AUTHOR=Romani Lorenza , Del Chierico Federica , Macari Gabriele , Pane Stefania , Ristori Maria Vittoria , Guarrasi Valerio , Gardini Simone , Pascucci Giuseppe Rubens , Cotugno Nicola , Perno Carlo Federico , Rossi Paolo , Villani Alberto , Bernardi Stefania , Campana Andrea , Palma Paolo , Putignani Lorenza ,  the CACTUS Study Team , Carducci Francesca Calo` , Cancrini Caterina , Chiurchiù Sara , Ciofi degli Atti Marta , Cursi Laura , Cutrera Renato , D’Amore Carmen , D’Argenio Patrizia , De Ioris Maria A. , De Luca Maia , Finocchi Andrea , Lancella Laura , Manno Emma Concetta , Morrocchi Elena , Pansa Paola , Sessa Libera , Zangari Paola 

TITLE=The Relationship Between Pediatric Gut Microbiota and SARS-CoV-2 Infection

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.908492

DOI=10.3389/fcimb.2022.908492

ISSN=2235-2988

ABSTRACT=<p>This is the first study on gut microbiota (GM) in children affected by coronavirus disease 2019 (COVID-19). Stool samples from 88 patients with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 95 healthy subjects were collected (admission: 3–7 days, discharge) to study GM profile by 16S rRNA gene sequencing and relationship to disease severity. The study group was divided in COVID-19 (68), Non–COVID-19 (16), and MIS-C (multisystem inflammatory syndrome in children) (4). Correlations among GM ecology, predicted functions, multiple machine learning (ML) models, and inflammatory response were provided for COVID-19 and Non–COVID-19 cohorts. The GM of COVID-19 cohort resulted as dysbiotic, with the lowest α-diversity compared with Non–COVID-19 and CTRLs and by a specific β-diversity. Its profile appeared enriched in <italic>Faecalibacterium</italic>, <italic>Fusobacterium</italic>, and <italic>Neisseria</italic> and reduced in <italic>Bifidobacterium</italic>, <italic>Blautia</italic>, <italic>Ruminococcus</italic>, <italic>Collinsella</italic>, <italic>Coprococcus</italic>, <italic>Eggerthella</italic>, and <italic>Akkermansia</italic>, compared with CTRLs (<italic>p &lt;</italic> 0.05). All GM paired-comparisons disclosed comparable results through all time points. The comparison between COVID-19 and Non–COVID-19 cohorts highlighted a reduction of <italic>Abiotrophia</italic> in the COVID-19 cohort (<italic>p</italic> &lt; 0.05). The GM of MIS-C cohort was characterized by an increase of <italic>Veillonella</italic>, <italic>Clostridium</italic>, <italic>Dialister</italic>, <italic>Ruminococcus</italic>, and <italic>Streptococcus</italic> and a decrease of <italic>Bifidobacterium</italic>, <italic>Blautia</italic>, <italic>Granulicatella</italic>, and <italic>Prevotella</italic>, compared with CTRLs. Stratifying for disease severity, the GM associated to “moderate” COVID-19 was characterized by lower α-diversity compared with “mild” and “asymptomatic” and by a GM profile deprived in <italic>Neisseria</italic>, <italic>Lachnospira</italic>, <italic>Streptococcus</italic>, and <italic>Prevotella</italic> and enriched in <italic>Dialister</italic>, <italic>Acidaminococcus</italic>, <italic>Oscillospora</italic>, <italic>Ruminococcus</italic>, <italic>Clostridium</italic>, <italic>Alistipes</italic>, and <italic>Bacteroides.</italic> The ML models identified <italic>Staphylococcus</italic>, <italic>Anaerostipes</italic>, <italic>Faecalibacterium</italic>, <italic>Dorea</italic>, <italic>Dialister</italic>, <italic>Streptococcus</italic>, <italic>Roseburia</italic>, <italic>Haemophilus</italic>, <italic>Granulicatella</italic>, <italic>Gemmiger</italic>, <italic>Lachnospira</italic>, <italic>Corynebacterium</italic>, <italic>Prevotella</italic>, <italic>Bilophila</italic>, <italic>Phascolarctobacterium</italic>, <italic>Oscillospira</italic>, and <italic>Veillonella</italic> as microbial markers of COVID-19. The KEGG ortholog (KO)–based prediction of GM functional profile highlighted 28 and 39 KO-associated pathways to COVID-19 and CTRLs, respectively. Finally, <italic>Bacteroides</italic> and <italic>Sutterella</italic> correlated with proinflammatory cytokines regardless disease severity. Unlike adult GM profiles, <italic>Faecalibacterium</italic> was a specific marker of pediatric COVID-19 GM. The durable modification of patients’ GM profile suggested a prompt GM quenching response to SARS-CoV-2 infection since the first symptoms. <italic>Faecalibacterium</italic> and reduced fatty acid and amino acid degradation were proposed as specific COVID-19 disease traits, possibly associated to restrained severity of SARS-CoV-2–infected children. Altogether, this evidence provides a characterization of the pediatric COVID-19–related GM.</p>