Diagnostic, Prognostic, and Therapeutic Roles of Gut Microbiota in COVID-19: A Comprehensive Systematic Review

Abstract

Introduction:

The Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) emerged in late December 2019. Considering the important role of gut microbiota in maturation, regulation, and induction of the immune system and subsequent inflammatory processes, it seems that evaluating the composition of gut microbiota in COVID-19 patients compared with healthy individuals may have potential value as a diagnostic and/or prognostic biomarker for the disease. Also, therapeutic interventions affecting gut microbial flora may open new horizons in the treatment of COVID-19 patients and accelerating their recovery.

Methods:

A systematic search was conducted for relevant studies published from December 2019 to December 2021 using Pubmed/Medline, Embase, and Scopus. Articles containing the following keywords in titles or abstracts were selected: “SARS-CoV-2” or “COVID-19” or “Coronavirus Disease 19” and “gastrointestinal microbes” or “dysbiosis” or “gut microbiota” or “gut bacteria” or “gut microbes” or “gastrointestinal microbiota”.

Results:

Out of 1,668 studies, 22 articles fulfilled the inclusion criteria and a total of 1,255 confirmed COVID-19 patients were examined. All included studies showed a significant association between COVID-19 and gut microbiota dysbiosis. The most alteration in bacterial composition of COVID-19 patients was depletion in genera Ruminococcus, Alistipes, Eubacterium, Bifidobacterium, Faecalibacterium, Roseburia, Fusicathenibacter, and Blautia and enrichment of Eggerthella, Bacteroides, Actinomyces, Clostridium, Streptococcus, Rothia, and Collinsella. Also, some gut microbiome alterations were associated with COVID-19 severity and poor prognosis including the increment of Bacteroides, Parabacteroides, Clostridium, Bifidobacterium, Ruminococcus, Campylobacter, Rothia, Corynebacterium, Megasphaera, Enterococcus, and Aspergillus spp. and the decrement of Roseburia, Eubacterium, Lachnospira, Faecalibacterium, and the Firmicutes/Bacteroidetes ratio.

Conclusion:

Our study showed a significant change of gut microbiome composition in COVID-19 patients compared with healthy individuals. This great extent of impact has proposed the gut microbiota as a potential diagnostic, prognostic, and therapeutic strategy for COVID-19. There is much evidence about this issue, and it is expected to be increased in near future.

Introduction

A pandemic caused by Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) emerged in late December 2019 (Zhu et al., 2020). The World Health Organization (WHO) named the consequent disease as Coronavirus Disease 2019 (COVID-19) and declared it as a global emergency due to the serious public health effects (Jamshidi et al., 2021). According to the report of the WHO, until February 1, 2022, there have been about 376 million confirmed cases and about 5.6 million deaths due to COVID-19 around the world.

The angiotensin-converting enzyme 2 (ACE2) receptor is a known SARS-CoV-2 receptor for entering host cells (Li et al., 2003; Zhou et al., 2020). This receptor is detected in various cells of the body such as the respiratory, digestive, renal, and skin epithelium, suggesting that each of these organs could be a potential target for the virus (Jamshidi et al., 2021; Xue et al., 2021). Moreover, virus RNA and viral particles have been identified in the fecal sample of COVID-19 patients, which may indicate the possibility of virus replication and activity in the human intestine (Gu et al., 2020a; Lamers et al., 2020; Xu et al., 2020).

Gut microbiota plays a well-known role in regulating immune system responses (Donaldson et al., 2016;; Schirmer et al., 2016). Recent studies indicate the role of gut dysbiosis in the pathogenesis of various diseases such as inflammatory bowel disease, type 1 and type 2 diabetes, and celiac disease, as well as chronic respiratory diseases such as asthma, COPD, and cystic fibrosis (Jamshidi et al., 2019; Enaud et al., 2020).

Bacteria in the human intestinal flora appear to affect the respiratory system and lungs (especially the lung microbiota) by producing metabolites, endotoxins, cytokines, and intestinal hormones reaching the bloodstream, which is called the gut–lung axis (Budden et al., 2017; Dang and Marsland, 2019; Zhang et al., 2020).

On the other hand, there is evidence of the role of gut dysbiosis in the severity and prognosis of bacterial (e.g., Streptococcus pneumonia, Klebsiella pneumonia, Pseudomonas aeruginosa, Mycobacterium tuberculosis) and viral (e.g., H1N1 influenza) respiratory infectious diseases in animal models (Ichinohe et al., 2011; Fagundes et al., 2012; Fox et al., 2012; Brown et al., 2017). The use of broad-spectrum antibiotics that target the gut microbiota has led to a poor prognosis in mouse models with infectious lung diseases (Enaud et al., 2020).

Considering the important role of gut microbiota in maturation, regulation, and induction of the immune system and subsequent inflammatory processes, it seems that evaluating the composition of gut microbiota in COVID-19 patients compared with healthy individuals may have potential value as a diagnostic and/or prognostic biomarker of the disease. Also, therapeutic interventions affecting gut microbial flora may open new horizons in the treatment of COVID-19 patients and accelerating their recovery.

Methods

This review conforms to the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) statement (Moher et al., 2009).

Search Strategy and Selection Criteria

To investigate the diagnostic, prognostic, and therapeutic role of the gut microbiota composition in COVID-19, a systematic search was conducted for relevant studies published from December 2019 to December 2021 using Pubmed/Medline, Embase, and Scopus.

Articles containing the following keywords in titles or abstracts were selected: “SARS-CoV-2” or “COVID-19” or “Coronavirus Disease 19” and “gastrointestinal microbes” or “dysbiosis” or “gut microbiota” or “gut bacteria” or “gut microbes” or “gastrointestinal microbiota”. Only studies included if they contained data about the gut microbiota composition in COVID-19 patients. There were no language restrictions. Review articles, duplicate publications, letters, commentary, animal studies, and articles with no relevant data were excluded from the analysis. Two authors (MA and FV) independently screened the articles by title and abstract. Full-text screening was conducted by two other authors independently (AT and YF). In each step, contrarieties were discussed with a third reviewer (PJ).

Data Extraction

A data extraction form designed by two authors (PJ and MJN) and, finally, selected data were extracted from the full text of eligible publications by PJ, YF, AT, MA, and FV. The following data were extracted for further analysis: first author’s name, year of publication, country where the study was executed, type of study, study population, mean age, gender, COVID-19 severity of the cases, comorbidity(ies), microbiota analysis technique, intestinal microbiota alterations, biochemical and immunological alterations, and studied value of gut microbiota alterations in COVID-19. The data were jointly reconciled, and disagreements were discussed and resolved by review authors (PJ, MJN).

Quality Assessment

The critical appraisal checklist for case reports provided by the Joanna Briggs Institute (JBI) was used to perform a quality assessment of the studies (Institute, 2021).

Results

As shown in Figure 1, the primary search resulted in 1,668 relevant articles, of which 47 articles were selected after title and abstract screening. Following the full-text screening, 22 articles fulfilled the inclusion criteria. Most of the studies were case–control (n = 9) followed by cohort (n = 9), clinical trial (n = 2), and cross-sectional (n = 2) studies. Fifteen of the studies were executed in China, 2 in Italy and 1 in UK, Portugal, India, Egypt, and Korea (Table 1).

Figure 1

A total of 1,255 confirmed COVID-19 patients were examined in 22 included articles (Table 1). Among the COVID-19 patients whose comorbidity was mentioned by the authors, the most common ones were hypertension (32.8%) and diabetes mellitus (17.8%). Other reported comorbidities were chronic respiratory disease (6.9%), cardiovascular disease (3%), immunosuppression (2.9%), dyslipidemia (2.3%), thrombotic events (2%), and renal impairment (1.6%). See Table 2.

Ten studies assessed gut microbiota composition alteration by fecal samples; one study used plasma samples, and it was not mentioned by the rest. The most commonly used techniques in these studies for detection and assessment of gut microbiota were 16s rRNA sequencing and shotgun metagenomic sequencing analysis (Table 1).

Gut Microbiome Dysbiosis of COVID-19 Patients

All included studies showed a significant association between COVID-19 and gut microbiota dysbiosis (Table 3). The most alteration in the bacterial composition of COVID-19 patients was depletion in genera Ruminococcus, Alistipes, Eubacterium, Bifidobacterium, Faecalibacterium, Roseburia, Fusicathenibacter, and Blautia and enrichment of Eggerthella, Bacteroides, Actinomyces, Clostridium, Streptococcus, Rotia, and Collinsella. Details are shown in Table 4.

Three articles surveyed the gut mycobiota alterations, and different results have been reported for different species of the same genus. About the Candida spp., an increase in Candida albicans and a decrease in Candida glabrata and Candida parapsilosis were mentioned. In regard to Aspergillus spp., enrichment of Aspergillus flavus and Aspergillus niger and a depletion of Aspergillus rugulosus, Aspergillus tritici, and Aspergillus penicillioides were reported. Also, one study indicated a reduction in seven unclassified species belonging to order Helotiales, Pleosporales, and Sordariales, family Exidiaceae, and genera Microscypha and Emericellopsis in COVID-19 patients (Table 4).

According to all gut microbiota changes that were mentioned in the reviewed articles, a decrease in phyla Firmicutes and Bacteroidetes and an increase in phylum Actinobacteria among COVID-19 patients were inferred.

Association Between Gut Microbiota Composition and COVID-19 Severity

A few studies indicated the role of gut microbiome in COVID-19 severity (Table 4). In severe COVID-19 cases, Bacteroides spp., Parabacteroides spp., Clostridium spp., Bifidobacterium spp., Ruminococcus spp., Campylobacter spp., Rothia spp., Corynebacterium spp., Megasphaera spp., Enterococcus spp., and Aspergillus spp. were increased and Roseburia spp., Eubacterium spp., Lachnospira spp., Faecalibacterium spp., and Firmicutes/Bacteroidetes ratio were decreased significantly. In subjects with mild disease the observed significant change was in the enrichment of Eubacterium spp.

