A new study found that gut flora is positively correlated with human pro-inflammatory factors, which may underlie the susceptibility to severe novel coronavirus pneumonia in healthy individuals.
On April 25, local time, the medical preprinting platform medRxiv published online a research article entitled "Gut microbiota may underlie the predisposition of healthy individuals to COVID-19" (not peer-reviewed) with a research team including the Key Laboratory of Growth Regulation and Translational Research in Zhejiang Province, Xihu University, and the Key Laboratory of School of Public Health, Sun Yat-sen University.
In the context of the global pandemic of novel coronavirus pneumonia (COVID-19), the susceptibility of different individuals has become one of the research topics for scientists.
The World Health Organization (WHO) reports that 80% of patients with novel coronavirus pneumonia are less symptomatic, but in the absence of medical resources, the readmission rate for novel coronavirus pneumonia can be as high as 20% and the overall mortality rate for readmitted patients can exceed 50%.
This new study by Westlake University and others explores the biological mechanisms that may predict susceptibility to severe novel coronavirus pneumonia in healthy individuals.
The study constructed a proteomic risk scoring system based on 20 blood biomarkers that can predict the progression of severe COVID-19, and machine learning models demonstrated that gut flora can accurately predict the aforementioned blood biomarkers while being highly correlated with pro-inflammatory cytokines.
Fecal metabolomics analysis suggests potential amino acid-related pathways linking intestinal flora to inflammation.
This also suggests that gut flora may be a trigger for severe novel coronavirus pneumonia in healthy individuals.
To date, individuals who are older, male, or with other clinical comorbidities are considered more likely to develop severe cases of COVID-19, based on numerous published research papers.
However, little is known in the scientific community about the underlying biological mechanisms or predictors of susceptibility to this disease.
This study addresses the large differences in susceptibility to novel coronavirus pneumonia and its progression in different individuals and illustrates the underlying biological mechanisms behind the differences in susceptibility between different populations.
Notably, the study also contributed to the identification of potential targets for drug development for the treatment of novel coronavirus pneumonia, suggesting that core gut microbial profiles and associated metabolites may serve as potential targets for the prevention of susceptible individuals.
Constructing a risk score: a valid predictor of susceptibility to severe novel coronavirus pneumonia in healthy individuals
Several studies have demonstrated that human angiotensin-converting enzyme 2 (hACE2) is a key receptor for the invasion of novel coronavirus into human cells, and it is worth noting that ACE2 is an important regulator of intestinal inflammation and that ACE2 is expressed in the ileum and colon in higher amounts than in the lungs.
Previous studies have indicated that ACE2 also plays an important role in the composition of the intestinal flora, thus influencing the formation of cardiopulmonary disease.
In addition, more than 60% of patients with novel coronavirus pneumonia have gastrointestinal symptoms such as diarrhea, nausea and vomiting, and those with gastrointestinal symptoms are more likely to progress to serious or critical cases.
This evidence suggests that the gut microbiota may play an important role in the susceptibility and progression of novel coronavirus pneumitis.
Previous studies of blood biomarkers in patients with novel coronavirus pneumonia have identified a group of proteins that can help predict disease progression in patients with novel coronavirus pneumonia.
However, for healthy populations, it is unclear whether these biomarkers can be used to predict susceptibility to novel coronavirus pneumonia and whether gut flora can modulate these biomarkers.
Research design and analysis process
To address these issues, the researchers collected blood proteomic data from 31 patients with novel coronavirus pneumonia (13 critically ill patients) and multiple histology data from 2413 uninfected healthy patients from Guangzhou.
Based on 20 proteomic biomarker data, the team constructed a blood proteomics risk score (PRS) for predicting severe novel coronavirus pneumonia.
In COVID-19 patients, regression analysis showed that for every 10% increase in PRS, patients had a 57% increased risk of progressing to the clinically serious stage, suggesting that PRS could serve as a biomarker of prognosis for severe new coronavirus pneumonia.
Then, based on proteomic and blood inflammatory biomarker data from 990 healthy individuals, the researchers investigated the association of novel coronavirus pneumonia-associated PRS with inflammatory biomarkers to verify the association of PRS with disease susceptibility in non-infected individuals.
