-SARS-CoV-2 IgGRecruiting
NCT04854941Efficacy of probiotics in the treatment of hospitalized patients with novel coronavirus infection22 April 2021RandomizedL. rhamnosus, B. bifidum, B. longum subsp. infantis and B. longumMoscow, RussianMortalityCompleted
NCT04877704Symprove (Probiotic) as an add-on to COVID-19 management7 May 2021RandomizedSymprove ( L. rhamnosus, E. faecium, L. acidophilus and L. plantarum)London, United KingdomLength of hospital stayNot yet recruiting
NCT04884776Modulation of gut microbiota to enhance health and immunity13 May 2021RCTProbiotics blend (3 Bifidobacteria)Hong KongRestoration of gut dysbiosisNot yet recruiting
NCT04907877Bifidobacteria and Lactobacillus in symptomatic adult COVID-19 outpatients (ProCOVID)1 June 2021RandomizedNordBiotic ImmunoVir (mixture of Bifidobacteria and Lactobacillus)Not revealedGlobal symptom scoreNot yet recruiting
NCT04922918Ligilactobacillus salivarius MP101 for elderly in a nursing home (PROBELDERLY)11 June 2021Single groupLigilactobacillus salivarius MP101Madrid, SpainBarthel index, functional status scoreRecruiting
RCT: randomized controlled trial; ICU: intensive care unit; IgG: immunoglobulin G.
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Hung, Y.-P.; Lee, C.-C.; Lee, J.-C.; Tsai, P.-J.; Ko, W.-C. Gut Dysbiosis during COVID-19 and Potential Effect of Probiotics. Microorganisms 2021, 9, 1605.

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Hung Y-P, Lee C-C, Lee J-C, Tsai P-J, Ko W-C. Gut Dysbiosis during COVID-19 and Potential Effect of Probiotics. Microorganisms. 2021; 9(8):1605.

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Hung, Yuan-Pin, Ching-Chi Lee, Jen-Chieh Lee, Pei-Jane Tsai, and Wen-Chien Ko. 2021. "Gut Dysbiosis during COVID-19 and Potential Effect of Probiotics" Microorganisms 9, no. 8: 1605.

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