The alteration of the gut virome composition in severe COVID-19 cases was mentioned in two studies. In severe cases, fourteen Microviridae phages, one Inoviridae phage, one Podoviridae phage, and one unclassified virus were increased and plant-derived RNA virus, pepper chlorotic spot virus (PCSV), Myxococcus phage, Rheinheimera phage, Microcystis virus, Bacteroides phage, Murmansk poxvirus, Saudi moumouvirus, Sphaerotilus phage, Tomelloso virus, and Ruegeria phage were decreased significantly. See Table 4.

One study evaluated the associations between gut microbiota disturbance and SARS-CoV-2 viral loads and revealed that Prevotella copri and Eubacterium dolichum were positively correlated and Streptococcus anginosus, Dialister spp., Alistipes spp., Ruminococcus spp., Clostridium citroniae, Bifidobacterium spp., Haemophilus spp., and Haemophilus parainfluenzae were negatively correlated with the viral load of SARS-CoV-2.

Biochemical and Immunologic Modifications in Relation to Gut Microbiota Alternations in COVID-19 Patients

In most studies, compared with healthy controls, COVID-19 patients had significantly higher levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) and lower lymphocyte counts.

According to one study, a positive correlation between Bifidobacterium spp. and prothrombin time (PT) and lactate dehydrogenase (LDH) was shown. Also, a negative correlation was reported between Atopobium spp. and D-dimer, Bacteroides spp. and LDH and creatine kinase (CK) level, Clostridium butyricum, and CRP and neutrophil count, and Faecalibacterium prausnitzii and CRP in critical COVID-19 patients. One study showed a specific relation between some genus of gut microbiota and immunological and biochemical modifications in critical and severe COVID-19 patients. In severe patients, Faecalibacterium prausnitzii and Clostridium leptum had a positive correlation with neutrophil count as well as Eubacterium rectale with IL-6 and Enterobacteriaceae with AST.

Another study indicated the specific relation of some species of gut microbiome and immune cells as the following: Bacteroides ovatus, Lachnospiraceae bacterium, and Eubacterium ventriosum had a positive correlation with CD4 and CD8 lymphocytes and other T-cells, in contrast to Bifidobacterium animalis and Escherichia spp. On the other hand, Faecalibacterium prausnitzii had a positive correlation with NK cells and Coprobacillus spp., Clostridium ramosum, and Clostridium symbiosum had a negative correlation with them.

Studied Value of Gut Microbiome in COVID-19

All of the included studies showed a correlation between intestinal microbiota and COVID-19, and they studied the correlation in different aspects as in the following.

Four studies suggested that microbiota could have therapeutic properties with reducing gastrointestinal (GI) symptoms. Streptococcus, Lactobacillus, and Bifidobacterium were the most common bacterial genera interventions used so far. Nine articles demonstrated intestinal microbiota modifications in infected cases with COVID-19 in which two of them confirmed the value of specified gut microbiota as a diagnostic tool and one of them studied gut microbiota changes during recovery time. Lachnospiraceae are a large family including Fusicathenibacter, Eubacterium hallii group, and Roseburia, and the Ruminococcaceae family including Faecalibacterium prausnitzii and Ruminococcus as well as Clostridium spp., Bacteroides spp., Lactobacillus spp., Rothia spp., Actinomyces spp., Lactobacillus spp., and Streptococcus spp. were the most common bacteria with diagnostic value. Thirteen studies demonstrated a relationship between gut microbiota changes and the intensity and prognosis of COVID-19. Eubacterium, Faecalibacterium, Ruminococcus, Bacteroides, Clostridium, Lactobacillus, Bifidobacterium, and Roseburia were the most notable bacterial genera with prognostic values. Details are shown in Table 3.

Discussion

The interaction between gut microbiota and viral respiratory diseases such as COVID-19 is a complex, bilateral, and dynamic association. The current study emphasizes the role of the gut–lung axis (GLA) in the pathogenesis of COVID-19. One of the important aspects of GLA is the impact of gut microbiota on the supply and maintenance of the lung immune system, and its correlation with respiratory diseases and infections (He et al., 2017; Dang and Marsland, 2019; Ahmadi Badi et al., 2021; Allali et al., 2021). The gut and lung microbiome are closely related in health or disease conditions (Dickson and Huffnagle, 2015; Enaud et al., 2020; Ahmadi Badi et al., 2021). SARS-CoV-2 may cause a dysbiosis in the lung microbiota to increase the population of inflammatory bacteria such as Klebsiella oxytoca and Rothia mucilaginosa which is associated with acute respiratory distress syndrome (Aktaş and Aslim, 2020; Han et al., 2020; van der Lelie and Taghavi, 2020; Battaglini et al., 2021; Chattopadhyay and Shankar, 2021). The high levels of inflammatory cytokine productions during SARS-CoV-2 invasion interfere with gut mucosal integrity and increasing risk of bacterial disposition to the bloodstream (Chattopadhyay and Shankar, 2021; Prasad et al., 2021).

Based on our findings, gut microbiota in patients with SARS-CoV-2 is significantly affected, possibly due to systemic inflammatory response. Although the underlying mechanism for the observed dysbiosis is unclear, it might happen via downregulation of ACE2 expression that alleviates the intestinal absorption of tryptophan leading to decreased secretion of antimicrobial peptides and changes the composition of gut microbiota (He et al., 2020). In a healthy individual, intact bacteria and their fragments or metabolites such as des-amino-tyrosine and short-chain fatty acids (SCFAs) pass across the intestinal barrier via the mesenteric lymphatic system, reach the lung, and activate the innate immune system by the production of cytokines like type 1 interferon (IFN1) (Antunes et al., 2019). In the current study, Faecalibacterium prausnitzii and Clostridium leptum have a positive correlation with neutrophil counts in COVID-19 patients and a negative correlation with Clostridium butyricum. In addition to the innate immunity, gut microbiota improves the function of CD8+ T-cell effectors (Trompette et al., 2018). There is also evidence that few bacterial species such as Bacteroides ovatus, Lachnospiraceae bacterium 5_1_63FAA, and Eubacterium ventriosum have an anti-inflammatory property in CD4⁺ and CD8⁺ T cells (Cao et al., 2021). Natural killer (NK) cells and B cells are also affected by gut microbiota; Coprobacillus spp., Clostridium ramosum, and Clostridium symbiosum are negatively associated with NK cell activity and Bacteroides uniformis, Faecalibacterium prausnitzii, and Subdoligranulum are positively correlated with B cells (Cao et al., 2021).

We found that the dysbiosis of gut microbiota may be a determinant factor in the clinical severity of COVID-19. Increase of the dominant Enterococcus and reduction of Ruminococcaceae and Lachnospiraceae are reported in severe cases of COVID-19 who were admitted to the medical intensive unit (MICU) (Gaibani et al., 2021).

Diversity of gut microbiota reduces in patients with COVID-19, which is associated with pro-inflammatory reaction and increased risk of opportunistic infections. GI symptoms of COVID-19 are reported to be strongly affected by gut microbial composition (Din et al., 2021; Katz-Agranov and Zandman-Goddard, 2021). The expression of the ACE-2 receptor on the surface of small intestine epithelial cells has been significantly associated with the extent of GI symptoms and fecal viral shedding during the course of disease (D’Amico et al., 2020; Patel et al., 2020; Wu et al., 2020; Katz-Agranov and Zandman-Goddard, 2021; Suárez-Fariñas et al., 2021). An increased expression of ACE-2 receptor in COVID-19 may occur due to a dominance of Coprobacillus in gut microbiota (Geva-Zatorsky et al., 2017; Enaud et al., 2020; Zuo et al., 2020a; Massip Copiz, 2021; Rajput et al., 2021; Walton et al., 2021). It is also noteworthy to imply that the expression of ACE-2 on luminal cells may be a determinant factor in microbial composition as the ACE-2 receptor plays some role in amino-acid absorption (Harmer et al., 2002; Dang and Marsland, 2019).

Eggerthella is another genus of bacteria which significantly increases in patients with COVID-19 (d’Ettorre et al., 2020; Cao et al., 2021). Eggerthella may induce colitis via abnormal activation of Th17 in patients with inflammatory diseases. It can interfere with gut integrity and make the patient more susceptible to pathogen invasion including SARS-CoV-2 (Alexander et al., 2019; Katz-Agranov and Zandman-Goddard, 2021).

There is a dominancy of genus Clostridium in patients with COVID-19 (Gu et al., 2020b; Zuo et al., 2020a; Cao et al., 2021; Yamamoto et al., 2021). The increase in Clostridium ramosum and Clostridium hathewayi is associated with the disease severity which may be a risk factor of acute portal vein thrombosis (Zuo et al., 2020; Rokkam et al., 2021). Clostridium difficile may complicate COVID-19 and worsen the GI symptoms (Ferreira et al., 2020; Oba et al., 2020; Sandhu et al., 2020; Khanna and Kraft, 2021). Two butyrate-producing members of this genus, Clostridium butyricum and Clostridium leptum, are decreased in patients with COVID-19 (Tang et al., 2020).

Streptococcus is another important bacterial genus which increases in COVID-19 (d’Ettorre et al., 2020; Donati Zeppa et al., 2020; Gu et al., 2020b; Zuo et al., 2021a). The abundance of Streptococcus is also an indicator of the extent of opportunistic bacterial invasion (Weiser et al., 2018; Tao et al., 2020). Streptococcus abundance is associated with more expressions of IL-18, TNF-α, and IFN-γ and other inflammatory cytokines worsening clinical outcomes (Tao et al., 2020; van der Lelie and Taghavi, 2020; Chhibber-Goel et al., 2021). An altered gut integrity affected by dysbiosis and inflammatory cytokines seems to be the main cause of increase in Streptococcus abundance in COVID-19 (Donati Zeppa et al., 2020). Streptococcus also affects the lung microbiome with proinflammatory activity (Kyo et al., 2019; Yamamoto et al., 2021).

Genus Rothia dominancy increases in patients with COVID-19 (Gu et al., 2020b; Lv et al., 2021a). This genus seems to be associated with inflammatory lung injuries (Han et al., 2020; Chattopadhyay and Shankar, 2021).

