Study of the resistome of human microbial communities using a targeted panel of antibiotic resistance genes in COVID-19 patients

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Abstract

Aim. To study overall drug resistance genes (resistome) in the human gut microbiome and the changes in these genes during COVID-19 in-hospital therapy.

Materials and methods. A single-center retrospective cohort study was conducted. Only cases with laboratory-confirmed SARS-CoV-2 RNA using polymerase chain reaction in oro-/nasopharyngeal swab samples were subject to analysis. The patients with a documented history of or current comorbidities of the hepatobiliary system, malignant neoplasms of any localization, systemic and autoimmune diseases, as well as pregnant women were excluded. Feces were collected from all study subjects for subsequent metagenomic sequencing. The final cohort was divided into two groups depending on the disease severity: mild (group 1) and severe (group 2). Within group 2, five subgroups were formed, depending on the use of antibacterial drugs (ABD): group 2A (receiving ABD), group 2AC (receiving ABD before hospitalization), group 2AD (receiving ABD during hospitalization), group 2AE (receiving ABD during and before hospitalization), group 2B (not receiving ABD).

Results. The median number of antibiotic resistance (ABR) genes (cumulative at all time points) was significantly higher in the group of patients treated with ABD: 81.0 (95% CI 73.8–84.5) vs. 51.0 (95% CI 31.1–68.4). In the group of patients treated with ABD (2A), the average number of multidrug resistance genes (efflux systems) was significantly higher than in controls (group 2B): 47.0 (95% CI 46.0–51.2) vs. 21.5 (95% CI 7.0–43.9). Patients with severe coronavirus infection tended to have a higher median number of ABR genes but without statistical significance. Patients in the severe COVID-19 group who did not receive ABD before and during hospitalization also had more resistance genes than the patients in the comparison group.

Conclusion. This study demonstrated that fewer ABR genes were identified in the group with a milder disease than in the group with a more severe disease associated with more ABR genes, with the following five being the most common: SULI, MSRC, ACRE, EFMA, SAT.

About the authors

Oleg O. Yanushevich

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-4293-8465

акад. РАН, д-р мед. наук, проф., ректор, зав. каф. пародонтологии

Russian Federation, Moscow

Igor V. Maev

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0001-6114-564X

акад. РАН, д-р мед. наук, проф., зав. каф. пропедевтики внутренних болезней и гастроэнтерологии лечебного фак-та

Russian Federation, Moscow

Natella I. Krikheli

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-8035-0638

д-р мед. наук, проф., зав. каф. клинической стоматологии 

Russian Federation, Moscow

Oleg V. Levchenko

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0003-0857-9398

д-р мед. наук, проф., зав. каф. нейрохирургии и нейрореанимации 

Russian Federation, Moscow

Julia S. Galeeva

Research Institute for Systems Biology and Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0001-6304-4607

мл. науч. сотр. 

Russian Federation, Moscow

Elizaveta V. Starikova

Research Institute for Systems Biology and Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0001-6582-210X

науч. сотр. 

Russian Federation, Moscow

Dmitry N. Andreev

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-4007-7112

канд. мед. наук, доц., доц. каф. пропедевтики внутренних болезней и гастроэнтерологии лечебного фак-та 

Russian Federation, Moscow

Philipp S. Sokolov

Russian University of Medicine

Author for correspondence.
Email: phlppsokolov@gmail.com
ORCID iD: 0000-0003-2813-6498

преподаватель каф. фармакологии лечебного фак-та НОИ «Высшая школа клинической медицины им. Н.А. Семашко» 

Russian Federation, Moscow

Aleksei K. Fomenko

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-1794-7263

преп. каф. фармакологии лечебного фак-та

Russian Federation, Moscow

Mikhail K. Devkota

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-3736-4196

преп. каф. фармакологии лечебного фак-та 

Russian Federation, Moscow

Nikolai G. Andreev

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-5136-0140

канд. мед. наук, доц., доц. каф. пропедевтики внутренних болезней и гастроэнтерологии лечебного фак-та

Russian Federation, Moscow

Andrew V. Zaborovsky

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-7923-9916

д-р мед. наук, доц., зав. каф. фармакологии лечебного фак-та

Russian Federation, Moscow

Vladimir V. Evdokimov

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0001-9281-579X

д-р мед. наук, проф. каф. клинической функциональной диагностики

Russian Federation, Moscow

Sergey V. Tsaregorodtsev

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-0254-0516

преп. каф. фармакологии лечебного фак-та 

Russian Federation, Moscow

Elena N. Ilina

Research Institute for Systems Biology and Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0003-0130-5079

чл.-кор. РАН, проф. РАН, д-р биол. наук, гл. науч. сотр. 

