Inflammation, which constitutes the host’s immune response to injury or infection, plays a pivotal role in the development of AF. Chronic inflammation, in particular, serves as a fundamental mechanistic bridge linking LPS to AF pathogenesis (26). When LPS enters the circulation due to intestinal barrier dysfunction or other pathways, it binds to pattern recognition receptors—primarily Toll-like receptor 4 (TLR4)—on the surface of immune cells (e.g., monocytes and macrophages) and cardiomyocytes (27, 28). The activation of TLR4 initiates the downstream NF-κB (Nuclear Factor kappa-B) signaling pathway, a key regulator of inflammation (29). Subsequent nuclear translocation of NF-κB leads to a significant increase in the production of inflammatory cytokines, including IL-6, IL-1β, and TNF-α (29). These mediators create a persistent inflammatory microenvironment that exerts multifaceted detrimental effects on the atrial myocardium. Supporting this, animal studies have confirmed that LPS administration elevates pro-inflammatory cytokines in the pericardium of rabbits and promotes atrial arrhythmias through a TLR4-dependent mechanism (30, 31). Correspondingly, clinical studies report that serum levels of LPS, TLR4, and the aforementioned inflammatory factors are significantly elevated in AF patients compared to those in sinus rhythm, with their concentrations showing a positive correlation with AF duration (32). Furthermore, LPS-related inflammation can induce atrial conduction heterogeneity, thereby increasing the likelihood of AF recurrence. In summary, chronic inflammation driven by the LPS-TLR4 axis creates a ‘fertile ground’ for the initiation and perpetuation of AF.

Myocardial fibrosis represents a core feature of structural remodeling in AF and a key pathological basis for its progression from paroxysmal to persistent forms (33). LPS is a potent pro-fibrotic driver. Animal studies indicate that gut microbiota dysbiosis can partially promote AF by elevating circulating LPS levels, thereby inducing atrial fibrosis (34). The underlying mechanism may involve LPS-induced upregulation of the inflammasome protein NLRP3, which enhances atrial fibrosis and facilitates AF progression. This is supported by the observation that administration of LPS-RS (an LPS antagonist) significantly reduces both the incidence and duration of AF in rats. Furthermore, Wang et al. reported a positive correlation between circulating LPS levels and serum TGF-β1, a central mediator of myocardial fibrosis (35, 36). Activation of the TGF-β1/Smad signaling pathway strongly promotes the synthesis and secretion of collagen (predominantly types I and III) by myofibroblasts, while simultaneously inhibiting matrix metalloproteinase (MMP) activity (37). It also upregulates their tissue inhibitors (TIMPs), leading to an imbalance between extracellular matrix (ECM) synthesis and degradation and resulting in excessive collagen deposition (38). Myeloid differentiation protein 2 (MD2) has also been implicated in cardiac fibrosis (39). MD2 binds to the extracellular domain of TLR4, facilitating the recognition of LPS and the formation of an LPS–MD2–TLR4 complex. Upon LPS exposure, the TLR4/MD2 complex recruits Toll/IL-1 receptor (TIR) domain-containing adaptors such as myeloid differentiation primary response 88 (MyD88) (40, 41), which in turn activates downstream signaling cascades, including NF-κB and mitogen-activated protein kinase (MAPK) pathways (42). Thus, MD2 plays a significant role in LPS-induced AF.

Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and the body’s antioxidant defense capacity, resulting in oxidative damage to biomolecules. Substantial clinical evidence indicates that oxidative stress plays a pivotal role in both the initiation and progression of AF (43, 44). LPS serves as a potent stimulus that triggers significant oxidative stress through multiple pathways (45). This is supported by the finding of Menichelli et al., who demonstrated that circulating LPS directly induces a state of oxidative stress (46). Within the cardiovascular system, major sources of ROS include NADPH oxidase (NOX), mitochondria, xanthine oxidase, and uncoupled endothelial nitric oxide synthase (eNOS) (47, 48). LPS has been shown to promote ROS production via mitochondrial dysfunction (49) and through the activation of NADPH oxidase, leading to the generation of superoxide, hydrogen peroxide, and hydroxyl radicals (50). This excess ROS contributes to impaired mitochondrial function and abnormal calcium handling in cardiomyocytes (51), thereby predisposing to AF (52).