The genus Collinsella is an opportunistic pathogenic genus which is widely found in the gut of patients with COVID-19 especially in severe cases and higher infectivity status (Chhibber-Goel et al., 2021; Liu et al., 2021; Massip Copiz, 2021; Rajput et al., 2021; Zuo et al., 2021a). Collinsella aerofaciens abundance altered with the gut mucosal integrity and production of inflammatory mediators such as IL-17, CXCL1, and CXCL5 from the luminal cells (Kalinkovich and Livshits, 2019).

The alteration of genus Parabacteroides in COVID-19 is an area of controversy (Tang et al., 2020; Tao et al., 2020; Chhibber-Goel et al., 2021; Zuo et al., 2021a; Yeoh et al., 2021). It has been suggested that higher levels of Parabacteroides in microbiota are associated with better gut mucosal integrity (Venegas et al., 2019; Tang et al., 2020; Chhibber-Goel et al., 2021).

Ruminococcus species such as Ruminococcus gnavus and Ruminococcus torques increase (Cao et al., 2021; Yeoh et al., 2021), and species including Ruminococcus bromii, Ruminococcus obeum, and Ruminococcus sp. 5139BFAA are reduced in patients with COVID-19 (Zuo et al., 2020a; Cao et al., 2021; Lv et al., 2021). Ruminococcus gnavus and Ruminococcus torques are known as proinflammatory bacteria which previously have been shown to be associated with proinflammatory status and higher production of inflammatory mediators (Matsuoka and Kanai, 2015; Hall et al., 2017; Henke et al., 2019; Yeoh et al., 2021). Reduction of Ruminococcus obeum seems to be secondary to the wide use/misuse of antibiotics in the management of COVID-19 patients (Cyprian et al., 2021). Among Alistipes genera, Alistipes_sp_AP11, Alistipes indistinctus, and Alistipes shahii are reduced and Alistipes onderdonkii increased in COVID-19 (Zuo et al., 2020a; Cao et al., 2021). Alistipes onderdonkii is one of the most important sources of short-chain fatty acid (SCFA) production in the gut that helps to the gut homeostasis (Venegas et al., 2019; Tang et al., 2020). Alistipes is also important in preservation of the gut immunity via being involved in tryptophan synthesis pathways (Gao et al., 2018).

Bacteroides alteration is reported in COVID-19, especially in critically ill patients (Tang et al., 2020; Cao et al., 2021; Chattopadhyay and Shankar, 2021; Yeoh et al., 2021; Zuo et al., 2021a). Bacteroides are the most critical commensal bacterial genera in gut whose alterations are associated with several conditions affecting human health and disease (Ley et al., 2006; Turnbaugh et al., 2006; Larsen et al., 2010; Claesson et al., 2012; Yu et al., 2015; Boursier et al., 2016; Salazar et al., 2017; Belizário et al., 2018; O’Toole and Jeffery, 2018; Yildiz et al., 2018; Antosca et al., 2019; Rahayu et al., 2019; Crovesy et al., 2020; Juárez-Fernández et al., 2021). Bacteroides also have immunomodulatory effects, which is mainly mediated by alterations in production of polysaccharide A, IL-6, IL-7, IL-10, dendritic cells, and CD4+ and CD8+ T cells (Abt et al., 2012; Zhang et al., 2018; Jia et al., 2018; Ramakrishna et al., 2019; Alvarez et al., 2020; Gautier et al., 2021). Bacteroides are also associated with reduction of the expression of the ACE-2 receptor (Chattopadhyay and Shankar, 2021). Use of antibiotics seems to result in increase of Bacteroides caccae in a COVID-19 patient. In antibiotic-naive COVID-19 patients, Bacteroides nordii are more common (Chattopadhyay and Shankar, 2021). On the other hand, species such as Bacteroides massiliensis, Bacteroides dorei, Bacteroides thetaiotaomicron, and Bacteroides ovatus decrease in SARS-CoV-2 infection (Zuo et al., 2020a; Cao et al., 2021). Bacteroides dorei itself is a controversial bacterium with both evidence of increase and decrease in COVID-19 patients. This species is associated with IL-6 and IL-8 and downregulation of the ACE-2 receptor (Yoshida et al., 2018; Yeoh et al., 2021).

Bifidobacterium, a major bacterial genus in the gut, reduces by SARS-CoV-2 (Gu et al., 2020b). In patients who received fecal microbial transplant (FMT), a re-expansion of Bifidobacterium in their gut was demonstrated (Liu et al., 2021). Bifidobacterium spp. are well known for their immunomodulatory effects especially on Th17 and in the amelioration of inflammatory process (de Vrese et al., 2005; Wang et al., 2011; Groeger et al., 2013; Jungersen et al., 2014; King et al., 2014; Han et al., 2016; Schiavi et al., 2016; Bozkurt et al., 2019; Bozkurt and Kara, 2020; Tian et al., 2020; Arenas-Padilla et al., 2021; Chen and Vitetta, 2021; Hong et al., 2021; Milner et al., 2021). Bifidobacterium may be considered as a supplemental therapeutic agent for controlling cytokine storm and inflammation in patients with COVID-19 (Bozkurt and Quigley, 2020; Bozkurt and Quigley, 2020a; Schett et al., 2020; Bhushan et al., 2021Gautier et al., 2021; Mohseni et al., 2021).

Faecalibacterium decreases in COVID-19 and has been related to the severity of disease (Zuo et al., 2020; Gu et al., 2020; Tang et al., 2020; Yamamoto et al., 2021; Lv et al., 2021). Faecalibacterium is a butyrate-producing genus which positively impacts on intestinal mucosal integrity and is also known to have anti-inflammatory effects (Alameddine et al., 2019; Zuo et al., 2020a; Chhibber-Goel et al., 2021). Fecal transplantation significantly increases the abundance of Faecalibacterium in discharged patients with COVID-19 and has been shown to improve the inflammation states (Sokol et al., 2008; van den Munckhof et al., 2018; Venegas et al., 2019; Liu et al., 2021).

Lachnospiraceae, which is known as SCFA-producing bacteria, decreases in patients with COVID-19 (d’Ettorre et al., 2020; Gu et al., 2020b; Zuo et al., 2020a; Cao et al., 2021; Gaibani et al., 2021; Gautier et al., 2021; Zuo et al., 2021a). It may be attributed to common use of azithromycin and other antibiotics in the management of COVID-19 (Segal et al., 2020).

Genus Roseburia is another commensal gut microbiota which decreases in patients with COVID-19 and other viral diseases such as influenza (Wang et al., 2017; Gu et al., 2020b; Cao et al., 2021; Lv et al., 2021a). SCFAs produced by Roseburia maintain mucosal integrity in healthy adults via modulation of inflammatory mediators especially IL-10 (Koh et al., 2016; Zheng et al., 2017; Haak et al., 2018; Gautier et al., 2021). It has been shown previously that butyrate may preserve lung integrity from cytokine-induced injuries in influenza (Chakraborty et al., 2017; Dang and Marsland, 2019). If we assume that it is true in COVID-19, lower levels of Roseburia result in lower levels of butyrate and consequently more extensive lung injuries due to inflammatory processes.

Eubacterium is a genus with immunomodulatory effects which significantly decrease in gut microbiota of patients with COVID-19 (d’Ettorre et al., 2020; Zuo et al., 2020a; Gu et al., 2020b; Cao et al., 2021; Chattopadhyay and Shankar, 2021; Gautier et al., 2021; Lv et al., 2021; Yeoh et al., 2021). Wide use of antibiotics is considered to be associated with reduction of this genus (Zuo et al., 2020a). This genus similar to Roseburia spp. produces butyrate and modulates inflammation in inflammation-mediated injuries (Koh et al., 2016; Zheng et al., 2017; Haak et al., 2018; Gautier et al., 2021).

Fusicatenibacter is another bacterial genus that reduced during the course of COVID-19 (Gu et al., 2020; Chattopadhyay and Shankar, 2021; Lv et al., 2021a). Fusicatenibacter alteration is a very sensitive biomarker during COVID-19. It is proposed to be a diagnostic tool for COVID-19 (Gu et al., 2020b; Segal et al., 2020; Cyprian et al., 2021; Howell et al., 2021). This genus is also negatively correlated with CRP and procalcitonin levels in patients with COVID-19 (Gu et al., 2020b).

Other members of the gut microbiota are viruses and fungi. Although pathogenic gut viruses are known for more than a century, the term “gut virome” is recently introduced (Reyes et al., 2012). Most of the gut virome consists of bacteriophages that can explain the fact that the virome structure is related to gut bacterial composition in both healthy and COVID-19 people (Minot et al., 2011; Cao et al., 2021). There is a bidirectional relationship between gut virome and infectious diseases; bacteriophages have a significant role in protecting against bacterial infections (Wilks and Golovkina, 2012). Gut virome composition might be affected during COVID-19 (Cao et al., 2021). There are limited data on the alterations of commensal viral and fungal populations in the gut during COVID-19 infection.

Lv et al. showed a strong correlation between altered fungal gut microbiome and inflammatory blood biomarkers (Lv et al., 2021b). Further studies focusing on viral and fungal alterations during the COVID-19 are desired.

The gut microbiota alteration in COVID-19 patients should be considered as a dynamic process (d’Ettorre et al., 2020; Liu et al., 2021; Hussain et al., 2021; Zuo et al., 2020a). To the date of revising this manuscript (January 2022), several registered clinical trials are in progress and the results are not provided yet; however, growing evidence supports the effectiveness of microbiota modulatory actions on fastening the recovery of patients with COVID-19 (Chen and Vitetta, 2021; Hussain et al., 2021; Wang et al., 2021a).

Limitations and Suggestions

A few studies have documented the comorbidities of subjects. However, almost all the studies have missed the impact of comorbidities on gut microbiota alterations in COVID-19 patients compared with the healthy control. It has been shown that gut microbiota may change in patients with hypertension, cardiovascular diseases, diabetes mellitus, hyperlipidemia, and thrombotic events (Huynh, 2020; Avery et al., 2021; Kyriakidou et al., 2021; Mineshita et al., 2021). We strongly propose to investigate the effects of underlying comorbidities in gut microbial composition in patients with COVID-19.

