Lipids are crucial components and energy reserves of cells with significant regulatory functions in metabolism, inflammation, immunity, and various other pathways. Lipid metabolism disorders are considered primary pathological factors contributing to obesity. Patients with asthma exhibit significant alterations in phospholipid and sphingolipid levels, suggesting that abnormalities in lipid metabolism are involved in asthma development (Murphy et al., 2021; Rago et al., 2021). Adenosine monophosphate activated protein kinase (AMPK) is a key regulator of lipid metabolic balance in vivo (Herzig and Shaw, 2018). AMPK suppresses the process of de novo fatty acid synthesis (FAS) by causing inhibitory phosphorylation of Acetyl-CoA Carboxylase 1 (ACC1) (Jeon, 2016). Simultaneously, it promotes fatty acid oxidation (FAO) by facilitating inhibitory phosphorylation of ACC2, leading to the activation of Carnitine Palmitoyltransferase-1 (CPT-1) activity (Fang et al., 2022). AMPK levels are negatively correlated with obesity and asthma (Herzig and Shaw, 2018; Garcia et al., 2019). The AMPK pathway was inhibited in an obesity-related asthma model constructed through ovalbumin sensitization and stimulation; however, AMPK activation alleviated both airway inflammation and airway hyper-responsiveness (AHR) in a mouse model (Zhu et al., 2019).

Lipid mediators produced via arachidonic acid (AA) pathway influence asthma (Monga et al., 2020). AA is stored in membrane phospholipids and released by phospholipase A2 (PLA2) upon exposure to allergens (Wang et al., 2021). PLA2 induces the enzymatic and non-enzymatic oxidation of AA to prostaglandins, leukotrienes, and other bioactive mediators, exerting receptor-specific stimulatory and inhibitory effects that influence the pathophysiology of asthma (Samuchiwal and Boyce, 2018). Increased protein expression of sPLA2-X in the airway epithelial cells of patients with asthma is associated with AHR (Hallstrand et al., 2013). In asthma models, prostaglandins E₂ reduces lung inflammation and remodeling, showing beneficial effects in asthma patients (Insuela et al., 2020).

The adipocytokines leptin and adiponectin regulate lipid metabolism by influencing appetite. Leptin inhibits orexic neurons and stimulates anorexic proleptin neurons to regulate appetite (Obradovic et al., 2021). Adiponectin, on the other hand, increases during fasting, and activates the AMPK pathway by binding to its receptor AdipoR1 (Okada-Iwabu et al., 2013). In the adipose tissue of individuals with obesity, adipocyte cytokine leptin levels increase, whereas adiponectin levels decrease (Frithioff-Bøjsøe et al., 2020). Both adipocytokines and their receptors are expressed in human lungs and are associated with asthma severity in children. Leptin levels are positively correlated with the prevalence and severity of childhood asthma, whereas adiponectin levels are negatively correlated, particularly in boys (Assad and Sood, 2012).

The impact of the gut microbiota on host lipid metabolism has been extensively demonstrated in both human and animal models. Implementing energy restriction and dietary interventions in obese individuals can increase the microbiota gene abundance while simultaneously reducing blood lipid levels (Cotillard et al., 2013). Conventional mice had a 60% higher body fat content and insulin resistance level than germ-free (GF) mice (Bäckhed et al., 2004). GF mice exhibited HFD-induced insulin resistance and improved cholesterol metabolism, which might be related to an increase in FAO in the peripheral tissues owing to enhanced AMPK activity in vivo (Rabot et al., 2010). The transplantation of gut microbiota from ob/ob mice into GF mice resulted in a notable increase in both body weight and body fat content (Turnbaugh et al., 2006). Young mice treated with antibiotics showed an altered gut microbiota composition and elevated levels of hormones related to carbohydrate, lipid, and cholesterol metabolism (Cho et al., 2012).

