Infectious diseases are major causes of global morbidity and mortality, affecting hundreds of millions of people worldwide annually [1, 2]. Severe infections, which can rapidly evolve into sepsis, multi-organ failure, and even death, account for more than 20% of global deaths [3]. Infectious diseases that commonly require hospitalization include viral infections (Coronavirus disease 2019, Influenza), bacterial pneumonia, intestinal infections, and sepsis. Identifying the underlying risk factors for these infectious diseases is crucial for improving global public health.

Metabolic syndrome (MetS) encompasses a range of metabolic disorders, including central obesity, high blood pressure, elevated blood glucose levels, increased triglyceride (TG) levels, and reduced high-density lipoprotein cholesterol (HDL-C) levels. MetS prevalence exhibits a steady global increase, ranging from 20% to 50%, with severely obese adolescents reaching 50% [4, 5]. MetS significantly increases the likelihood of developing diabetes, stroke, and cardiovascular diseases [6]. Numerous studies have suggested that metabolic syndrome and its associated conditions, including obesity, diabetes, and fatty liver diseases, are linked to a heightened risk of several infectious diseases [7]. For instance, pre-existing metabolic dysfunction, such as obesity, hypertension, and diabetes, has been identified as exacerbating the course of COVID-19, and high blood glucose levels and fluctuating blood glucose levels may unfavorably impact COVID-19 outcomes [8]. It is important to acknowledge that the relationship between MetS and infectious diseases might be affected by confounders, limited sample sizes, and constrained follow-up duration, thus yielding inconclusive findings.

Mendelian randomization (MR) is an approach that uses genetic variations as instrumental variables (IVs) to estimate the causal association between exposure and outcome. Compared to traditional observational studies, MR studies minimize confounding factors and reverse causation as genetic variation arises during meiosis [9]. Numerous genome-wide association studies (GWAS) and the corresponding summary-level datasets provide the feasibility of conducting MR studies. Here, we conducted a bidirectional two-sample MR strategy to ascertain the causal associations between MetS (including its components) and various infectious diseases.

The present study employed a bidirectional MR approach to scrutinize the causal association between MetS and its components and various infectious diseases. Our findings unveiled that MetS and WC increased the likelihood of three phenotypes of COVID-19 and sepsis; WC increased the risk of bacterial pneumonia; HDL cholesterol decreased the incidence of intestinal infection and sepsis. However, no causal relationships were observed between FG, TG, systolic blood pressure, and these infectious diseases. Reverse MR analysis revealed that genetic liability to infectious diseases infectious diseases did not appear to causally affect MetS and its components.

A retrospective cross-sectional study involving American adults has revealed that individuals with MetS experience significantly higher hospitalization and mortality rates due to COVID-19, even after controlling for covariates [13]. A meta-analysis has further suggested that MetS is linked to a 2.3-fold higher risk of short-term mortality due to COVID-19 [14]. Findings from an observational study demonstrated that obesity, diabetes, and a history of stroke are associated with a greater likelihood of death from COVID-19 in comparison to individuals who succumb to non-COVID-19 causes [15]. Notably, up to 50% of COVID-19 fatalities have been found to possess underlying metabolic and vascular disorders [16]. The presence of age-related comorbidities, like hypertension, diabetes, obesity, and cardiovascular diseases, which are prevalent among older individuals (≥65 years), significantly impacts the progression and prognosis of COVID-19 [17]. Using a Mendelian randomization approach, our study demonstrated that MetS could potentially elevate COVID-19 infection risk, hospitalization rate, and disease severity, thereby reinforcing previous observational findings.

WC, as a constituent of MetS, has demonstrated superior efficacy as an anthropometric measure for assessing visceral adipose tissue mass and serves as a reliable indicator of abdominal obesity [18]. Given the pivotal role of obesity in MetS and its significant association with COVID-19, it is imperative to explore this relationship further. Raeisi et al. recently reported that obesity escalates the likelihood of contracting COVID-19, progressing to severe illness, necessitating hospitalization, admission to intensive care units, and even death [19]. Similarly, Brenda et al. evaluated obesity-related traits in COVID-19 patients and found that BMI and WC were associated with severe respiratory COVID-19 and hospitalized COVID-19 [20], which is consistent with our results. Moreover, an additional study revealed a J-shaped relationship between BMI and the risk of COVID-19 severity and mortality [21]. However, a prospective observational study indicated that, compared to individuals with modest COVID-19, individuals with severe COVID-19 exhibited elevated FG and TG levels, while no statistically significant variations were identified in WC, BMI, systolic blood pressure, and HDL-C levels [22]. This discrepancy may be attributed to a smaller sample size and other confounding factors.