Due to the variations in data analysis techniques such as 16S rRNA sequencing, qPCR, and metagenome sequencing, there was a challenge to compare the bacterial taxa across studies. Since there was a fair diversity in geographical distribution of the current studies (most of them are from China), we cannot ignore the effect of diet and genetic predisposing factors like HLA in gut microbiome compositions. Future studies in different countries are required in this regard.

It is important to mention that different levels of p-value significance were reported in reviewed articles; however, in this study we used only statistically significant findings from the included studies.

Further studies with a larger study population, including the range of patients from mild to severe symptoms, involving the patients who are managed out patiently, focusing on the effectiveness of gut microbiota-targeted therapies for prevention and improvement of COVID-19 patients’ symptoms are desired to light up this topic.

Conclusion

Our study showed a significant alteration of gut microbiome composition in patients with COVID-19 compared to healthy individuals. This great extent of impact has proposed the gut microbiota as a potential diagnostic, prognostic, and potentially therapeutic strategy for COVID-19.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1

  AbtM. C.OsborneL. C.MonticelliL. A.DoeringT. A.AlenghatT.SonnenbergG. F.et al. (2012). Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity. Immunity37 (1), 158–170. doi: 10.1016/j.immuni.2012.04.011

  • CrossRef
  • Google Scholar

• 2

  Ahmadi BadiS.TarashiS.FatehA.RohaniP.MasottiA.SiadatS. D. (2021). From the Role of Microbiota in Gut-Lung Axis to SARS-CoV-2 Pathogenesis. Mediators Inflamm.2021, 6611222. doi: 10.1155/2021/6611222

  • CrossRef
  • Google Scholar

• 3

  AktaşB.AslimB. (2020). Gut-Lung Axis and Dysbiosis in COVID-19. Turkish J. Biol.44 (SI-1), 265–272. doi: 10.3906/biy-2005-102

  • CrossRef
  • Google Scholar

• 4

  AlameddineJ.GodefroyE.PapargyrisL.SarrabayrouseG.TabiascoJ.BridonneauC.et al. (2019). Faecalibacterium Prausnitzii Skews Human DC to Prime IL10-Producing T Cells Through TLR2/6/JNK Signaling and IL-10, IL-27, CD39, and IDO-1 Induction. Front. Immunol.10, 143. doi: 10.3389/fimmu.2019.00143

  • CrossRef
  • Google Scholar

• 5

  AlexanderM.AngQ. Y.TurnbaughP. J. (2019). A Diet-Dependent Enzyme From the Human Gut Microbiome Promotes Th17 Accumulation and Colitis. bioRxiv Preprint Server Biol., 766899. doi: 10.1101/766899

  • CrossRef
  • Google Scholar

• 6

  AllaliI.BakriY.AmzaziS.GhazalH. (2021). Gut-Lung Axis in COVID-19. Interdiscip. Perspect. Infect. Dis.2021, 6655380. doi: 10.1155/2021/6655380

  • CrossRef
  • Google Scholar

• 7

  AlvarezC. A.JonesM. B.HamborJ.CobbB. A. (2020). Characterization of Polysaccharide A Response Reveals Interferon Responsive Gene Signature and Immunomodulatory Marker Expression. Front. Immunol.11 (2677). doi: 10.3389/fimmu.2020.556813

  • CrossRef
  • Google Scholar

• 8

  AntoscaK. M.ChernikovaD. A.PriceC. E.RuoffK. L.LiK.GuillM. F.et al. (2019). Altered Stool Microbiota of Infants With Cystic Fibrosis Shows a Reduction in Genera Associated With Immune Programming From Birth. J. Bacteriol.201 (16), e00274–e00219. doi: 10.1128/JB.00274-19

  • CrossRef
  • Google Scholar

• 9

  AntunesK. H.FachiJ. L.de PaulaR.da SilvaE. F.PralL. P.Dos SantosA.et al. (2019). Microbiota-Derived Acetate Protects Against Respiratory Syncytial Virus Infection Through a GPR43-Type 1 Interferon Response. Nat. Commun.10 (1), 3273. doi: 10.1038/s41467-019-11152-6

  • CrossRef
  • Google Scholar

• 10

  Arenas-PadillaM.González-RascónA.Hernández-MendozaA.Calderón de la BarcaA. M.HernándezJ.Mata-HaroV. (2021). Immunomodulation by Bifidobacterium Animalis Subsp. Lactis Bb12: Integrative Analysis of miRNA Expression and TLR2 Pathway-Related Target Proteins in Swine Monocytes. Probiot. Antimicrob. Proteins20, 1–13. doi: 10.1007/s12602-021-09816-1

  • CrossRef
  • Google Scholar

• 11

  AveryE. G.BartolomaeusH.MaifeldA.MarkoL.WiigH.WilckN.et al. (2021). The Gut Microbiome in Hypertension: Recent Advances and Future Perspectives. Circ. Res.128 (7), 934–950. doi: 10.1161/CIRCRESAHA.121.318065

  • CrossRef
  • Google Scholar

• 12

  BattagliniD.RobbaC.FedeleA.TrancǎS.SukkarS. G.Di PilatoV.et al. (2021). The Role of Dysbiosis in Critically Ill Patients With COVID-19 and Acute Respiratory Distress Syndrome. Front. Med.8, 671714. doi: 10.3389/fmed.2021.671714

  • CrossRef
  • Google Scholar

• 13

  BelizárioJ. E.FaintuchJ.Garay-MalpartidaM. (2018). Gut Microbiome Dysbiosis and Immunometabolism: New Frontiers for Treatment of Metabolic Diseases. Mediators Inflamm.2018, 2037838. doi: 10.1155/2018/2037838

  • CrossRef
  • Google Scholar

• 14

  BhushanI.SharmaM.MehtaM.BadyalS.SharmaV.SharmaI.et al. (2021). Bioactive Compounds and Probiotics–a Ray of Hope in COVID-19 Management. Food Sci. Hum. Wellness10 (2), 131–140. doi: 10.1016/j.fshw.2021.02.001

  • CrossRef
  • Google Scholar

• 15

  BoursierJ.MuellerO.BarretM.MachadoM.FizanneL.Araujo-PerezF.et al. (2016). The Severity of Nonalcoholic Fatty Liver Disease is Associated With Gut Dysbiosis and Shift in the Metabolic Function of the Gut Microbiota. Hepatology63 (3), 764–775. doi: 10.1002/hep.28356

  • CrossRef
  • Google Scholar

• 16

  BozkurtH. S.KaraB. (2020). A New Treatment for Ulcerative Colitis: Intracolonic Bifidobacterium and Xyloglucan Application. Eur. J. Inflamm.18, 2058739220942626. doi: 10.1177/2058739220942626

  • CrossRef
  • Google Scholar

• 17

  BozkurtH. S.QuigleyE. M. (2020a). The Probiotic Bifidobacterium in the Management of Coronavirus: A Theoretical Basis. Int. J. Immunopathol. Pharmacol.34, 2058738420961304. doi: 10.1177/2058738420961304

  • CrossRef
  • Google Scholar

• 18

  BozkurtH.QuigleyE. (2020b). Probiotic Bifidobacteria Against the COVİD-19: A New Way Out! Int. J. Immunopathol. Pharmacol.34. doi: 10.1177/2058738420961304

  • CrossRef
  • Google Scholar

• 19

  BozkurtH. S.QuigleyE. M.KaraB. (2019). Bifidobacterium Animalis Subspecies Lactis Engineered to Produce Mycosporin-Like Amino Acids in Colorectal Cancer Prevention. SAGE Open Med.7, 2050312119825784. doi: 10.1177/2050312119825784

  • CrossRef
  • Google Scholar

• 20

  BrownR. L.SequeiraR. P.ClarkeT. B. (2017). The Microbiota Protects Against Respiratory Infection via GM-CSF Signaling. Nat. Commun.8 (1), 1512. doi: 10.1038/s41467-017-01803-x

  • CrossRef
  • Google Scholar

• 21

  BuddenK. F.GellatlyS. L.WoodD. L.CooperM. A.MorrisonM.HugenholtzP.et al. (2017). Emerging Pathogenic Links Between Microbiota and the Gut-Lung Axis. Nat. Rev. Microbiol.15 (1), 55–63. doi: 10.1038/nrmicro.2016.142

  • CrossRef
  • Google Scholar

• 22

  CaoJ.WangC.ZhangY.LeiG.XuK.ZhaoN.et al. (2021). Integrated Gut Virome and Bacteriome Dynamics in COVID-19 Patients. Gut Microbes13 (1), 1887722. doi: 10.1080/19490976.2021.1887722

  • CrossRef
  • Google Scholar

• 23

  ChakrabortyK.RaundhalM.ChenB. B.MorseC.TyurinaY. Y.KhareA.et al. (2017). The Mito-DAMP Cardiolipin Blocks IL-10 Production Causing Persistent Inflammation During Bacterial Pneumonia. Nat. Commun.8, 13944. doi: 10.1038/ncomms13944

  • CrossRef
  • Google Scholar

• 24

  ChattopadhyayI.ShankarE. M. (2021). SARS-CoV-2-Indigenous Microbiota Nexus: Does Gut Microbiota Contribute to Inflammation and Disease Severity in COVID-19? Front. Cell. Infect. Microbiol.11 (96). doi: 10.3389/fcimb.2021.590874

  • CrossRef
  • Google Scholar

• 25

  ChenJ.VitettaL. (2021). Modulation of Gut Microbiota for the Prevention and Treatment of COVID-19. J. Clin. Med.10 (13), 2903. doi: 10.3390/jcm10132903

  • CrossRef
  • Google Scholar

• 26

  Chhibber-GoelJ.GopinathanS.SharmaA. (2021). Interplay Between Severities of COVID-19 and the Gut Microbiome: Implications of Bacterial Co-Infections? Gut Pathogens13 (1), 14. doi: 10.1186/s13099-021-00407-7

  • CrossRef
  • Google Scholar

• 27

  ClaessonM. J.JefferyI. B.CondeS.PowerS. E.O’ConnorE. M.CusackS.et al. (2012). Gut Microbiota Composition Correlates With Diet and Health in the Elderly. Nature488 (7410), 178–184. doi: 10.1038/nature11319