They found that this PRS was positively correlated with proinflammatory cytokines, suggesting that the team constructed a PRS that effectively predicts the susceptibility of healthy individuals to severe novel coronavirus pneumonia.
Notably, the researchers found that older people were more likely to have a higher risk score, while younger people had a lower score and gender had no significant effect on that score.
Intestinal flora associated with susceptibility to COVID-19 in uninfected individuals may be a therapeutic target
To investigate the potential role of gut flora on COVID-19 susceptibility in healthy individuals, the research team next used a machine modeling approach to discuss the relationship between gut flora and the aforementioned COVID-19-associated PRS in a sub-cohort study with 301 participants, and measured both gut microbiota (16s rRNA) and blood proteomics data.
Correlation between core microbial OTU and host inflammatory cytokines
Using a conservative and rigorous machine modeling approach, the team identified the 20 most predictive operational classification units (OTUs) in the gut flora, and these core OTUs explained an average of 21.5% of the aforementioned PRS changes.
These OTUs mainly belong to the genus Anthomycetes, Streptococcus, Lactobacillus, etc.
In addition, the team further tested the covariance between the 20 core OTUs and the aforementioned 20 severe COVID-19 predicted proteomic student markers using covariance analysis (CIA), which showed that these OTUs were strongly associated with proteomic biomarkers.
Importantly, the results of the above analyses were able to be successfully replicated in an independent subgroup containing 169 individuals, and these findings suggest that alterations in indicators of the gut microbiota may precede changes in blood proteomic biomarkers in the development of novel coronavirus pneum disease.
Further fecal metabolomics analysis revealed potential biological mechanisms as researchers evaluated the relationship between the core gut flora and the fecal metabolome in 987 participants and found that a total of 183 fecal metabolites were significantly associated with at least one selected microbial OTU in all samples.
Notably, 45 fecal metabolites of the amino acid, fatty acid and bile acid categories were significantly associated with more than half of the selected microbial OTUs, suggesting that these metabolites may play a key role in mediating the effects of core gut flora on host metabolism and inflammation.
Finally, the team identified 40 host and environmental factors that contribute to variation in the core gut flora characteristics described above, including demographic or clinical factors such as gender, education, physical activity, diastolic blood pressure, blood glucose, blood lipids, and medication use for type 2 diabetes; but also dietary, nutritional category factors such as dairy product consumption.
Overall, these findings link gut flora to susceptibility to COVID-19 in uninfected individuals. In healthy uninfected individuals, gut microbiome characteristics are highly predictive of blood proteomic student markers of severe COVID-19 disease, and disruption of corresponding gut microbiome characteristics may put healthy individuals in an abnormal inflammatory state.
In fact, the maintenance of the steady state of the gut has been recommended as a treatment option in the Plan for the Diagnosis and Treatment of Novel Coronavirus Diseases (6th edition) published by the National Commission on Health Care, thus maintaining the micro-ecological balance of the gut and preventing secondary bacterial infection.
The research team believes that the results of this study provide important evidence and recommendations on the underlying biological mechanisms behind differences in susceptibility between different populations.
In addition, there is growing evidence that the "cytokine storm" is an overproduction of inflammatory cytokines and may be an important mechanism for the severity and death of COVID-19 patients. Therefore, anti-cytokine therapy that suppresses the high inflammatory state of patients is a recommended strategy for the treatment of critically ill COVID-19 patients.
And among the 20 proteomic predictors of severe COVID-19 in this study, several of the most upregulated (upregulated) proteins, such as serum amyloid A-1 (SAA1), SAA2, SAA4, and α-1-antitrypsin, are activated acute proteins.
These proteins can be activated along with proinflammatory cytokines such as IL-6 and TNF-α after invasion by novel coronaviruses.
Therefore, the team also proposed that this group of proteomic student markers could serve as important biomarkers or therapeutic targets for the treatment of novel coronavirus infections, as well as potential targets for the development of therapeutic drugs for novel coronavirus pneumonia.
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