Russian Federation, Moscow

Vadim M. Govorun

Research Institute for Systems Biology and Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0003-0837-8764

акад. РАН, д-р биол. наук, проф., дир. 

Russian Federation, Moscow

Petr A. Bely

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0001-5998-4874

канд. мед. наук, доц. каф. пропедевтики внутренних болезней и гастроэнтерологии лечебного фак-та 

Russian Federation, Moscow

Elena A. Sabelnikova

Russian University of Medicine; Loginov Moscow Clinical Scientific Center

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0001-7519-2041

д-р мед. наук, проф. каф. пропедевтики внутренних болезней и гастроэнтерологии лечебного фак-та ФГБОУ ВО «Российский университет медицины», зам. дир. по научной работе ГБУЗ «МКНЦ им. А.С. Логинова»

Russian Federation, Moscow; Moscow

Aleksandr A. Solodov

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-8263-1433

д-р мед. наук, дир. НОИ «Высшая школа клинической медицины им. Н.А. Семашко» 

Russian Federation, Moscow

Sergei V. Cheremushkin

Russian University of Medicine; Central Clinical Hospital «Russian Railways Medicine»

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-0982-2006

канд. мед. наук, доц. каф. пропедевтики внутренних болезней и гастроэнтерологии лечебного фак-та НОИ «Высшая школа клинической медицины им. Н.А. Семашко» ФГБОУ ВО «Российский университет медицины», зам. гл. врача по терапевтической деятельности ЧУЗ «ЦКБ "РЖД-Медицина"»

Russian Federation, Moscow; Moscow

Rafik I. Shaburov

Russian University of Medicine; Central Clinical Hospital «Russian Railways Medicine»

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0001-9741-0150

канд. мед. наук, доц. каф. пропедевтики внутренних болезней и гастроэнтерологии лечебного фак-та НОИ «Высшая школа клинической медицины им. Н.А. Семашко» ФГБОУ ВО «Российский университет медицины», гл. врач ЧУЗ «ЦКБ "РЖД-Медицина"»

Russian Federation, Moscow; Moscow

Anastasia L. Kebina

Russian University of Medicine

Email: phlppsokolov@gmail.com
ORCID iD: 0000-0002-7570-9650

зам. глав. врача НОИ «Высшая школа клинической медицины им. Н.А. Семашко» Университетской клиники, ассистент каф. терапии, клинической фармакологии и скорой медицинской помощи 

Russian Federation, Moscow

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Supplementary files

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2. Fig. 1. Distribution of patients by groups.

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3. Fig. 2. Distribution of patients of study groups depending on the severity of the patient's condition according to the ECOG/WHO PS scale and the degree of lung damage according to CT.

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4. Fig. 3. The log2foldchange values obtained from the DESeq2 analysis. Positive log2FC values (right) correspond to genes overrepresented in group 2 (severe) patients, and negative log2FC values (left) correspond to genes overrepresented in group 1 (mild) patients.

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5. Fig. 4. The proportion of readings mapped to each of 15 genes with significantly different representation between two groups of patients [red – readings related to samples from group 2 (severe) patients, blue – readings related to group 1 (mild) patients].

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6. Fig. 5. The median number of antibiotic resistance genes (cumulative at all time points) in patients with mild (group 1) and severe coronavirus infection (group 2).

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7. Fig. 6. The median number of resistance genes in patients of group 2A (receiving ABD) and group 2B (not receiving ABD).

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8. Fig. 7. The median number of resistance genes in patients of group 2AE and 2AD.

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9. Fig. 8. The median number of multidrug resistance genes (efflux systems) in control patients group 1 and group 2B.

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