  • CrossRef
  • Google Scholar

• 28

  CrovesyL.MastersonD.RosadoE. L. (2020). Profile of the Gut Microbiota of Adults With Obesity: A Systematic Review. Eur. J. Clin. Nutr.74 (9), 1251–1262. doi: 10.1038/s41430-020-0607-6

  • CrossRef
  • Google Scholar

• 29

  CyprianF.SohailM. U.AbdelhafezI.SalmanS.AttiqueZ.KamareddineL.et al. (2021). SARS-CoV-2 and Immune-Microbiome Interactions: Lessons From Respiratory Viral Infections. Int. J. Infect. Dis.105, 540–550. doi: 10.1016/j.ijid.2021.02.071

  • CrossRef
  • Google Scholar

• 30

  D’AmicoF.BaumgartD. C.DaneseS.Peyrin-BirouletL. (2020). Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention, and Management. Clin. Gastroenterol. Hepatol.18 (8), 1663–1672. doi: 10.1016/j.cgh.2020.04.001

  • CrossRef
  • Google Scholar

• 31

  DangA. T.MarslandB. J. (2019). Microbes, Metabolites, and the Gut-Lung Axis. Mucosal Immunol.12 (4), 843–850. doi: 10.1038/s41385-019-0160-6

  • CrossRef
  • Google Scholar

• 32

  d’EttorreG.CeccarelliG.MarazzatoM.CampagnaG.PinacchioC.AlessandriF.et al. (2020). 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.7, 389. doi: 10.3389/fmed.2020.00389

  • CrossRef
  • Google Scholar

• 33

  de VreseM.WinklerP.RautenbergP.HarderT.NoahC.LaueC.et al. (2005). Effect of Lactobacillus Gasseri PA 16/8, Bifidobacterium Longum SP 07/3, B. Bifidum MF 20/5 on Common Cold Episodes: A Double Blind, Randomized, Controlled Trial. Clin. Nutr. (Edinburgh Scotland)24 (4), 481–491. doi: 10.1016/j.clnu.2005.02.006

  • CrossRef
  • Google Scholar

• 34

  DicksonR. P.HuffnagleG. B. (2015). The Lung Microbiome: New Principles for Respiratory Bacteriology in Health and Disease. PloS Pathogens11 (7), e1004923. doi: 10.1371/journal.ppat.1004923

  • CrossRef
  • Google Scholar

• 35

  DinA. U.MazharM.WaseemM.AhmadW.BibiA.HassanA.et al. (2021). SARS-CoV-2 Microbiome Dysbiosis Linked Disorders and Possible Probiotics Role. Biomed. Pharmacother. = Biomed. Pharmacother.133, 110947. doi: 10.1016/j.biopha.2020.110947

  • CrossRef
  • Google Scholar

• 36

  DonaldsonG. P.LeeS. M.MazmanianS. K. (2016). Gut Biogeography of the Bacterial Microbiota. Nat. Rev. Microbiol.14 (1), 20–32. doi: 10.1038/nrmicro3552

  • CrossRef
  • Google Scholar

• 37

  Donati ZeppaS.AgostiniD.PiccoliG.StocchiV.SestiliP. (2020). Gut Microbiota Status in COVID-19: An Unrecognized Player? Front. Cell. Infect. Microbiol.10 (742). doi: 10.3389/fcimb.2020.576551

  • CrossRef
  • Google Scholar

• 38

  EnaudR.PrevelR.CiarloE.BeaufilsF.WieërsG.GueryB.et al. (2020). The Gut-Lung Axis in Health and Respiratory Diseases: A Place for Inter-Organ and Inter-Kingdom Crosstalks. Front. Cell. Infect. Microbiol.10 (9). doi: 10.3389/fcimb.2020.00009

  • CrossRef
  • Google Scholar

• 39

  FagundesC. T.AmaralF. A.VieiraA. T.SoaresA. C.PinhoV.NicoliJ. R.et al. (2012). Transient TLR Activation Restores Inflammatory Response and Ability to Control Pulmonary Bacterial Infection in Germfree Mice. J. Immunol. (Baltimore Md 1950)188 (3), 1411–1420. doi: 10.4049/jimmunol.1101682

  • CrossRef
  • Google Scholar

• 40

  FerreiraE.PennaB.YatesE. A. (2020). Should We Be Worried About Clostridioides Difficile During the SARS-CoV2 Pandemic? Front. Microbiol.11 (2292). doi: 10.3389/fmicb.2020.581343

  • CrossRef
  • Google Scholar

• 41

  FoxA. C.McConnellK. W.YosephB. P.BreedE.LiangZ.ClarkA. T.et al. (2012). The Endogenous Bacteria Alter Gut Epithelial Apoptosis and Decrease Mortality Following Pseudomonas Aeruginosa Pneumonia. Shock (Augusta Ga)38 (5), 508–514. doi: 10.1097/SHK.0b013e31826e47e8

  • CrossRef
  • Google Scholar

• 42

  GaibaniP.D’AmicoF.BartolettiM.LombardoD.RampelliS.FornaroG.et al. (2021). The Gut Microbiota of Critically Ill Patients With COVID-19. Front. Cell. Infect. Microbiol.11 (554). doi: 10.3389/fcimb.2021.670424

  • CrossRef
  • Google Scholar

• 43

  GaoJ.XuK.LiuH.LiuG.BaiM.PengC.et al. (2018). Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism. Front. Cell. Infect. Microbiol.8, 13. doi: 10.3389/fcimb.2018.00013

  • CrossRef
  • Google Scholar

• 44

  GautierT.David-Le GallS.SweidanA.Tamanai-ShacooriZ.Jolivet-GougeonA.LoréalO.et al. (2021). Next-Generation Probiotics and Their Metabolites in COVID-19. Microorganisms9 (5), 941. doi: 10.3390/microorganisms9050941

  • CrossRef
  • Google Scholar

• 45

  Geva-ZatorskyN.SefikE.KuaL.PasmanL.TanT. G.Ortiz-LopezA.et al. (2017). Mining the Human Gut Microbiota for Immunomodulatory Organisms. Cell168 (5), 928–943.e11. doi: 10.1016/j.cell.2017.01.022

  • CrossRef
  • Google Scholar

• 46

  GroegerD.O’MahonyL.MurphyE. F.BourkeJ. F.DinanT. G.KielyB.et al. (2013). Bifidobacterium Infantis 35624 Modulates Host Inflammatory Processes Beyond the Gut. Gut Microbes4 (4), 325–339. doi: 10.4161/gmic.25487

  • CrossRef
  • Google Scholar

• 47

  GuJ.HanB.WangJ. (2020a). COVID-19: Gastrointestinal Manifestations and Potential Fecal-Oral Transmission. Gastroenterology158 (6), 1518–1519. doi: 10.1053/j.gastro.2020.02.054

  • CrossRef
  • Google Scholar

• 48

  GuS.ChenY.WuZ.ChenY.GaoH.LvL.et al. (2020b). Alterations of the Gut Microbiota in Patients With Coronavirus Disease 2019 or H1N1 Influenza. Clin. Infect. Dis.71 (10), 2669–2678. doi: 10.1093/cid/ciaa709

  • CrossRef
  • Google Scholar

• 49

  HaakB. W.LittmannE. R.ChaubardJ. L.PickardA. J.FontanaE.AdhiF.et al. (2018). Impact of Gut Colonization With Butyrate-Producing Microbiota on Respiratory Viral Infection Following Allo-HCT. Blood131 (26), 2978–2986. doi: 10.1182/blood-2018-01-828996

  • CrossRef
  • Google Scholar

• 50

  HallA. B.YassourM.SaukJ.GarnerA.JiangX.ArthurT.et al. (2017). A Novel Ruminococcus Gnavus Clade Enriched in Inflammatory Bowel Disease Patients. Genome Med.9 (1), 103. doi: 10.1186/s13073-017-0490-5

  • CrossRef
  • Google Scholar

• 51

  HanC.DingZ.ShiH.QianW.HouX.LinR. (2016). The Role of Probiotics in Lipopolysaccharide-Induced Autophagy in Intestinal Epithelial Cells. Cell. Physiol. Biochem.38 (6), 2464–2478. doi: 10.1159/000445597

  • CrossRef
  • Google Scholar

• 52

  HanY.JiaZ.ShiJ.WangW.HeK. (2020). The Active Lung Microbiota Landscape of COVID-19 Patients. medRxiv. doi: 10.1101/2020.08.20.20144014

  • CrossRef
  • Google Scholar

• 53

  HarmerD.GilbertM.BormanR.ClarkK. L. (2002). Quantitative mRNA Expression Profiling of ACE 2, a Novel Homologue of Angiotensin Converting Enzyme. FEBS Lett.532 (1-2), 107–110. doi: 10.1016/S0014-5793(02)03640-2

  • CrossRef
  • Google Scholar

• 54

  HegazyM.Ahmed AshoushO.Tharwat HegazyM.WahbaM.LithyR. M.Abdel-HamidH. M.et al. (2021). Beyond Probiotic Legend: ESSAP Gut Microbiota Health Score to Delineate SARS-COV-2 Infection Severity. Br. J. Nutr.7, 1–10. doi: 10.1017/S0007114521001926

  • CrossRef
  • Google Scholar

• 55

  HenkeM. T.KennyD. J.CassillyC. D.VlamakisH.XavierR. J.ClardyJ. (2019). Ruminococcus Gnavus, a Member of the Human Gut Microbiome Associated With Crohn’s Disease, Produces an Inflammatory Polysaccharide. Proc. Natl. Acad. Sci. U. S. A.116 (26), 12672–12677. doi: 10.1073/pnas.1904099116

  • CrossRef
  • Google Scholar

• 56

  HeY.WangJ.LiF.ShiY. (2020). Main Clinical Features of COVID-19 and Potential Prognostic and Therapeutic Value of the Microbiota in SARS-CoV-2 Infections. Front. Microbiol.11, 1302. doi: 10.3389/fmicb.2020.01302

