Stroke remains a significant global health challenge, causing 93.8 million prevalent cases and 11.9 million incident strokes, and resulting in 7.3 million stroke-related deaths worldwide in 2021. It ranks as the third leading cause of mortality and the fourth leading cause of disability-adjusted life years globally (Collaborators, 2024). The incidence of stroke in China is rising annually, resulting in approximately 2.9 million deaths (Ma et al., 2021). Beyond its high mortality and morbidity rates, stroke frequently leads to secondary complications, with around 50 % of stroke patients experiencing subsequent gastrointestinal complications, such as impaired intestinal motility and enteric dysbiosis (Camilleri, 2021). With the rising number of stroke survivors, there is a heightened demand for improving post-stroke quality of life. Nevertheless, the therapeutics predominantly employed focus on gastric mucosal protection, enhancement of gastric motility, anti-infective measures, and modulation of intestinal flora (Chen et al., 2019a; Huang et al., 2023). These interventions generally target the entire intestinal system, lacking specificity, and frequently encounter limitations related to efficacy, adverse effects and cost.

Diabetes mellitus is extensively acknowledged as both an independent risk factor for ischemic stroke and a determinant of adverse outcomes in stroke patients (Hassaballa et al., 2001; Lo et al., 2020; O'Donnell et al., 2016; Rosso et al., 2019). It is estimated that up to 30 % of ischemic strokes occur in individuals with diabetes (Mishra et al., 2023; Shukla et al., 2017). Post-stroke intestinal disturbances have been associated with malnutrition, prolonged hospitalization, increased dependency, unfavorable outcomes, and even mortality (Tuz et al., 2022). A critical element in intestinal injury is intestinal epithelial barriers (Stanley et al., 2016). However, it has not been reported which specific component of the intestinal barrier damage is markedly exacerbated in stroke patients with diabetes.

The gut-brain axis, a complex bidirectional communication system between the gastrointestinal tract and the central nervous system (Wang et al., 2023; Zhou et al., 2023), plays a significant role in the pathogenesis of ischemic stroke through multiple mechanisms. Notably, the disruption of intestinal barrier function is critical in the progression of ischemic stroke (Zhao et al., 2018; Zhou et al., 2023). Alterations in intestinal permeability and intestinal inflammation are recognized as key pathological processes in the onset and progression of various diseases. Cerebral ischemia swiftly precipitates intestinal ischemia, resulting in increased intestinal barrier permeability (Lian et al., 2023; Prame Kumar et al., 2023), which exacerbates the resultant damage. In diabetes, the inflammatory response is intensified following stroke, which further aggravates intestinal damage.

Sodium butyrate (NaB), a short-chain fatty acid, functions as an essential energy source for colonic epithelial cells. It has been demonstrated to attenuate intestinal inflammation, fortify the intestinal barrier, and modulate intestinal immunity (Beisner et al., 2021; Chen et al., 2018). NaB may exert protective effects in conditions such as ischemic stroke injury (Zhou et al., 2021), diabetic renal injury (Tang et al., 2022), and various intestinal diseases (Ma et al., 2020; Wang et al., 2022). Our previous study demonstrated that administering 300 mg/kg of NaB plays an important protective role in neurological outcomes following diabetic stroke, and contributes to a stable weight regulation effect (Li et al., 2023). Therefore, the present study investigates the role and underlying mechanisms of NaB in colon injury following diabetic stroke.

Pyroptosis is a form of programmed cell death characterized by the disruption of the plasma membrane, which plays a crucial immunoprotective function (Rao et al., 2022). The classical pyroptosis pathway is initiated by Caspase-1 and is known to contribute to the progression of both ischemic stroke (Coll et al., 2022; Kim et al., 2020) and diabetes (Coll et al., 2022; Li et al., 2022b). Upon activation, Caspase-1 processes pro-inflammatory cytokines such as interleukin (IL)-18 and IL-1β and cleaves gasdermin D (GSDMD), resulting in the formation of pores in the cell membrane that ultimately lead to pyroptosis (Loveless et al., 2021; Rao et al., 2022). Pyroptosis has the potential to exacerbate damage to intestinal epithelium, thereby increasing mucosal permeability (Coll et al., 2022). Inhibition of this pathway may delay the progression of diabetic stroke and enhance patients’ quality of life. We hypothesize that NaB may mitigate stroke-related intestinal injury and inflammation in diabetic mice by modulating the classical pyroptosis pathway, although the specific mechanisms require further investigation.

This study aimed to explore the effects of NaB on colonic barrier dysfunction and inflammation following diabetic stroke, particularly its influence on regulating the classical pyroptosis pathway in colonic epithelial cells. These findings may provide a foundation for the potential use of NaB in treating diabetic stroke patients in the intensive care units, expanding its clinical applications and enhancing patient outcomes.