Short-chain FAs (SCFAs), such as acetate, propionate and butyrate, are the final products of microbial fermentation (Ŕıos-Covián et al., 2016; Agus et al., 2021). SCFAs provide substrates for lipid synthesis and serve as regulatory factors to modulate lipid metabolism in both brown and white adipose tissues (Gao et al., 2009; Li et al., 2018; He et al., 2020). SCFAs regulate host biological processes via ligand receptor interactions with G protein-coupled receptors (GPRs), while peroxisome proliferator activated receptors (PPARs) are a key family of ligand activated transcription factors that serve as crucial mediators in SCFA-induced regulation of metabolic syndrome (Kim et al., 2013; Den Besten et al., 2015). SCFAs stimulate secretion of the satiety hormones glucagon-like peptide-1 and peptide YY (PYY) in a GPR41- and GPR43-dependent manner and increase leptin levels in adipose tissue, thereby reducing food intake and weight gain (Tolhurst et al., 2012; Lu et al., 2016; Larraufie et al., 2018). PPARγ is predominantly expressed in the adipose tissue, and in mice with adipose-specific PPARγ destruction, SCFA-induced weight loss and insulin sensitivity stimulation disappeared (Den Besten et al., 2015; Yip et al., 2021). In a mouse model of asthma with GPR43 deficiency, the beneficial therapeutic effects of SCFAs on inflammation were lost (Maslowski et al., 2009). Higher levels of butyrate and propionate in stool samples from 1-year-old humans are associated with reduced atopic sensitization in children and a reduced likelihood of asthma at 3–6 years of age, indicating that SCFAs affect a child's susceptibility to allergic diseases (Roduit et al., 2019). Treatment with vancomycin reduced the decreased levels of SCFAs in mice, making them more susceptible to OVA-induced asthma, and supplementing exogenous SCFAs could alleviate this effect (Cait et al., 2018). This evidence supports the idea that SCFAs produced by fermentation of the gut microbiota may be a significant factor in obesity-related asthma susceptibility (Figure 2).

Obese individuals exhibit characteristics of systemic chronic low-grade inflammation driven by relative hypoperfusion or increased oxygen consumption and sustained by leptin, leading to systemic monocyte activation (Lee et al., 2014; Reyes-Angel et al., 2022). Monocyte chemoattractant protein 1, secreted by the adipose tissue, binds to the monocyte surface receptor C-C chemokine receptor type 2 to promote monocyte activation and recruitment into the adipose tissue to form macrophages (Yao et al., 2022). Clinical studies revealed an inverse correlation between circulating monocytes in children with obesity-related asthma and low high-density lipoprotein levels along with significantly increased levels of soluble CD163, a measure of macrophage activation (Periyalil et al., 2015; Rastogi et al., 2015).

Macrophages directly sense pathogens through the expression of Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) (Sharma et al., 2018). FAs enhance TLR activation signals and are associated with the onset and progression of adolescent metabolic syndrome and asthma (Hardy et al., 2013; Zuo et al., 2015; Rocha et al., 2016; Meghnem et al., 2022). TLR recognition ligands activate various adaptor proteins downstream of myeloid differentiation factor 88 (MyD88)-dependent or non-MyD88-dependent pathways, initiating an inflammatory cascade that leads to the activation of nuclear factor-kappa B (NF-κB), resulting in an increased release of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-1β (Kawai and Akira, 2010; Jialal et al., 2014). Lipopolysaccharide (LPS) is a classical TLR ligand. Whether LPS exposure is a protective or aggravating factor against asthma remains controversial. The role of LPS in airway inflammation has been observed in children with neutrophil asthma, and it induces macrophage inflammatory responses in mice (Camargo et al., 2018; Ciesielska et al., 2022). However, other studies suggested that the protective effect of the “farm effect” on asthma is specifically associated with LPS exposure. Importantly, this protective effect has only been observed during infancy (Schuijs et al., 2015; Gao et al., 2021).

NLRP3 is an important member of the NLR family (Wang and Hauenstein, 2020). NLRP3 expression is upregulated in response to TLR, activated by phosphorylation and deubiquitination, and then activated by stimuli such as porotoxins, leading to subsequent oligomerization, and inflammasome assembly (Song and Li, 2018). The assembled NLRP3 inflammasome cleaves pro-Caspase-1 proteolysis into mature Caspase-1 to promote the release of the inflammatory factors IL-1β and IL-18, mediating immune imbalances in asthma (Huang et al., 2021). NLRP3 inflammasome activation is a key phenotypic feature of obesity-related asthma, and NLRP3 gene expression in the sputum of patients with obesity-related asthma is significantly increased and correlated with BMI (Wood et al., 2019).

