Helicobacter pylori (H. pylori) infection, which represents a high worldwide burden (Doulberis et al., 2023), has recently received increasing attention for its potential role in various systemic pathologies, including neurodegenerative disorders (Boziki et al., 2018, 2021a; Doulberis et al., 2018; Kountouras et al., 2023a). This bacterium can exert a systemic influence, affecting diverse pathophysiological processes beyond the gastrointestinal tract (Doulberis et al., 2018; Kountouras et al., 2023a). The complex relationship between H. pylori and the immune system, along with its potential to induce chronic low-grade ("smoldering") inflammation in distant organs, has raised intriguing questions about its involvement in extragastric diseases.

Similarly, metabolic syndrome (MetS) has emerged as a global health burden of epidemic proportions. In this context, H. pylori infection is positively associated with MetS (Liu et al., 2023) and appear to promote the pathogenesis of each other (Xie et al., 2023a). Likewise, H. pylori infection is an independent risk factor for MetS-related nonalcoholic fatty liver disease (NAFLD), recently renamed as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) (De et al., 2024), and correlates with severity and other MetS-related parameters, including insulin resistance (IR), dyslipidemia, and arterial hypertension, all of which contributing to neurodegeneration (Abo-Amer et al., 2020; Doulberis et al., 2020a). Active H. pylori infection is associated with MetS-related systemic pathologies, including neurodegenerative disorders, representing the endpoint of MetS (Kountouras et al., 2019, 2022).

Mast cells (MC), a subgroup of immune cells initially identified for their role in mediating allergic and anaphylactic reactions, serve as innate immune system effector cells with a crucial role in innate immune responses and the modulation of adaptive immunity (Kountouras et al., 2023b). Recent research has revealed their involvement in non-allergic and non-anaphylactic inflammatory conditions, including MetS-related disorders such as MAFLD. MAFLD is strongly connected with a higher risk of systemic disorders including neuroautoimmune pathologies, which are also considered endpoint of MetS-linked MAFLD (Kountouras et al., 2023b). MAFLD parameters have been found to be associated with brain impairment leading to cognitive decline (Boccara et al., 2023). The activation of innate immune cells, including MC, could contribute to the pathophysiology of MAFLD and its complications, suggesting that targeting MC activation could be a novel therapeutic approach for MAFLD and its complications (Kountouras et al., 2023b, 2023c).

Recent evidence also indicates that trained innate immunity, which can lead to chronic inflammatory conditions, is associated with various MetS-related disorders (Kountouras et al., 2023c). The training of innate immune cells, such as monocytes, macrophages, natural killer cells (NK), and MC may play a role in the pathophysiology of MAFLD and its complications (Kountouras et al., 2023c; Lyons and Pullen, 2020; De Zuani et al., 2022). Specifcally, trained innate immunity of microglia may contribute to neurodegeneration (Camacho-Morales, 2022). MC may also be involved in systemic H. pylori and MetS-connected inflammatory pathologies, such as Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS) and/or glaucoma (referred to as ocular AD), through various mechanisms (Kountouras et al., 2017a; Sandhu and Kulka, 2021; Gurung et al., 2019; Zhang and Shi, 2012)

In addition to MC involvement in MetS-related disorders, the direct activation of MC by H. pylori infection may also play a role in H. pylori-related pathologies at the local level (Supajatura et al., 2002; Shishkina et al., 2022). Specifically, interactions between MC and H. pylori appear to contribute to the pathophysiology of gastritis (Shishkina et al., 2022); interactions among H. pylori, gastric epithelium and MC through inflammatory cytokine induction may contribute to H. pylori-associated gastric pathologies including gastritis. While H. pylori can frequently be eradicated with oral antibiotics, chronic gastritis may persist even after successful H. pylori eradication, particularly in cases of chronic gastritis-related dysplasia (Zhu et al., 2023; Veijola et al., 2007). Therefore, addressing the underlying inflammatory process, including MC as a potential therapeutic target, can be beneficial for clinical prognosis (Lv et al., 2018).

At the systemic level, H. pylori-related stimulation of the innate immune cells, such as MC, may be involved in the mentioned systemic MetS-related inflammatory pathologies, including brain disorders, by various mechanisms (Kountouras et al., 2017a). In this regard, MC is associated with dyslipidemia, atherosclerosis and/or arterial hypertension (Cheng et al., 2017; Harper et al., 2023). These disorders, also linked with H. pylori infection and MetS, serve as risk factors for cardio-cerebrovascular diseases (C-CVD) and neurogenerative pathologies (Riad, 2021; Duong et al., 2021; Jia et al., 2023; Kountouras et al., 2023d). Moreover, H. pylori-induced vacuolating cytotoxin A (vacA) exhibits chemotactic activities toward bone marrow-derived MC (BMDMC) and induces them to produce proinflammatory cytokines involved in topical and systemic pathologies. BMDMC and MC activation-related mediators by disrupting the blood-brain barrier (BBB) lead to neurodegenerative pathologies (Kountouras et al., 2017a), contributing to cognitive impairment (Yue et al., 2023). H. pylori VacA also promotes intracellular survival of H. pylori, and activated monocytes (possibly infected with H. pylori owing to defective autophagy) could access the brain (Trojan horse theory) through BBB damage, thereby leading to neurodegeneration (Kountouras et al., 2023a). Additionaly, H. pylori infection may be linked to trained immunity and, by provoking gut dysbiosis, may contribute to MAFLD and other MetS-related disorders, such as brain pathologies, through several mechanisms (Kountouras et al., 2023c; Girolamo et al., 2017). Thus, H. pylori infection and MetS-related MC involvement in the pathophysiology of both topical and systemic pathologies, including neurodegenerative disorders, may offer potential benefits via the application novel strategies, especially in increasing H. pylori eradication.

Given the aforementioned considerations, when inserting the following keywords in the international database PubMed: H. pylori, metabolic syndrome, mast cell activation, neurodegeneration, this research retrieved zero results. Therefore, we aimed to investigate the potential impact of combined H. pylori and MetS on MC activation-related pathophysiology and neurodegeneration, urging further research and providing opportunities for potential application of therapeutic strategies for this critical and timely topic.