Asthma is a chronic airway disease with various etiologies (1, 2), affecting approximately 358 million people worldwide (3, 4). Epidemiological surveys have reported that about 250000 deaths are directly caused by asthma every year. And asthma was classified as the 23rd leading cause of premature mortality in 2016. With the development of society, the prevalence and socioeconomic burden of asthma are increasing year by year. According to reports, at present, the prevalence of asthma in adults is estimated to be 7.9% in the USA (5). Another study demonstrated that the cost of asthma treatment and mortality in the USA was estimated at $81 billion from 2008 to 2013 (6).

For many years, eosinophils in asthmatic inflammation have been recognized as an essential factor in the pathophysiology of asthma (7). Asthma is a heterogeneous disease comprising several endotypes and clinical phenotypes. Type 2 (T2) inflammation as key immune response in asthma pathobiology, resulting in the broad classification of T2-high and T2-low asthma. And eosinophils are also key inflammatory cells of ‘T2 high’ asthma (8). Quite a few studies reported a significant correlation between blood eosinophil counts and asthma (9–15). For example, eosinophilia has been confirmed to be a risk factor for future asthma exacerbations among asthmatic adults (16–18). And another study indicated increasing blood eosinophil counts might be correlated with rising mortality in patients with asthma (12). Besides, blood eosinophils are also used to guide and regulate treatment with corticosteroids, anti-IL antibodies in asthma, resulting in controlling asthma and reducing exacerbation frequency (19, 20). In short, eosinophils play a vital part in the occurrence, evolution, and therapy of asthma.

Asthma of underlying mechanisms maybe probably multifactorial, which may be affected by environmental, genetic, lifestyle factors, and so on, including dietary intake (21). A noticeable factor in a diet is folate. It takes part in synthesis of amino acid, purine, and pyrimidine, which is also a source of methyl donors for DNA methylation (22). Folate may contribute to the pathogenesis of asthma by affecting DNA methylation, further increasing or decreasing the expression of disease susceptibility genes (23, 24). Previous studies have reported, in animal models, folate plays a potential role in the pathogenesis of asthma (21, 24). In addition, some clinical researches reported that serum folate levels were correlated with the risk of asthma occurrence (21, 25–27).

At present, most studies have focused on exploring the relationship between folate and asthma occurrence. Nevertheless, to date, few researches have discussed whether folate status is correlated with disease severity or progression in asthmatic individuals; whether folate status affects asthma control is also unclear (24, 28). To gain insight into the role of folate in the control, progression, and treatment of asthma, we explored the correlation of serum folate concentration and blood eosinophil counts in asthmatic adults by using the data from the National Health and Nutrition Examination Survey (NHANES) of 2011–2018 cycles.

The prevalence of atopy has risen over recent decades, possibly because of changes in lifestyle and environmental factors. Recently, it was suggested that changes in the intake of certain nutrients might partly explain the asthma epidemic worldwide (29–31). Folic acid, a special nutritional component that has attracted much attention recently, is necessary for protein and DNA protein methylation, and for nucleotide synthesis (24). Folate could result in asthma risk by affecting DNA methylation and, further, genetic expression (23, 32). However, at present, there are few studies on the relationship between folate status with asthma severity or progression in asthmatic individuals. Thus, in our study, we used a largely representative sample of individuals who took part in the 2011-2018 of NHANES to explore the correlation of serum folate concentrations and blood eosinophil counts among asthmatic individuals.

To our knowledge, our investigation is the first research to discuss the correlation of serum folic acid levels and blood eosinophil counts in asthmatic adults and is also one of the most extensive cross-sectional studies. Therefore, we investigated the correlation of serum folic acid levels and blood eosinophil counts among 2332 asthmatic adults who took part in the NHANES survey from 2011 to 2018 in the USA. Three types of weighted multiple linear regression models were used to identify the association between the serum folate concentrations and blood eosinophil counts. Among three models, we all observed that serum folate levels were negatively correlated with blood eosinophil counts with statistical significance. Also, we observed that blood eosinophil counts decreased by 0.20 (-0.34, -0.06)/uL for each additional unit of serum folate (nmol/L) in the Model III, which adjusted for the demographic, laboratory, examination, dietary, and comorbidities data. Next, we constructed the machine learning of XGBoost model to identify the relative importance of chosen variables correlated with blood eosinophils, and we observed that folate intake, Vitamin A intake, Vitamin B12 intake, BMI, blood basophil counts, blood creatinine, serum folate, Vitamin D intake, age and blood cotinine were the ten most important variables in the blood eosinophil counts. Then, we observed that the linear relationship between serum folate concentrations and blood eosinophil counts through constructing the generalized linear model. The above results suggested that serum folate might be correlated with the immune status of asthmatic adults in some way.

