Gut microbiota and COVID-19: An intriguing pediatric perspective

Table 1 Potential effects of coronavirus disease 2019 on gut and lung microbiome

Gut microbiome	Lung microbiome
Changes in the diversity of the intestinal microbiota have been found: (1) Decrease in the relative abundance of beneficial microbes (such as Agathobacter, Fusicatenibacter, Roseburia and Ruminococcaceae UCG−013); and (2) Oredominance of opportunistic genera (such as Actinomyces, Rothia, Streptococcus) and Veillonella[24]	Changes in the diversity of the lung microbiota have been found: (1) Prevalence of Acinetobacter, Brevundimonas, Burkholderia, Chryseobacterium, Sphingobium species and Enterobacteriaceae members; and (2) Among mycetes, prevalence of Cryptococcus, followed by Aspergillus, Alternaria, Dipodascus, Mortierella, Naganishia, Diutina, Candida, Cladosporium, Issatchenkia, and Wallemia[29]
COVID-19 severity: (1) Was positively associated to the relative abundance of Coprobacillus, Clostridium ramosum, and Clostridium hathewayi; and (2) Was inversely associated to the abundance of Faecalibacterium prausnitzii (which favors an anti-inflammatory microenvironment)[25]	The bronchoalveolar lavage fluid of COVID-19 patients characterized by relative abundance of: (1) Lactic acid bacteria such as Lactobacillus fermentum, Lactobacillus reuteri, Lactobacillus delbrueckii, and Lactobacillus salivarius; (2) Some pathogens such as Klebsiella oxytoca, Enterobacter cloacae (positively correlated with COVID-19 severity), and Bacillus cereus; (3) Some nosocomial infection pathogens such as Enterobacter kobei, Enterobacter cloacae, and Ralstonia pickettii; and (4) Several gut bacteria like Faecalibacterium prausnitzii, Enterococcus faecium, and Citrobacter freundii, and commensal bacteria residing in the mouth and respiratory tracts such as Rothia mucilaginosa[30]
Viral load in feces of COVID-19 patients inversely correlated to the relative abundance of Bacteroides dorei, B. massiliensis, B. ovatus, and B. thetaiotaomicron (that downregulate the ACE-2 expression in mouse intestine)[25]	Bacterial and fungal DNA burden in BAL specimens of patients with COVID-19-induced ARDS significantly higher than in negative experimental controls, with relative abundance of Staphylococcus, Streptococcus, and Enterococcus spp[31]
SARS-CoV-2 infectivity: (1) Was positively related to relative abundance of Collinsella aerofaciens, C. tanakaei, Morganella morganii, and Streptococcus infantis; and (2) Was inversely related to prevalence of Alistipes onderdonkii, Bacteroides stercoris, Lachnospiraceae bacterium and Parabacteroides merdae[26]
Increased abundance of opportunistic fungi (including Candida albicans, C. auris, Aspergillus flavus and A. niger) in feces of COVID-19 patients was found when compared to controls[27]
In patients with MIS-C a predominance of Eubacterium dolichum, Eggerthella lenta, Bacillus thermoamylovorans, Prevotella tannerae, and Bacteroides coprophilus and a decrease of Faecalibacterium prausnitzii were reported. In COVID-19 group an increase of Bifidobacterium adolescents and Dorea formicigenerasus was found[28]

ACE-2: Angiotensin-converting enzyme 2; ARDS: Acute respiratory distress syndrome; COVID-19: Coronavirus disease 2019; MIS-C: Multisystem inflammatory syndrome in children; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Table 2 Main findings of the pediatric studies on the association between gut microbiota and coronavirus disease 2019

Ref.	Study design and methods	Population (n)	Main findings
Romano-Keeler et al[44]	Observational cohort study	Twenty-one COVID-19 positive mothers delivering between March and August 2020 with a mean age of 26 (17-42) yr	Delayed cord clamping and skin-to-skin avoided; infants admitted to the NICU with maternal breast milk restricted. Discharge arranged with COVID-19 negative family members. All 21 infants COVID-19 negative at 24 and 48 h. Changes in perinatal care might negatively affect gut microbiome pattern early in life
Nashed et al[40]	Case-control study	595 children aged 0-24 mo	Significantly different abundant species between SARS-CoV-2 positive infants and controls were found. A decreased abundance of Bifidobacterium bifidum and Akkermansia muciniphila in positive samples (both linked to protection against inflammation) was found
Xu et al[43]	Case-control study	(1) 9 children diagnosed with COVID-19 aged 7-139 mo; and (2) 14 age-matched healthy control children	Altered microbiome in COVID-19 children, with increased abundance of opportunistic pathogenic and environmental bacteria such as Pseudomonas, Herbaspirillum, and Burkholderia both in the upper respiratory tract and the gut was found. Dysbiosis up to 25-28 d in different subjects was reported

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; COVID-19: Coronavirus disease 2019; NICU: Neonatal Intensive Care Unit.

Table 3 Main findings of the studies on the association between infant gut microbiota and coronavirus disease 2019

Ref.	Study design and methods	Population (n)	Main findings
Romano-Keeler et al[44]	Observational cohort study	Twenty-one COVID-19 positive mothers delivering between March and August 2020 with a mean age of 26 (17-42) yr	Delayed cord clamping and skin-to-skin avoided; infants admitted to the NICU with maternal breast milk restricted. Discharge arranged with COVID-19 negative family members. All infants COVID-19 negative at 24 and 48 h. Changes in perinatal care might negatively affect gut microbiome pattern early in life
Salvatori et al[57]	Case report	Two maternal–infant dyads with a positive nasopharyngeal swab for SARS-CoV-2 both in the mother and in the child	SARS-CoV-2 was not detected by RT-PCR in breast milk samples of both mothers
Gómez-Torres et al[68]	Prospective case-control study	(1) 37 women with full-term pregnancies and mild SARS-CoV-2 infection; and (2) 63 healthy controls	No difference nor in Alpha-neither in Beta-diversity between breast milk samples collected from the two groups; Staphylococcus and Streptococcus were the most abundant genera and the only ones detected in all the samples. Disease state (symptomatic or asymptomatic infection) did not affect the metataxonomic profile

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; COVID-19: Coronavirus disease 2019; NICU: Neonatal Intensive Care Unit; MS: Multiple sclerosis; MIS-C: Multisystem inflammatory syndrome in children.