In general, this study first indicated that MetS increased the incidence and severity of COVID-19. Subsequently, causality between individual components of MetS and COVID-19 was estimated, highlighting the critical role of WC. Although previous observational studies have reported associations between SBP, FG, HDL-C, TG, and COVID-19, this MR study suggests no causal association between these four MetS components and COVID-19. There are several potential mechanisms that could explain the role of WC being the most essential component of MetS that contributes to COVID-19 progression. Studies have posited that the presence of abdominal obesity correlates with augmented deposition of visceral adipose tissue, potentially facilitating the progression toward severe manifestations of COVID-19 [23]. Adipose tissue, an active metabolic organ, exhibits hormonal and cytokine secretion [24]. In the setting of obesity, dysfunctional adipose tissue triggers the release of pro-inflammatory cytokines, including interleukin-6, tumor necrosis factor-α, and C-reactive protein [25]. Such cytokines have the potential to contribute to cytokine storms in COVID-19, thereby intensifying the severity of the disease and causing harm to various organs, including the lungs [26]. Furthermore, adipose tissue exhibits a pronounced upregulation of ACE-2 receptors, which serve as the entry point for the SARS-CoV-2 virus. The elevated presence of ACE-2 receptors may result in a heightened viral load and consequently exacerbate the severity of COVID-19 in Obese individuals [27]. Additionally, obesity has been recognized as a contributing factor for endothelial dysfunction, magnifying the preexisting impairment of endothelial function induced by COVID-19 [28]. Consequently, this pathological cascade may culminate in the formation of blood clots, precipitating severe complications including stroke and pulmonary embolism [29].

Additionally, multiple studies revealed that obesity, a key component of metabolic syndrome, doubles the likelihood of developing influenza and is associated with increased severity of influenza [30]. Nevertheless, our findings showed a trend toward a positive but non-significant association between MetS, WC, SBP, TG, and influenza. These relationships should be explored further using future GWAS datasets with larger sample sizes.

The present study showed that MetS and WC were linked to an increased sepsis risk, and elevated WC was related to a higher risk of bacterial pneumonia. Consistently, previous studies have reported metabolic syndrome and increased waist circumference as significant risk factors for sepsis [31]. A population-based cohort investigation in the USA showed WC as a better predictor of sepsis risk than BMI [31]. Patients with abdominal obesity were at a 1.74-fold greater risk for sepsis mortality [32]. Metabolic syndrome is linked to chronic low-grade inflammation, which may impair immune function and increase susceptibility to severe bacterial infections [33]. Moreover, studies have suggested that patients hospitalized with community-acquired bacterial pneumonia frequently have abdominal obesity [34]. The excess belly fat in abdominal obesity can pose pressure on the stomach, contributing to gastroesophageal reflux, which is a risk factor for aspiration pneumonia, a common cause of sepsis [35].

In this study, we also identified a remarkable relationship between elevated HDL-C and decreased risks of intestinal infection and sepsis. This finding is consistent with prior studies. HDL-C has been found to regulate innate and adaptive immunity, impacting the immune response to infections [36]. Studies indicate that HDL-C levels reduce rapidly at the onset of sepsis, and low serum HDL-C levels are linked to poor outcomes [37]. Low HDL-C levels are indicative of increased severity of septic diseases [38], and are linked to an amplified systemic inflammatory response [39]. HDL, alongside various plasma lipids, demonstrates a remarkable ability to interact with and counteract components such as Gram-negative bacterial lipopolysaccharide and Gram-positive bacterial lipoteichoic acid [40]. This interaction is beneficial in promoting the removal of these bacterial products from the system. However, exceedingly high HDL-C levels may also be linked to a greater risk of infectious disease, potentially due to genetic variants or functional impairment of HDL particles [41].

This study has several strengths. Firstly, multiple phenotypes of both exposure and outcome were included, increasing the comprehensiveness of the research. Secondly, the two-sample MR study utilized various large-scale GWAS summary datasets, thereby increasing the robustness of the findings. Thirdly, multiple sensitivity analyses were employed to enhance the credibility of the MR causal estimates.

There are certain limitations in this MR study that require clarification. First, since all the GWAS data included were from individuals of European descent, it remained uncertain whether the conclusions could be generalized to other populations. Second, because this MR study was based on summary-level GWAS statistics, it was not possible to conduct stratified analyses by age or gender. Lastly, although extensive sensitivity tests were performed, it was not possible to completely rule out the influence of potential horizontal pleiotropy.