Gut Microbiota Diversity and C-Reactive Protein Are Predictors of Disease Severity in COVID-19 Patients

André Moreira-Rosário; Cláudia Marques; Hélder Pinheiro; João Ricardo Araújo; Pedro Ribeiro; Rita Rocha; Inês Mota; Diogo Pestana; Rita Ribeiro; Ana Pereira; Maria José de Sousa; José Pereira-Leal; José de Sousa; Juliana Morais; Diana Teixeira; Júlio César Rocha; Marta Silvestre; Nuno Príncipe; Nuno Gatta; José Amado; Lurdes Santos; Fernando Maltez; Ana Boquinhas; Germano de Sousa; Nuno Germano; Gonçalo Sarmento; Cristina Granja; Pedro Póvoa; Ana Faria; Conceição Calhau

doi:10.3389/fmicb.2021.705020

Gut Microbiota Diversity and C-Reactive Protein Are Predictors of Disease Severity in COVID-19 Patients

Front Microbiol. 2021 Jul 19:12:705020. doi: 10.3389/fmicb.2021.705020. eCollection 2021.

Authors

André Moreira-Rosário^{1

2}, Cláudia Marques^{1

2}, Hélder Pinheiro^{1

3}, João Ricardo Araújo^{1

2}, Pedro Ribeiro⁴, Rita Rocha^{5

6}, Inês Mota^{1

2}, Diogo Pestana^{1

2}, Rita Ribeiro⁴, Ana Pereira⁴, Maria José de Sousa^{1

4}, José Pereira-Leal⁷, José de Sousa⁴, Juliana Morais^{1

2

8}, Diana Teixeira^{1

8}, Júlio César Rocha^{1

2}, Marta Silvestre^{1

2}, Nuno Príncipe⁹, Nuno Gatta⁹, José Amado⁹, Lurdes Santos¹⁰, Fernando Maltez³, Ana Boquinhas¹¹, Germano de Sousa⁴, Nuno Germano¹², Gonçalo Sarmento¹³, Cristina Granja^{2

14

15}, Pedro Póvoa^{1

16

17}, Ana Faria^{1

8}, Conceição Calhau^{1

2}

Affiliations

¹ Faculdade de Ciências M dicas, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal.
² Faculdade de Ciências Médicas, CINTESIS - Center for Health Technology and Services Research, NOVA Medical School, Universidade NOVA de Lisboa, Lisboa, Portugal.
³ Department of Infectious Diseases, Hospital Curry Cabral, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal.
⁴ Centro de Medicina Laboratorial Germano de Sousa, Lisboa, Portugal.
⁵ i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
⁶ Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
⁷ Ophiomics - Precision Medicine, Lisboa, Portugal.
⁸ Faculdade de Ciências Médicas, Comprehensive Health Research Centre (CHRC), NOVA Medical School, Universidade NOVA de Lisboa, Lisboa, Portugal.
⁹ Department of Emergency and Intensive Care Medicine, Centro Hospitalar Universitário de São João, Porto, Portugal.
¹⁰ Infectious Diseases Service, ID Intensive Care Unit, Faculdade de Medicina, Centro Hospitalar Universitário de São João, Universidade do Porto, Porto, Portugal.
¹¹ Department of Emergency, CUF Infante Santo Hospital, Lisboa, Portugal.
¹² Polyvalent Intensive Care Unit, Hospital Curry Cabral, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal.
¹³ Department of Internal Medicine, Centro Hospitalar de Entre o Douro e Vouga, Santa Maria da Feira, Portugal.
¹⁴ Department of Anesthesiology, Centro Hospitalar Universitário de São João, Porto, Portugal.
¹⁵ Department of Surgery and Physiology, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
¹⁶ Polyvalent Intensive Care Unit, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal.
¹⁷ Center for Clinical Epidemiology, Research Unit of Clinical Epidemiology, OUH Odense University Hospital, Odense, Denmark.

Abstract

The risk factors for coronavirus disease 2019 (COVID-19) severity are still poorly understood. Considering the pivotal role of the gut microbiota on host immune and inflammatory functions, we investigated the association between changes in the gut microbiota composition and the clinical severity of COVID-19. We conducted a multicenter cross-sectional study prospectively enrolling 115 COVID-19 patients categorized according to: (1) the WHO Clinical Progression Scale-mild, 19 (16.5%); moderate, 37 (32.2%); or severe, 59 (51.3%), and (2) the location of recovery from COVID-19-ambulatory, 14 (household isolation, 12.2%); hospitalized in ward, 40 (34.8%); or hospitalized in the intensive care unit, 61 (53.0%). Gut microbiota analysis was performed through 16S rRNA gene sequencing, and the data obtained were further related to the clinical parameters of COVID-19 patients. The risk factors for COVID-19 severity were identified by univariate and multivariable logistic regression models. In comparison to mild COVID-19 patients, the gut microbiota of moderate and severe patients have: (a) lower Firmicutes/Bacteroidetes ratio; (b) higher abundance of Proteobacteria; and (c) lower abundance of beneficial butyrate-producing bacteria such as the genera Roseburia and Lachnospira. Multivariable regression analysis showed that the Shannon diversity index [odds ratio (OR) = 2.85, 95% CI = 1.09-7.41, p = 0.032) and C-reactive protein (OR = 3.45, 95% CI = 1.33-8.91, p = 0.011) are risk factors for severe COVID-19 (a score of 6 or higher in the WHO Clinical Progression Scale). In conclusion, our results demonstrated that hospitalized patients with moderate and severe COVID-19 have microbial signatures of gut dysbiosis; for the first time, the gut microbiota diversity is pointed out as a prognostic biomarker of COVID-19 severity.

Keywords: COVID-19; Shannon—Weiner diversity index; WHO Clinical Progression Scale; dysbiosis; gut microbiota.

Copyright © 2021 Moreira-Rosário, Marques, Pinheiro, Araújo, Ribeiro, Rocha, Mota, Pestana, Ribeiro, Pereira, de Sousa, Pereira-Leal, de Sousa, Morais, Teixeira, Rocha, Silvestre, Príncipe, Gatta, Amado, Santos, Maltez, Boquinhas, de Sousa, Germano, Sarmento, Granja, Póvoa, Faria and Calhau.