Mechanistic insights from animal models further underscore this link. A study employing transesophageal pacing in NOX2 transgenic mice revealed that increased NOX2 expression elevates susceptibility to induced AF (53). Correspondingly, clinical observations in patients with community-acquired pneumonia have shown a positive correlation between NOX2 expression and AF occurrence (51), with NOX2 activation itself being associated with endotoxin exposure (54). Furthermore, LPS may promote AF by inducing cardiac iron overload and iron-dependent oxidative stress (55). Supporting this notion, an animal study utilizing an LPS-induced endotoxemia rat model reported that LPS-mediated disturbances in iron homeostasis can trigger the onset of AF (56). Previous clinical studies have similarly demonstrated that sepsis significantly alters systemic iron homeostasis, with elevated serum iron levels being independently associated with increased 90-day mortality in septic patients (57, 58). In addition, mitochondrial alterations in cardiomyocytes induced by LPS were found to correspond morphologically to those observed in siderophages (iron-laden macrophages) (59). The underlying mechanism may involve the activation of ferroptosis and the TLR4/NF-κB/NLRP3 inflammasome signaling pathway, which collectively contribute to sustained inflammation and dysregulated atrial pathological remodeling (60). In summary, by triggering robust oxidative stress, LPS directly contributes to both electrical and structural remodeling in the atria, thereby serving as a critical link between systemic inflammation and atrial dysfunction in AF.

An imbalance in the autonomic nervous system, comprising the sympathetic and parasympathetic branches, is a significant trigger for AF. LPS has been shown to modulate both vagal and sympathetic nerve activities. Research indicates that chronic low-level LPS infusion in rats activates TLR4 in the nodose ganglion (NG), where the cell bodies of vagal afferent neurons reside, leading to heightened vagal tone (61). Enhanced vagal activity releases substantial acetylcholine (ACh), which activates acetylcholine-sensitive potassium currents (I_kACh). This signaling cascade shortens the atrial effective refractory period, increases its spatial dispersion, and promotes rapid focal discharges from sites like the pulmonary veins, thereby precipitating AF (62–64).

Concurrently, LPS also potentiates sympathetic excitation. A study by Hao et al. reported that LPS exposure in pregnant rats increased renin-angiotensin system (RAS) activity and oxidative stress within the hypothalamic paraventricular nucleus (PVN), a key central regulator of sympathetic outflow, alongside the activation of renal sympathetic nerve activity (RSNA) (65). Chronic activation of the renin-angiotensin-aldosterone system (RAAS) can promote hypertension by increasing renin secretion, enhancing sodium reabsorption, and inducing renal vasoconstriction (66). Hypertensive heart disease, in turn, promotes myocardial hypertrophy and fibrosis, leading to left ventricular remodeling and creating a substrate for AF (67). In a subsequent intervention, Hao et al. demonstrated that co-administration of melatonin with LPS in pregnant rats attenuated RAS activity and oxidative stress in the offspring’s PVN, reduced RSNA and blood pressure, and increased urinary sodium excretion (68). These findings collectively underscore that LPS-induced inflammation and oxidative damage are key mechanisms driving sympathetic overactivation, renal dysfunction, and hypertension. In summary, LPS induces autonomic dysregulation by triggering excessive central and peripheral sympathetic activity, altering cardiac autonomic neural tone, and directly disrupting myocardial electrophysiology, thereby emerging as a significant proarrhythmic mechanism.

LPS promotes AF not through an isolated pathway, but by establishing a complex pathophysiological network (Figure 1). This network is centered on chronic inflammation, supported by two core effector pillars—myocardial fibrosis and oxidative stress—and overlaid by autonomic dysregulation acting as a potent accelerator. These components are intricately intertwined and engage in causal interactions, forming a vicious cycle that collectively drives atrial electrical, structural, and autonomic remodeling, ultimately leading to the initiation and perpetuation of AF (Table 1).