A significant quantity of LPS accumulates in the intestine and enters the circulatory system by attaching to newly synthesized chylomicrons in the intestinal cell epithelium or increasing intestinal permeability, stimulating the immune response, and activating the TLR signaling pathway (Ghoshal et al., 2009; Velasquez, 2018). A host's LPS levels are influenced by the gut microbiota. Proinflammatory bacteria such as Proteobacteria carry Gram-negative LPS, and the HFD mice exhibited an increase in Proteobacteria abundance along with elevated levels of LPS (Mujico et al., 2013). Antibiotic intervention significantly reduces in LPS levels in the gut and circulation of HFD and ob/ob mice (Cani et al., 2008). Additionally, supplementation with Bifidobacterium reduced mouse intestinal LPS levels and improved gut barrier function (Cani et al., 2007). The gut microbiota stimulates the mucosal epithelial cells to release secretory immunoglobulin (Ig) A, mucin 2, and β-defensin, which are crucial for maintaining the intestinal mucosal barrier, reducing LPS translocation, and alleviating lung inflammatory damage (Dicks et al., 2018). Mouse experiments demonstrated that the gut microbiota activates the lung TLR4/NF-κB signaling pathway via the lung intestinal axis, aggravating LPS-induced acute lung injury (ALI) and that fecal microbiota transplantation can restore intestinal microbiotal homeostasis, increase intestinal flora diversity, and inhibit LPS-induced ALI (Tang et al., 2021). A cohort study reported that the immune response of asthmatic 17q21 risk allele carriers to LPS is regulated by the gut microbiota (Illi et al., 2022).

The gut microbiota plays a crucial role in mediating NLRP3 activation and inflammatory damage (Pellegrini et al., 2020; Pan et al., 2022). El Tor Vibrio cholerae triggers the NLRP3-dependent pathway, which induces IL-1β-mediated inflammatory responses that drive mouse macrophage death (BMDMs) (Mamantopoulos et al., 2019). In addition to specific species of gut microbes, he Rho GTPase activator CNF1, from Escherichia coli (E. coli) activates NLRP3 in BMDMs and leads to caspase-1 cleavage and IL-1β (Dufies et al., 2021). Probiotics present in the gut inhibit inflammasome expression. For instance, Lactobacillus rhamnosus GR-1 effectively reduces the expression of NLRP3 inflammatory bodies and caspase-1 induced by E. Coli, thereby limiting the occurrence of harmful inflammatory responses (Wu et al., 2016b). In an inflammatory bowel disease mouse model, it was discovered that NLRP3 mediated lung neutrophilic infiltrative inflammation in microbial pattern recognition, leading to increased levels of TNF and IL-1β levels in murine lungs (Liu et al., 2019). Furthermore, the gut microbiota exacerbated OVA-induced allergic asthma through the NLRP3/IL-1β signaling pathway in asthma model mice (Huang et al., 2018a; Zheng et al., 2022) (Figure 2).

CD4⁺ T cells play a central role in the pathogenesis of asthma. Activated CD4⁺ T cells are divided into two subsets—T regulatory (Treg) and T effector (Teff) cells (Th1/Th2/Th17) with the former playing an immune regulatory role and the latter driving asthma pathogenesis and determining the asthmatic phenotype (Zhu et al., 2009). Under the influence of obesity, children with asthma exhibit a tendency for Teff cells to polarize toward Th1 and Th17 profiles. Multiple cytokines secreted by Th1 and Th17 cells mediate the development of neutrophilic asthma and are associated with asthma severity and steroid resistance (Nyambuya et al., 2020; Sze et al., 2020). Teff differentiation depends on the FAS pathway (Berod et al., 2014). Th17 cells polarization is boosted by increased ACC1 gene expression and retinoic acid receptor related orphan receptor-γ t (RORγ t) binding to the IL-17 gene locus (Zhang et al., 2021). Additionally, Th1 polarization in obesity-related asthma is influenced by macrophage activation and correlated with IL-6 and leptin levels (Reyes-Angel et al., 2022). Monocytes produce large amounts of IL-1β, which mediates Th17 cell differentiation (Revu et al., 2018). Obesity and atopic immunity are not mutually exclusive (Reyes-Angel et al., 2022). In obese children and adolescents, Th2-type asthma is associated with increased eosinophil infiltration and activity (Grotta et al., 2013). Furthermore, increased IgE levels and eosinophilic activation have been observed in obese mice (Amorim et al., 2018; Cvejoska-Cholakovska et al., 2019; Ying et al., 2022). This phenomenon is positively correlated with serum leptin and TNF-α levels (Grotta et al., 2013). Additionally, lipid mediators prostaglandin D₂ and cysteinyl leukotriene can also activate Th2 cells and enhance the production of Th2 cell cytokines (Xue et al., 2015).