  • CrossRef
  • Google Scholar

• 57

  HeY.WenQ.YaoF.XuD.HuangY.WangJ. (2017). Gut-Lung Axis: The Microbial Contributions and Clinical Implications. Crit. Rev. Microbiol.43 (1), 81–95. doi: 10.1080/1040841X.2016.1176988

  • CrossRef
  • Google Scholar

• 58

  HeF.ZhangT.XueK.FangZ.JiangG.HuangS.et al. (2021). Fecal Multi-Omics Analysis Reveals Diverse Molecular Alterations of Gut Ecosystem in COVID-19 Patients. Analyt. Chim. Acta1180, 338881. doi: 10.1016/j.aca.2021.338881

  • CrossRef
  • Google Scholar

• 59

  HongN.KuS.YukK.JohnstonT. V.JiG. E.ParkM. S. (2021). Production of Biologically Active Human Interleukin-10 by Bifidobacterium Bifidum BGN4. Microb. Cell Fact.20 (1), 16. doi: 10.1186/s12934-020-01505-y

  • CrossRef
  • Google Scholar

• 60

  HowellM. C.GreenR.McGillA. R.DuttaR.MohapatraS.MohapatraS. S. (2021). SARS-CoV-2-Induced Gut Microbiome Dysbiosis: Implications for Colorectal Cancer. Cancers13 (11), 2676. doi: 10.3390/cancers13112676

  • CrossRef
  • Google Scholar

• 61

  HussainI.CherG. L. Y.AbidM. A.AbidM. B. (2021). Role of Gut Microbiome in COVID-19: An Insight Into Pathogenesis and Therapeutic Potential. Front. Immunol.12. doi: 10.3389/fimmu.2021.765965

  • CrossRef
  • Google Scholar

• 62

  HuynhK. (2020). Novel Gut Microbiota-Derived Metabolite Promotes Platelet Thrombosis via Adrenergic Receptor Signalling. Nat. Rev. Cardiol.17 (5), 265. doi: 10.1038/s41569-020-0367-y

  • CrossRef
  • Google Scholar

• 63

  IchinoheT.PangI. K.KumamotoY.PeaperD. R.HoJ. H.MurrayT. S.et al. (2011). Microbiota Regulates Immune Defense Against Respiratory Tract Influenza A Virus Infection. Proc. Natl. Acad. Sci. U. S. A.108 (13), 5354–5359. doi: 10.1073/pnas.1019378108

  • CrossRef
  • Google Scholar

• 64

  JamshidiP.HajikhaniB.MirsaeidiM.VahidnezhadH.DadashiM.NasiriM. J. (2021). Skin Manifestations in COVID-19 Patients: Are They Indicators for Disease Severity? A Systematic Review. Front. Med.8, 634208. doi: 10.3389/fmed.2021.634208

  • CrossRef
  • Google Scholar

• 65

  JamshidiP.HasanzadehS.TahvildariA.FarsiY.ArbabiM.MotaJ. F.et al. (2019). Is There Any Association Between Gut Microbiota and Type 1 Diabetes? A Systematic Review. Gut Pathog.11 (1), 49. doi: 10.1186/s13099-019-0332-7

  • CrossRef
  • Google Scholar

• 66

  JiaW.XieG.JiaW. (2018). Bile Acid–Microbiota Crosstalk in Gastrointestinal Inflammation and Carcinogenesis. Nat. Rev. Gastroenterol. Hepatol.15 (2), 111–128. doi: 10.1038/nrgastro.2017.119

  • CrossRef
  • Google Scholar

• 67

  Joanna Briggs Institute. (2021). Critical Appraisal Tools (South Australia: Joanna Briggs Institute: University of Adelaide). Available at: https://jbi.global/critical-appraisal-tools.

  • Google Scholar

• 68

  Juárez-FernándezM.PorrasD.García-MediavillaM. V.Román-SagüilloS.González-GallegoJ.NistalE.et al. (2021). Aging, Gut Microbiota and Metabolic Diseases: Management Through Physical Exercise and Nutritional Interventions. Nutrients13 (1), 16. doi: 10.3390/nu13010016

  • CrossRef
  • Google Scholar

• 69

  JungersenM.WindA.JohansenE.ChristensenJ. E.Stuer-LauridsenB.EskesenD. (2014). The Science Behind the Probiotic Strain Bifidobacterium Animalis Subsp. lactis BB-12(®). Microorganisms2 (2), 92–110. doi: 10.3390/microorganisms2020092

  • CrossRef
  • Google Scholar

• 70

  KalinkovichA.LivshitsG. (2019). A Cross Talk Between Dysbiosis and Gut-Associated Immune System Governs the Development of Inflammatory Arthropathies. Semin. Arthritis Rheum.49 (3), 474–484. doi: 10.1016/j.semarthrit.2019.05.007

  • CrossRef
  • Google Scholar

• 71

  Katz-AgranovN.Zandman-GoddardG. (2021). Autoimmunity and COVID-19 - The Microbiotal Connection. Autoimmun. Rev.20 (8), 102865. doi: 10.1016/j.autrev.2021.102865

  • CrossRef
  • Google Scholar

• 72

  KhanM.MathewB. J.GuptaP.GargG.KhadangaS.VyasA. K.et al. (2021). Gut Dysbiosis and IL-21 Response in Patients With Severe COVID-19. Microorganisms9 (6), 1292. doi: 10.3390/microorganisms9061292

  • CrossRef
  • Google Scholar

• 73

  KhannaS.KraftC. S. (2021). The Interplay of SARS-CoV-2 and Clostridioides Difficile Infection. Future Microbiol.16 (6), 439–443. doi: 10.2217/fmb-2020-0275

  • CrossRef
  • Google Scholar

• 74

  KimH.-N.JooE.-J.LeeC.-W.AhnK.-S.KimH.-L.ParkD.-I.et al. (2021). Reversion of Gut Microbiota During the Recovery Phase in Patients With Asymptomatic or Mild COVID-19: Longitudinal Study. Microorganisms9 (6), 1237. doi: 10.3390/microorganisms9061237

  • CrossRef
  • Google Scholar

• 75

  KingS.GlanvilleJ.SandersM. E.FitzgeraldA.VarleyD. (2014). Effectiveness of Probiotics on the Duration of Illness in Healthy Children and Adults Who Develop Common Acute Respiratory Infectious Conditions: A Systematic Review and Meta-Analysis. Br. J. Nutr.112 (1), 41–54. doi: 10.1017/S0007114514000075

  • CrossRef
  • Google Scholar

• 76

  KohA.De VadderF.Kovatcheva-DatcharyP.BäckhedF. (2016). From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell165 (6), 1332–1345. doi: 10.1016/j.cell.2016.05.041

  • CrossRef
  • Google Scholar

• 77

  KyoM.NishiokaK.NakayaT.KidaY.TanabeY.OhshimoS.et al. (2019). Unique Patterns of Lower Respiratory Tract Microbiota are Associated With Inflammation and Hospital Mortality in Acute Respiratory Distress Syndrome. Respir. Res.20 (1), 246. doi: 10.1186/s12931-019-1203-y

  • CrossRef
  • Google Scholar

• 78

  KyriakidouA.KoufakisT.GoulisD. G.VasilopoulosY.ZebekakisP.KotsaK. (2021). Pharmacogenetics of the Glucagon-Like Peptide-1 Receptor Agonist Liraglutide: A Step Towards Personalized Type 2 Diabetes Management. Curr. Pharm. Des.27 (8), 1025–1034. doi: 10.2174/1381612826666201203145654

  • CrossRef
  • Google Scholar

• 79

  LamersM. M.BeumerJ.van der VaartJ.KnoopsK.PuschhofJ.BreugemT. I.et al. (2020). SARS-CoV-2 Productively Infects Human Gut Enterocytes. Sci. (New York NY)369 (6499), 50–54. doi: 10.1126/science.abc1669

  • CrossRef
  • Google Scholar

• 80

  LarsenN.VogensenF. K.van den BergF. W.NielsenD. S.AndreasenA. S.PedersenB. K.et al. (2010). Gut Microbiota in Human Adults With Type 2 Diabetes Differs From non-Diabetic Adults. PloS One5 (2), e9085. doi: 10.1371/journal.pone.0009085

  • CrossRef
  • Google Scholar

• 81

  LeyR. E.TurnbaughP. J.KleinS.GordonJ. I. (2006). Human Gut Microbes Associated With Obesity. Nature444 (7122), 1022–1023. doi: 10.1038/4441022a

  • CrossRef
  • Google Scholar

• 82

  LiW.MooreM. J.VasilievaN.SuiJ.WongS. K.BerneM. A.et al. (2003). Angiotensin-Converting Enzyme 2 is a Functional Receptor for the SARS Coronavirus. Nature426 (6965), 450–454. doi: 10.1038/nature02145

  • CrossRef
  • Google Scholar

• 83

  LiuF.YeS.ZhuX.HeX.WangS.LiY.et al. (2021). Gastrointestinal Disturbance and Effect of Fecal Microbiota Transplantation in Discharged COVID-19 Patients. J. Med. Case Rep.15 (1), 60. doi: 10.1186/s13256-020-02583-7

  • CrossRef
  • Google Scholar

• 84

  LvL.GuS.JiangH.YanR.ChenY.ChenY.et al. (2021b). Gut Mycobiota Alterations in Patients With COVID-19 and H1N1 Infections and Their Associations With Clinical Features. Commun. Biol.4 (1), 480. doi: 10.1038/s42003-021-02036-x

  • CrossRef
  • Google Scholar

• 85

  LvL.JiangH.ChenY.GuS.XiaJ.ZhangH.et al. (2021a). The Faecal Metabolome in COVID-19 Patients is Altered and Associated With Clinical Features and Gut Microbes. Analyt. Chim. Acta1152, 338267. doi: 10.1016/j.aca.2021.338267

  • CrossRef
  • Google Scholar

• 86

  Massip CopizM. M. (2021). The Gut Microbiota in Patients With COVID-19 and Obesity. FASEB J.35 (S1). doi: 10.1096/fasebj.2021.35.S1.05159

  • CrossRef
  • Google Scholar

• 87

  MatsuokaK.KanaiT. (Eds.) (2015). The Gut Microbiota and Inflammatory Bowel Disease. Seminars in Immunopathology (Springer).