DNA methylation, histone modifications and regulation of noncoding RNA, which are primary types of epigenetic regulatory mechanisms in humans, have been confirmed to be correlated with asthma, and might be regarded as biomarkers for asthma (33). DNA methylation, a crucial type of epigenetic regulation, is a mechanism underlying some gene-environment interactions of allergic diseases such as asthma. And DNA methylation plays a vital role in asthma through regulation of a substantial number of genes involved in allergic responses, indicating a strong correlation with the development of asthma and maintenance of inflammation via epigenetic control of IgE, eosinophils and fractional exhaled nitric oxide (FENO), among other mechanisms (34). Folic acid, a water-soluble vitamin, is called vitamin B9, too. It plays a critical role in purine, pyrimidine and amino acid of synthesis, which is also a source of methyl donors for DNA methylation. In a mouse model, one animal experiment demonstrated that a diet rich in folate enhanced allergic humoral responses and lung inflammation. However, in contrast, some studies reported that lower folate levels were correlated with various inflammation-mediated diseases such as rheumatoid arthritis, inflammatory bowel disease (35, 36), and cardiovascular disease (37–39). Thus, it is possible that folic acid may alleviate, rather than promote, allergic diseases.

Several clinical studies have reported the association between folate concentrations and asthma. In Denmark, research including 6784 adults observed that obvious correlations between folic acid of deficiency and physician-diagnosed asthma (40). One case-control study including 1030 adults in the UK observed that intake of folate was negatively correlated with physician-diagnosed asthma (41). But another case-control study including 1469 adults in Australia observed that no correlation between intake of folate and physician-diagnosed asthma (42). And a case-control study involving 754 Peruvian children observed that serum folic acid concentrations were negatively associated with asthma (21). In addition, a Korean study involving 6615 individuals aged >10 years found that serum folic acid concentrations were negatively correlated with physician-diagnosed asthma (26). In contrast, a case-control study in Egypt, which involved 180 adults, found no significant association between serum folate levels and asthma (43). Likewise, in another cross-sectional study including 8083 American participants aged 2–85 years, no significant correlation between serum folate levels with physician-diagnosed asthma was observed (25). Besides, in a prospective cohort study, which mainly included black, urban children and adolescents with asthma, researchers observed that there are significant associations between serum folic acid and FENO and total IgE levels (28). Previous studies demonstrated that increasing folate could serve as a protective factor in certain populations against allergic inflammatory outcomes such as wheeze, atopy, and high total IgE. For example, a cross-sectional study in the USA, which involved 8083 participants aged 2 to 85 years old, observed that serum folic acid concentrations were negatively correlated with wheeze, total IgE, and atopy (25). Likewise, an Egyptian study involving 120 asthmatic adults demonstrated that serum folate was inversely correlated with total IgE, too (43). And lower serum folate concentrations were correlated with a higher risk of uncontrolled asthma in a study of 412 asthmatic children (21). However, above most studies, which explored the correlation of serum folate and asthma, didn’t include accommodation and eating data such as intake of Vitamin A, Vitamin B12, Vitamin D, folate and so on, meanwhile, had small sample populations. In addition, these studies didn’t carry out stratified analyses in various populations to confirm the stability and reliability of analyzed results. Our results were similar to those of the above studies, which demonstrated that serum folate levels were inversely associated with blood eosinophil counts in asthmatic adults. What’s more, we observed that the association between serum folic acid concentrations and blood eosinophil counts had population differences among American asthmatic adults, too. Based on the stratified analysis, we determined possibly protective groups with higher folate levels, including female, age <40, Non-Hispanic White people, more than high school, single status, high group of PIR, owned housing, BMI≥28, smoke≥100 cigarettes in life, without hypertension, which had lower blood eosinophil counts. In a word, serum folate levels may potentially affect the control and progression of asthma through immunomodulation and modulation of inflammation.

Compared with previous investigations, our study has several advantages. Firstly, our research offers a nationally representative, relatively large sample of asthmatic adults, which includes information on a few potential confounders. Second, considering that confounders may affect the results, we identify the possibly protective population with higher folate levels through stratified analysis. Then, we use the machine learning of XGBoost Algorithm model to identify, among all selected variables, serum folate affects blood eosinophil counts most. Finally, we observed the linear relationship between serum folate levels and blood eosinophil counts by constructing the generalized linear model.

Nonetheless, we still acknowledge several limitations in our study. Though our study is national broad, most of the data is based on the American population. And dietary model may be different in different countries on account of unbalance in national development. Secondly, due to the cross-sectional study design limits, we can’t conclude the causal relationship between serum folate and blood eosinophil counts. Finally, we may not take certain potential confounders into consideration. Moreover, in future, information such as lung function, airflow obstruction, atopy and so on will be included into further studies. And more prospective researches will be conducted to get insight into the potential role of folate in the control, progression and treatment of asthma, and to determine potential mechanisms of action.

Our study observed that serum folate levels were inversely associated with blood eosinophil counts in asthmatic adult populations of America, which indicated serum folate might be correlated with the immune status of asthmatic adults in some way. We suggested that serum folate might affect the control, development, and treatment of asthma. Finally, we hope more people will recognize the role of folate in asthma.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: http://www.cdc.gov/nchs/nhanes/.

The studies involving human participants were reviewed and approved by the National Centers for Disease Control (CDC) and Prevention National Health Statistics Center. The patients/participants provided their written informed consent to participate in this study.

JW conducted the study design, data extraction, statistical analysis, drafted the manuscript, and revision of the paper. MG conducted data extraction, statistical analysis, and revision of the paper. CW conducted the study design, statistical analysis, drafted the manuscript, and revision of the paper. SG took part in the study design and revision of the paper. All authors contributed to the article and approved the submitted version.