Innate lymphoid cells (ILCs) are innate T lymphocytes that express a profile of effector cytokines similar to those of T cells, enhance T cell function, and play a crucial role in asthma progression (Vivier et al., 2018). High ILC3 cell counts and RORC mRNA expression have been observed in the peripheral blood circulation of children with obesity-related asthma (Wu et al., 2018). In the lungs of obesity-related asthma mice, the NLRP3-IL-1β pathway is activated to induce the expansion of lung IL-17⁺ILC3 cells, leading to neutrophilic inflammation (Kim et al., 2014). In obese mice with AHR, ILC2 counts are increased, acting as Th2 cells but producing 10 times more IL-5 and IL-13 than activated Th2 cells (Everaere et al., 2016; Chen et al., 2017). The proliferation and function of ILC2 are influenced by lipid metabolism. Lipid droplets provide an energy source for pathogenic ILC2 responses during airway inflammation (Karagiannis et al., 2020). FAO and leptin play roles in driving ILC2 proliferation and maintaining their function (Wilhelm et al., 2016; Zheng et al., 2017). Under the chemotactic influence of lipids and inflammation, ILCs migrate within and between organs (Soriani et al., 2018). For example, sphingosine-1-phosphate mediates the migration of ILC2 to different tissues, thereby promoting the accumulation of ILC2 in lymphoid tissues, the bloodstream, and the lungs (Huang et al., 2018c).

A series of studies on antibiotic-treated and GF mice support the role of the gut microbiota in influencing T cell differentiation. Antibiotic-treated mice showed elevated levels of Th2 cytokines and IgE (Bashir et al., 2004). GF mice exhibit a loss of Th17 cells in the intestinal lamina propria and are more likely to produce a Th2 response (Wu et al., 2010; Herbst et al., 2011). A recent single-cell transcriptome study revealed that gut Teff are shaped by the microbiota independent of the typical subgroup regulators, T-bet, GATA3, or RORγt (Kiner et al., 2021). Several microbes, such as Akkermansia muciniphila, Citrobacter rodentium, and Fusobacteriu varium, induce T cell differentiation (Geva-Zatorsky et al., 2017; Stockinger, 2021; Liu et al., 2022). The influence of the microbiota on immune regulation can be transmitted to the offspring through the mother's gut microbiota and metabolites, thus accelerating the postpartum transition of the offspring from a Th2-dominated immunophenotype to Th1- and Th17-dominated immunophenotypes (Gao et al., 2021). The microbiota colonizing in the gut crosstalk pulmonary immunity via the gut lung axis, influencing host atopy and asthma (Pascal et al., 2018). CD4⁺ T cell dysfunction caused by dysregulation of the gut microbiota has been observed in newborns and is associated with susceptibility to allergic asthma in childhood (Fujimura et al., 2016). Segmented filamentous bacteria trigger a strong Th17-cell response in the gut and are preferentially recruited to the lungs to trigger immune inflammation (Bradley et al., 2017; Wang et al., 2019). Ruminiclostridium 6 and Candidatus Arthromitus mediate Th1/Th2 and Treg/Th17 immune balance in eosinophilic asthma in mice, suggesting that gut microbes regulate the balance between Teff subsets and participate in the pathogenesis of asthma (Zhou et al., 2022).

The response of ILCs to the gut microbiota is highly heterogeneous. ILCs expression are suppressed by microbial signal deficiency resulting from antibiotic treatment, with a greater impact observed on the gene expression profiles of ILC1 and ILC2 than ILC3 (Gury-BenAri et al., 2016). Clostridioides difficile infection upregulates the expressions of ILC1 and ILC3 in the colon, whereas Helicobacter typhlonius and Helicobacter apodemus infections lead to the ILC3 loss in the colon (Abt et al., 2015; Bostick et al., 2019; Kong et al., 2021). SCFAs activate ILCs via GPR signaling, promote ILC3 proliferation and IL-22 production, and inhibit ILC2 amplification (Yang et al., 2020; Sepahi et al., 2021). Furthermore, the gut microbiota promotes ILC3 production in the intestinal mucosa by assisting mononuclear phagocytes in secreting IL-1β and facilitating crosstalk between colony-stimulating factor 2 and RORγt+ cells (Mortha et al., 2014). The increase in intestinal ILC3 in the offspring of GF female mice after the implantation of E. coli HA 107 during pregnancy suggests that ILC formation by gut microbiota can be transmitted from the parents to the offspring (Gomez de Agüero et al., 2016). The gut microbiota regulates ILCs through the gut lung axis and contribute to airway inflammation and asthma. A previous study reported that Proteobacteria may promote the accumulation of natural ILC2 in the lungs by regulating the IL-33-CXCL16-CXCR6 signaling axis and interfering with the lung immune response (Pu et al., 2021). In a mouse model of asthma sensitized to house dust mites and characterized by gut dysbiosis attributed to Candida spp., there was an increase in lung ILC2 content, which resulted in exacerbated allergic airway inflammation and worsened disease control (Kanj et al., 2023). It suggests that gut microbiota imbalance may affect asthma symptoms through the regulation of ILC2 pathways (Figure 2).