  • Google Scholar

• 88

  MilnerE.StevensB.AnM.LamV.AinsworthM.DihleP.et al. (2021). Utilizing Probiotics for the Prevention and Treatment of Gastrointestinal Diseases. Front. Microbiol.12, 689958. doi: 10.3389/fmicb.2021.689958

  • CrossRef
  • Google Scholar

• 89

  MineshitaY.SasakiH.H-kK.ShibataS. (2021). Relationship Between Fasting and Postprandial Glucose Levels and the Gut Microbiota, 24 September 2021, PREPRINT (Version 1). available at Research Square [https://doi.org/10.21203/rs.3.rs-917351/v1]

  • Google Scholar

• 90

  MinotS.SinhaR.ChenJ.LiH.KeilbaughS. A.WuG. D.et al. (2011). The Human Gut Virome: Inter-Individual Variation and Dynamic Response to Diet. Genome Res.21 (10), 1616–1625. doi: 10.1101/gr.122705.111

  • CrossRef
  • Google Scholar

• 91

  MoherD.LiberatiA.TetzlaffJ.AltmanD. G. (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Ann. Internal Med.151 (4), 264–269. doi: 10.7326/0003-4819-151-4-200908180-00135

  • CrossRef
  • Google Scholar

• 92

  MohseniA. H.CasolaroV.Bermúdez-HumaránL. G.KeyvaniH.TaghinezhadS. S. (2021). Modulation of the PI3K/Akt/mTOR Signaling Pathway by Probiotics as a Fruitful Target for Orchestrating the Immune Response. Gut Microbes13 (1), 1–17. doi: 10.1080/19490976.2021.1886844

  • CrossRef
  • Google Scholar

• 93

  Moreira-RosárioA.MarquesC.PinheiroH.AraújoJ. R.RibeiroP.RochaR.et al. (2021). Gut Microbiota Diversity and C-Reactive Protein Are Predictors of Disease Severity in COVID-19 Patients. Front. Microbiol.12, 705020. doi: 10.3389/fmicb.2021.705020

  • CrossRef
  • Google Scholar

• 94

  ObaJ.SilvaC. A.TomaR. K.CarvalhoW. B.DelgadoA. F. (2020). COVID-19 and Coinfection With Clostridioides (Clostridium) Difficile in an Infant With Gastrointestinal Manifestation. Einstein (Sao Paulo Brazil)18, eRC6048. doi: 10.31744/einstein_journal/2020RC6048

  • CrossRef
  • Google Scholar

• 95

  O’TooleP. W.JefferyI. B. (2018). Microbiome-Health Interactions in Older People. Cell. Mol. Life Sci.75 (1), 119–128. doi: 10.1007/s00018-017-2673-z

  • CrossRef
  • Google Scholar

• 96

  PatelK. P.PatelP. A.VunnamR. R.HewlettA. T.JainR.JingR.et al. (2020). Gastrointestinal, Hepatobiliary, and Pancreatic Manifestations of COVID-19. J. Clin. Virol.128, 104386. doi: 10.1016/j.jcv.2020.104386

  • CrossRef
  • Google Scholar

• 97

  PrasadR.PattonM. J.FloydJ. L.VieiraC. P.FortmannS.DuPontM.et al. (2021). Plasma Microbiome in COVID-19 Subjects: An Indicator of Gut Barrier Defects and Dysbiosis. bioRxiv Preprint Server Biol.33851159. doi: 10.1101/2021.04.06.438634

  • CrossRef
  • Google Scholar

• 98

  RahayuE. S.UtamiT.MariyatunM.HasanP. N.KamilR. Z.SetyawanR. H.et al. (2019). Gut Microbiota Profile in Healthy Indonesians. World J. Gastroenterol.25 (12), 1478–1491. doi: 10.3748/wjg.v25.i12.1478

  • CrossRef
  • Google Scholar

• 99

  RajputS.PaliwalD.NaithaniM.KothariA.MeenaK.RanaS. (2021). COVID-19 and Gut Microbiota: A Potential Connection. Indian J. Clin. Biochem.36 (3), 1–12. doi: 10.1007/s12291-020-00948-9

  • CrossRef
  • Google Scholar

• 100

  RamakrishnaC.KujawskiM.ChuH.LiL.MazmanianS. K.CantinE. M. (2019). Bacteroides Fragilis Polysaccharide A Induces IL-10 Secreting B and T Cells That Prevent Viral Encephalitis. Nat. Commun.10 (1), 2153. doi: 10.1038/s41467-019-09884-6

  • CrossRef
  • Google Scholar

• 101

  ReyesA.SemenkovichN. P.WhitesonK.RohwerF.GordonJ. I. (2012). Going Viral: Next-Generation Sequencing Applied to Phage Populations in the Human Gut. Nat. Rev. Microbiol.10 (9), 607–617. doi: 10.1038/nrmicro2853

  • CrossRef
  • Google Scholar

• 102

  RokkamV. R. P.KuttiG.SridharanVeguntaR.VeguntaR.BoregowdaU.MohanB. P. (2021). Clostridium Difficile and COVID-19: Novel Risk Factors for Acute Portal Vein Thrombosis. Case Rep. Vasc. Med.2021, 8832638. doi: 10.1155/2021/8832638

  • CrossRef
  • Google Scholar

• 103

  SalazarN.Valdés-VarelaL.GonzálezS.GueimondeM.de Los Reyes-GavilánC. G. (2017). Nutrition and the Gut Microbiome in the Elderly. Gut Microbes8 (2), 82–97. doi: 10.1080/19490976.2016.1256525

  • CrossRef
  • Google Scholar

• 104

  SandhuA.TillotsonG.PolisticoJ.SalimniaH.CranisM.MoshosJ.et al. (2020). Clostridioides Difficile in COVID-19 Patients, Detroit, Michigan, USA, March-April 2020. Emerg. Infect. Dis.26 (9), 2272–2274. doi: 10.3201/eid2609.202126

  • CrossRef
  • Google Scholar

• 105

  SchettG.SticherlingM.NeurathM. F. (2020). COVID-19: Risk for Cytokine Targeting in Chronic Inflammatory Diseases? Nat. Rev. Immunol.20 (5), 271–272. doi: 10.1038/s41577-020-0312-7

  • CrossRef
  • Google Scholar

• 106

  SchiaviE.GleinserM.MolloyE.GroegerD.FreiR.FerstlR.et al. (2016). The Surface-Associated Exopolysaccharide of Bifidobacterium Longum 35624 Plays an Essential Role in Dampening Host Proinflammatory Responses and Repressing Local TH17 Responses. Appl. Environ. Microbiol.82 (24), 7185–7196. doi: 10.1128/AEM.02238-16

  • CrossRef
  • Google Scholar

• 107

  SchirmerM.SmeekensS. P.VlamakisH.JaegerM.OostingM.FranzosaE. A.et al. (2016). Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity. Cell167 (4), 1125–1136.e8. doi: 10.1016/j.cell.2016.10.020

  • CrossRef
  • Google Scholar

• 108

  SegalJ. P.MakJ. W. Y.MullishB. H.AlexanderJ. L.NgS. C.MarchesiJ. R. (2020). The Gut Microbiome: An Under-Recognised Contributor to the COVID-19 Pandemic? Ther. Adv. Gastroenterol.13, 1756284820974914. doi: 10.1177/1756284820974914

  • CrossRef
  • Google Scholar

• 109

  SokolH.PigneurB.WatterlotL.LakhdariO.Bermúdez-HumaránL. G.GratadouxJ.-J.et al. (2008). Faecalibacterium Prausnitzii is an Anti-Inflammatory Commensal Bacterium Identified by Gut Microbiota Analysis of Crohn Disease Patients. Proc. Natl. Acad. Sci.105 (43), 16731–16736. doi: 10.1073/pnas.0804812105

  • CrossRef
  • Google Scholar

• 110

  Suárez-FariñasM.TokuyamaM.WeiG.HuangR.LivanosA.JhaD.et al. (2021). Intestinal Inflammation Modulates the Expression of ACE2 and TMPRSS2 and Potentially Overlaps With the Pathogenesis of SARS-CoV-2-Related Disease. Gastroenterology160 (1), 287–301.e20. doi: 10.1053/j.gastro.2020.09.029

  • CrossRef
  • Google Scholar

• 111

  TangL.GuS.GongY.LiB.LuH.LiQ.et al. (2020). Clinical Significance of the Correlation Between Changes in the Major Intestinal Bacteria Species and COVID-19 Severity. Eng. (Beijing China)6 (10), 1178–1184. doi: 10.1016/j.eng.2020.05.013

  • CrossRef
  • Google Scholar

• 112

  TaoW.ZhangG.WangX.GuoM.ZengW.XuZ.et al. (2020). Analysis of the Intestinal Microbiota in COVID-19 Patients and its Correlation With the Inflammatory Factor IL-18. Med. Microecol.5, 100023. doi: 10.1016/j.medmic.2020.100023

  • CrossRef
  • Google Scholar

• 113

  TianT.ZhaoY.YangY.WangT.JinS.GuoJ.et al. (2020). The Protective Role of Short-Chain Fatty Acids Acting as Signal Molecules in Chemotherapy- or Radiation-Induced Intestinal Inflammation. Am. J. Cancer Res.10 (11), 3508–3531.

