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. 2022 Jan 20;20(1):24.
doi: 10.1186/s12916-021-02212-0.

Gut microbiome alterations and gut barrier dysfunction are associated with host immune homeostasis in COVID-19 patients

Zhonghan Sun #  1   2 , Zhi-Gang Song #  3   4 , Chenglin Liu #  1 , Shishang Tan #  1 , Shuchun Lin  1 , Jiajun Zhu  1 , Fa-Hui Dai  3 , Jian Gao  1 , Jia-Lei She  3 , Zhendong Mei  1 , Tao Lou  1 , Jiao-Jiao Zheng  3 , Yi Liu  3 , Jiang He  1 , Yuanting Zheng  1 , Chen Ding  1 , Feng Qian  1 , Yan Zheng  5   6 , Yan-Mei Chen  7
Affiliations

Gut microbiome alterations and gut barrier dysfunction are associated with host immune homeostasis in COVID-19 patients

Zhonghan Sun et al. BMC Med. .

Abstract

Background: COVID-19 is an infectious disease characterized by multiple respiratory and extrapulmonary manifestations, including gastrointestinal symptoms. Although recent studies have linked gut microbiota to infectious diseases such as influenza, little is known about the role of the gut microbiota in COVID-19 pathophysiology.

Methods: To better understand the host-gut microbiota interactions in COVID-19, we characterized the gut microbial community and gut barrier function using metagenomic and metaproteomic approaches in 63 COVID-19 patients and 8 non-infected controls. Both immunohematological parameters and transcriptional profiles were measured to reflect the immune response in COVID-19 patients.

Results: Altered gut microbial composition was observed in COVID-19 patients, which was characterized by decreased commensal species and increased opportunistic pathogenic species. Severe illness was associated with higher abundance of four microbial species (i.e., Burkholderia contaminans, Bacteroides nordii, Bifidobacterium longum, and Blautia sp. CAG 257), six microbial pathways (e.g., glycolysis and fermentation), and 10 virulence genes. These severity-related microbial features were further associated with host immune response. For example, the abundance of Bu. contaminans was associated with higher levels of inflammation biomarkers and lower levels of immune cells. Furthermore, human-origin proteins identified from both blood and fecal samples suggested gut barrier dysfunction in COVID-19 patients. The circulating levels of lipopolysaccharide-binding protein increased in patients with severe illness and were associated with circulating inflammation biomarkers and immune cells. Besides, proteins of disease-related bacteria (e.g., B. longum) were detectable in blood samples from patients.

Conclusions: Our results suggest that the dysbiosis of the gut microbiome and the dysfunction of the gut barrier might play a role in the pathophysiology of COVID-19 by affecting host immune homeostasis.

Keywords: COVID-19; Gut barrier; Immune homeostasis; Metaproteomic; Microbiome; SARS-CoV-2.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Alterations in gut microbiome composition of COVID-19 patients. a The composition of gut microbiota significantly altered in COVID-19 patients. The microbial composition was represented by the β-diversity based on unweighted Unifrac distance. b The phylum (up) and genus (down) distribution of the gut microbiota of COVID-19 patients and non-COVID-19 controls. c The microbial variation explained by medication and basic characteristics. Asterisk (*) represents significant associations by PERMANOVA
Fig. 2
Fig. 2
Associations of gut microbial species with COVID-19 severity and host immune response. a Relative abundances of the 4 different species in patients with severe condition or mild condition at the criteria of P < 0.05 and LDA > 2 by LEfSe. The numbers represent P-value of the Wilcoxon rank-sum test. b Associations of differential microbial species with clinical traits with adjustment for age and sex. Red bars indicate positive associations, and blue bars indicate negative associations. White asterisks indicate associations with P < 0.05. The color key indicates the association strength and direction in terms of the t-value. The gray bar shows in which group the corresponding indicator is higher. The bottom color bar shows the classifications of clinical traits. The percent sign (%) represents the percentage, and the pound sign (#) represents the count value of the corresponding immune cells. c The associations between the relative abundance of Burkholderia contaminans and circulating levels of IL-6, CRP, and counts of CD4+ T cell and total lymphocyte
Fig. 3
Fig. 3
Relationships of microbial functional potentials with COVID-19 severity and host immune response. a Seven COVID-19 severity-related microbial pathways and their associations with clinical traits. Red bars indicate positive associations, and blue bars indicate negative associations. White asterisks indicate associations with P < 0.05. The color key indicates the association strength and direction in terms of the t value. The gray bar shows in which group the corresponding indicator is more abundant. The percent sign (%) represents the percentage, and the pound sign (#) represents the count value of the corresponding immune cells. b The associations of the relative abundance of carbohydrate pathway (PWY-6590) with levels of lactate dehydrogenase and counts of neutrophils. c The associations of the relative abundance of glycolysis pathway (ANAGLYCOLYSIS-PWY) with levels of complement C4 and bacterial infection score. d COVID-19 severity-related virulence genes and their associations with clinical traits. The VFs-color bar shows the classification of VFs
Fig. 4
Fig. 4
Gut barrier dysfunction in COVID-19 patients. a Number of human proteins detected in fecal samples from COVID-19 patients and controls. b Human-to-all DNA ratio detected in fecal samples from COVID-19 patients and controls. c The relative abundances of candidate human fecal proteins related to gastrointestinal damage
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