“Western diet”, a diet high in fat, cholesterol, protein, sugar, and salt, is known to promote obesity, metabolic syndromes, and cardiovascular diseases [1]. Recent evidence has shown that those unhealthy dietary patterns are a potential risk factor in autoimmune diseases [2]. In particular, a plausible relationship between the intake of soft drinks and an elevated risk of asthma was reported in several cohorts and clinical studies, and high amounts of sugar soft drinks contain have been suspected to contribute to asthma symptoms by causing inflammation [3,4]. Berentzen et al. (2015) also revealed that more frequent consumption of 100% fruit juices and total sugar-containing beverages is associated with an increased asthma risk in children [3]. A survey conducted by Xue et al. (2022) demonstrated a two-fold increase in the occurrence of asthma in children who consume sweetened beverages compared to non-consumers [5]. Furthermore, excessive sugar intake has been associated with a distinct asthma phenotype and the development of childhood asthma [6]. These reports suggest a link between HSI and asthma, but they were restricted to cohort studies. Furthermore, the mechanistic evidence linking HSI to asthma remains unclear.

In addition to sweetened beverages, high glucose levels and free fatty acids can also stimulate the production of reactive oxygen species (ROS) [7]. In general, a high sucrose diet induces the development of metabolic syndromes, which consist of oxidative stress, a pro-inflammatory state, and central obesity [8]. Especially, oxidative stress represents the disruption/dysregulation of the redox balance and signaling caused by the increase of ROS, which induces oxidative damage in lipids and proteins [9]. In an experimental animal model of allergic asthma, genetic and pharmacological inhibition of ROS production and MMPs suppressed allergic asthma symptoms [10]. A strong mechanistic link exists between increased ROS production and MMP activity, suggesting that therapies to limit HSI-induced ROS generation may be useful [11].

Moreover, diets might also influence susceptibility to allergic diseases as they contribute to the education and regulation of the immune system [12]. According to Julia et al. (2015), obesity-induced asthma is considered to be a distinct endotype from allergic asthma with a later onset, a more severe outcome, and the presence of neutrophils and IL-17 signatures. Furthermore, IL-17A-producing innate lymphoid cells, known as ILC3s, are required for the increased basal antigen-independent airway hyperreactivity that is induced by high-fat diets or by genetic obesity in mice [13]. Specifically, high amounts of glucose promote T helper type 17 (Th17) cell differentiation by activating transforming growth factor-β (TGF-β) from its latent form through the upregulation of ROS in T cells [14].

The widely accepted health impact of sucrose consumption is mostly limited to de novo lipogenesis in the liver, causing hepatic steatosis [15], [16], [17]. However, we investigated heretofore unrecognized roles that sucrose plays in chronic inflammatory diseases. For instance, we recently reported that excess sucrose intake along with a high-fat diet triggers hepatic inflammation and fibrosis, thereby, contributing osteoarthritis pathogenesis in mice [18]. Above mentioned-clinical outcomes [1], [2], [3], [4] also demonstrate that high sugar consumption is closely intertwined with pulmonary exacerbations, but the mechanisms underlying the link are not fully understood.

Asthma is one of the most prevalent inflammatory disorders of the respiratory system and is characterized by chronic inflammation in lung tissues, excessive mucus production, and abnormal bronchoconstriction [19]. As the first line of defense against inhaled allergens, barrier epithelial cells in the airway express Toll-like receptors (TLRs) and sense the same types of stimuli innate immune cells recognize [20]. TLRs are functionally expressed on barrier epithelial cells, macrophages, and T cells [21]. They enhance antigen presentation on both epithelial cells and macrophages and contribute directly to T cell-mediated immune response [21,22]. Additionally, they induce subsequent cytokine production, which also plays a critical role in the induction of inflammatory diseases [23]. According to Hammad et al. (2009), a major reason of obesity is the upregulation of the TLR4 pathway in the heart under obesogenic conditions such as high-fat diet feeding, which drives inflammatory processes as well as oxidative stress. We also reported that TLR2/4/7 are key proteins in OVA-sensitized allergic asthma mice through Th2/Th17 responses [24].

Asthma is generally considered to be facilitated through Th2 cells by the secretion of the Th2 cytokines interleukin (IL)-4 and IL-13, which cause the immunoglobulin (Ig) isotypes to switch to IgE, a crucial factor in allergy development. [25,26]. Moreover, activated Th2 cells induce inflammation and subsequent mucus hyperproduction [25]. Despite this, some evidence suggests that Th17 cells play a role in the development of neutrophilic allergic asthma, with increased levels of Th17 cytokines like IL-17A and IL-22 observed in moderate and severe asthma [25,27]. It has been shown that IL-17A enhances the expression of chemokine (CXC motif) ligands such as CXCL1, CXCL5, and CXCL8 [28]. This process involves the activation of the extracellular signal-regulated protein kinases (MAPK) and the nuclear factor-κB (NF-κB) pathway [29]. Monocyte chemoattractant protein 1 (MCP-1), also known as chemokine (C–C motif) ligand (CCL)2 secreted by macrophages, basophils, epithelial cells, airway smooth-muscle cells, and neutrophils, has been reported to mediate inflammatory cell activation and recruitment, which are skewed following OVA stimulation [30], [31], [32], [33]. Moreover, human consuming sweetened beverages enhances the chemokine levels in human blood, which can induce inflammatory cell infiltration [34,35].

In this study, we investigate that HSI can be detrimental to asthma, clarifying the mechanistic evidence between HSI and asthma using a commonly used animal model where mice were sensitized with OVA. We observed that HSI increased inflammation in adipose tissues, leading to ROS generation in livers and lungs of asthmatic mice. Moreover, we observed that signaling through TLR4, the major pathway of OVA sensitization, was greatly enhanced by HSI with the help of pathogenic Th2 and Th17 responses involving NF-κB pathway and MMP9, which eventually led to the activation of TGF-β from its latent form. Especially, we observed that numerous cytokines and chemokines secreted by Th2 and Th17 cells were involved in the promotion of airway inflammation and mucus overproduction.