  • Google Scholar

• 114

  TrompetteA.GollwitzerE. S.PattaroniC.Lopez-MejiaI. C.RivaE.PernotJ.et al. (2018). Dietary Fiber Confers Protection Against Flu by Shaping Ly6c(-) Patrolling Monocyte Hematopoiesis and CD8(+) T Cell Metabolism. Immunity48 (5), 992–1005.e8. doi: 10.1016/j.immuni.2018.04.022

  • CrossRef
  • Google Scholar

• 115

  TurnbaughP. J.LeyR. E.MahowaldM. A.MagriniV.MardisE. R.GordonJ. I. (2006). An Obesity-Associated Gut Microbiome With Increased Capacity for Energy Harvest. Nature444 (7122), 1027–1031. doi: 10.1038/nature05414

  • CrossRef
  • Google Scholar

• 116

  van den MunckhofI. C.KurilshikovA.ter HorstR.RiksenN. P.JoostenL.ZhernakovaA.et al. (2018). Role of Gut Microbiota in Chronic Low-Grade Inflammation as Potential Driver for Atherosclerotic Cardiovascular Disease: A Systematic Review of Human Studies. Obes. Rev.19 (12), 1719–1734. doi: 10.1111/obr.12750

  • CrossRef
  • Google Scholar

• 117

  van der LelieD.TaghaviS. (2020). COVID-19 and the Gut Microbiome: More Than a Gut Feeling. Msystems5 (4), e00453–e00420. doi: 10.1128/mSystems.00453-20

  • CrossRef
  • Google Scholar

• 118

  VenegasD.MarjorieK.LandskronG.GonzálezM.QueraR.DijkstraG.et al. (2019). Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and its Relevance for Inflammatory Bowel Diseases. Front. Immunol.10, 277. doi: 10.3389/fimmu.2019.00277

  • CrossRef
  • Google Scholar

• 119

  WaltonG. E.GibsonG. R.HunterK. A. (2021). Mechanisms Linking the Human Gut Microbiome to Prophylactic and Treatment Strategies for COVID-19. Br. J. Nutr.126 (2), 219–227. doi: 10.1017/S0007114520003980

  • CrossRef
  • Google Scholar

• 120

  WangZ.WangJ.ChengY.LiuX.HuangY. (2011). Secreted Factors From Bifidobacterium Animalis Subsp. Lactis Inhibit NF-κb-Mediated Interleukin-8 Gene Expression in Caco-2 Cells. Appl. Environ. Microbiol.77 (22), 8171–8174. doi: 10.1128/AEM.06145-11

  • CrossRef
  • Google Scholar

• 121

  WangH.WangH.SunY.RenZ.ZhuW.LiA.et al. (2021a). Potential Associations Between Microbiome and COVID-19. Front. Med.8. doi: 10.3389/fmed.2021.785496

  • CrossRef
  • Google Scholar

• 122

  WangH.WangY.LuC.QiuL.SongX.JiaH.et al. (2021b). The Efficacy of Probiotics in Patients With Severe COVID-19. Ann. Palliat. Med.10 (12), 12374–12380. doi: 10.21037/apm-21-3373

  • CrossRef
  • Google Scholar

• 123

  WangB.YaoM.LvL.LingZ.LiL. (2017). The Human Microbiota in Health and Disease. Engineering3 (1), 71–82. doi: 10.1016/J.ENG.2017.01.008

  • CrossRef
  • Google Scholar

• 124

  WeiserJ. N.FerreiraD. M.PatonJ. C. (2018). Streptococcus Pneumoniae: Transmission, Colonization and Invasion. Nat. Rev. Microbiol.16 (6), 355–367. doi: 10.1038/s41579-018-0001-8

  • CrossRef
  • Google Scholar

• 125

  WilksJ.GolovkinaT. (2012). Influence of Microbiota on Viral Infections. PloS Pathogens8 (5), e1002681. doi: 10.1371/journal.ppat.1002681

  • CrossRef
  • Google Scholar

• 126

  WuY.ChengX.JiangG.TangH.MingS.TangL.et al. (2021). Altered Oral and Gut Microbiota and its Association With SARS-CoV-2 Viral Load in COVID-19 Patients During Hospitalization. NPJ Biofilms Microbiomes7 (1), 61. doi: 10.1038/s41522-021-00232-5

  • CrossRef
  • Google Scholar

• 127

  WuY.GuoC.TangL.HongZ.ZhouJ.DongX.et al. (2020). Prolonged Presence of SARS-CoV-2 Viral RNA in Faecal Samples. Lancet Gastroenterol. Hepatol.5 (5), 434–435. doi: 10.1016/S2468-1253(20)30083-2

  • CrossRef
  • Google Scholar

• 128

  XueX.MiZ.WangZ.PangZ.LiuH.ZhangF. (2021). High Expression of ACE2 on Keratinocytes Reveals Skin as a Potential Target for SARS-CoV-2. J. Invest. Dermatol.141 (1), 206–209.e1. doi: 10.1016/j.jid.2020.05.087

  • CrossRef
  • Google Scholar

• 129

  XuY.LiX.ZhuB.LiangH.FangC.GongY.et al. (2020). Characteristics of Pediatric SARS-CoV-2 Infection and Potential Evidence for Persistent Fecal Viral Shedding. Nat. Med.26 (4), 502–505. doi: 10.1038/s41591-020-0817-4

  • CrossRef
  • Google Scholar

• 130

  YamamotoS.SaitoM.TamuraA.PrawisudaD.MizutaniT.YotsuyanagiH. (2021). The Human Microbiome and COVID-19: A Systematic Review. PloS One16 (6), e0253293. doi: 10.1371/journal.pone.0253293

  • CrossRef
  • Google Scholar

• 131

  YeohY. K.ZuoT.LuiG. C.ZhangF.LiuQ.LiA. Y.et al. (2021). Gut Microbiota Composition Reflects Disease Severity and Dysfunctional Immune Responses in Patients With COVID-19. Gut70 (4), 698–706. doi: 10.1136/gutjnl-2020-323020

  • CrossRef
  • Google Scholar

• 132

  YildizS.Mazel-SanchezB.KandasamyM.ManicassamyB.SchmolkeM. (2018). Influenza A Virus Infection Impacts Systemic Microbiota Dynamics and Causes Quantitative Enteric Dysbiosis. Microbiome6 (1), 9. doi: 10.1186/s40168-017-0386-z

  • CrossRef
  • Google Scholar

• 133

  YoshidaN.EmotoT.YamashitaT.WatanabeH.HayashiT.TabataT.et al. (2018). Bacteroides Vulgatus and Bacteroides Dorei Reduce Gut Microbial Lipopolysaccharide Production and Inhibit Atherosclerosis. Circulation138 (22), 2486–2498. doi: 10.1161/CIRCULATIONAHA.118.033714

  • CrossRef
  • Google Scholar

• 134

  YuB.DaiC. -Q.ChenJ.DengL.WuX. -I.WuS.et al. (2015). Dysbiosis of Gut Microbiota Induced the Disorder of Helper T Cells in Influenza Virus-Infected Mice. Hum. Vaccines Immunother.11 (5), 1140–1146. doi: 10.1080/21645515.2015.1009805

  • CrossRef
  • Google Scholar

• 135

  ZhangD.LiS.WangN.TanH. Y.ZhangZ.FengY. (2020). The Cross-Talk Between Gut Microbiota and Lungs in Common Lung Diseases. Front. Microbiol.11, 301. doi: 10.3389/fmicb.2020.00301

  • CrossRef
  • Google Scholar

• 136

  ZhangW.ZhuB.XuJ.LiuY.QiuE.LiZ.et al. (2018). Bacteroides Fragilis Protects Against Antibiotic-Associated Diarrhea in Rats by Modulating Intestinal Defenses. Front. Immunol.9 (1040). doi: 10.3389/fimmu.2018.01040

  • CrossRef
  • Google Scholar

• 137

  ZhengL.KellyC. J.BattistaK. D.SchaeferR.LanisJ. M.AlexeevE. E.et al. (2017). Microbial-Derived Butyrate Promotes Epithelial Barrier Function Through IL-10 Receptor-Dependent Repression of Claudin-2. J. Immunol. (Baltimore Md 1950)199 (8), 2976–2984. doi: 10.4049/jimmunol.1700105

  • CrossRef
  • Google Scholar

• 138

  ZhouP.YangX. L.WangX. G.HuB.ZhangL.ZhangW.et al. (2020). A Pneumonia Outbreak Associated With a New Coronavirus of Probable Bat Origin. Nature579 (7798), 270–273. doi: 10.1038/s41586-020-2012-7

  • CrossRef
  • Google Scholar

• 139

  ZhouY.ZhangJ.ZhangD.MaW. L.WangX. (2021). Linking the Gut Microbiota to Persistent Symptoms in Survivors of COVID-19 After Discharge. J. Microbiol. (Seoul Korea)59 (10), 941–948. doi: 10.1007/s12275-021-1206-5

  • CrossRef
  • Google Scholar

• 140

  ZhuN.ZhangD.WangW.LiX.YangB.SongJ.et al. (2020). A Novel Coronavirus From Patients With Pneumonia in China, 2019. New Engl. J. Med.382 (8), 727–733. doi: 10.1056/NEJMoa2001017

  • CrossRef
  • Google Scholar

• 141

  ZuoT.LiuQ.ZhangF.LuiG. C.-Y.TsoE. Y.YeohY. K.et al. (2021a). Depicting SARS-CoV-2 Faecal Viral Activity in Association With Gut Microbiota Composition in Patients With COVID-19. Gut70 (2), 276–284. doi: 10.1136/gutjnl-2020-322294

  • CrossRef
  • Google Scholar

• 142

  ZuoT.LiuQ.ZhangF.YeohY. K.WanY.ZhanH.et al. (2021). Temporal Landscape of Human Gut RNA and DNA Virome in SARS-CoV-2 Infection and Severity. Microbiome9 (1), 91. doi: 10.1186/s40168-021-01008-x

  • CrossRef
  • Google Scholar

• 143

  ZuoT.ZhangF.LuiG. C. Y.YeohY. K.LiA. Y. L.ZhanH.et al. (2020a). Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology159 (3), 944–955.e8. doi: 10.1053/j.gastro.2020.05.048

  • CrossRef
  • Google Scholar

• 144

  ZuoT.ZhanH.ZhangF.LiuQ.TsoE. Y. K.LuiG. C. Y.et al. (2020b). Alterations in Fecal Fungal Microbiome of Patients With COVID-19 During Time of Hospitalization Until Discharge. Gastroenterology159 (4), 1302–1310.e5. doi: 10.1053/j.gastro.2020.06.048

  • CrossRef
  • Google Scholar