The chronic inflammation triggered by the LPS/TLR4/NF-κB signaling axis serves as a central hub in the pathological network (69). It not only directly damages cardiomyocytes and the electrical conduction system (70), but also potently activates the transformation of cardiac fibroblasts into myofibroblasts by upregulating key factors such as TGF-β1 (71), promoting the excessive deposition of type I/III collagen, i.e., myocardial fibrosis (72). Conversely, the abnormal extracellular matrix (ECM) formed by fibrosis not only alters the anisotropy of electrical conduction but also provides a microenvironment for the retention and persistent activation of inflammatory cells, thereby amplifying and perpetuating the inflammatory response (73). Furthermore, inflammatory cells (such as activated macrophages) and cardiomyocytes damaged by inflammation or stress themselves become significant sources of ROS (74). Excessively produced ROS can further activate pro−inflammatory transcription factors like NF−κB (75, 76), forming a self−amplifying loop of “inflammation−oxidative stress.” Simultaneously, ROS directly attack cardiomyocyte membrane lipids, proteins, and mitochondrial DNA (77, 78), leading to cellular dysfunction and abnormal calcium handling (79), directly contributing to electrical instability. At the structural level, ROS can also activate matrix metalloproteinases (MMPs) (80), participating in the pathological remodeling of the ECM (81), thereby tightly coupling oxidative stress with the fibrotic process. LPS−induced autonomic nervous system imbalance is also deeply intertwined with this mechanism. On the one hand, enhanced vagal tone, through the release of acetylcholine, shortens the atrial effective refractory period and increases its dispersion, directly creating an electrophysiological substrate prone to reentry and triggered activity (82). On the other hand, LPS−induced sympathetic overactivation, mediated by the activation of central (e.g., hypothalamic paraventricular nucleus) and peripheral renin−angiotensin−aldosterone system (RAAS), not only elevates blood pressure and increases cardiac afterload (83), but also releases catecholamines (84) and angiotensin II (85)—which are themselves potent pro−inflammatory, pro−oxidative, and pro−fibrotic factors—thereby significantly exacerbating the processes of inflammation, oxidative stress, and fibrosis.

Collectively, these mechanisms constitute a self-perpetuating vicious cycle (Figure 2): Intestinal barrier dysfunction leads to LPS translocation into the bloodstream, triggering systemic inflammation and oxidative stress. These processes directly damage atrial tissue and induce autonomic nervous system imbalance via sympathetic activation and RAAS. Inflammation, oxidative stress, and neuroendocrine activation together promote atrial fibrosis and electrical remodeling; ultimately leading to the initiation and perpetuation of AF. AF itself, particularly when it induces heart failure, causes intestinal congestion and hypoperfusion, which further impairs intestinal barrier function and increases LPS translocation. This perpetuates the entire cycle, relentlessly driving disease progression.

Therefore, understanding the mechanisms by LPS promotes AF requires shifting from a static “list of pathways” perspective to a dynamic “network interaction” viewpoint. Intervention at any single node may exert an inhibitory effect on the entire network, providing a theoretical foundation for multi-target therapeutic strategies targeting the gut-heart axis.

Numerous studies have now confirmed that multiple lifestyle factors can increase the risk of developing AF by influencing the gut microbiota, such as high-fat diets (86), physical activity (87, 88), and aging (34). It is noteworthy that, in addition to traditional lifestyle factors, emerging evidence suggests smoking may also increase the risk of AF by disrupting the gut-heart axis. Smoking is a well-established independent risk factor for AF (89). Components in tobacco such as tar, nicotine, and carbon monoxide can increase heart rate and myocardial contractility, promote inflammation, cause endothelial dysfunction and thrombosis, reduce serum levels of high-density lipoprotein cholesterol (90–92), exert pro-inflammatory effects (93), and elevate the risk of developing atrial fibrillation (94). Recent research has revealed that it may participate in the development of AF through an indirect pathway by impairing the intestinal barrier and promoting LPS translocation. On one hand, smoking can cause direct damage to the intestinal microenvironment (95). Studies indicate that various harmful components in tobacco smoke can alter the permeability of the intestinal mucosal barrier, induce local oxidative stress in the gut, change the composition and thickness of the mucus layer, and disrupt the expression of tight junction proteins between intestinal epithelial cells, thereby significantly compromising the integrity of the intestinal epithelial barrier (96). This impairment of barrier function creates conditions for the translocation of lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, from the gut into the portal vein and systemic circulation, potentially leading to or exacerbating “endotoxemia” (97). On the other hand, heavy metals contained in tobacco, such as cadmium, arsenic, chromium, mercury, and nickel, may be ingested and contribute to gut microbiota dysbiosis (98, 99). The LPS that enters the circulation can activate the TLR4/NF-κB signaling axis, triggering systemic chronic inflammation and oxidative stress. This, in turn, drives the initiation and progression of AF through multiple mechanisms, including promoting myocardial fibrosis, electrical remodeling, and autonomic nervous system dysfunction.

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. They colonize the gastrointestinal mucosa and exert various clinical and immunomodulatory functions (100). Endotoxins such as LPS are primarily derived from Gram-negative bacteria, which often include putrefactive or transient flora. Supplementation with native probiotics—indigenous microorganisms that permanently colonize the gut—especially strains with immunomodulatory properties, can induce multiple beneficial biological effects (101, 102). Certain probiotic strains have been shown to influence the host and its immune system through diverse mechanisms. These include inhibiting the overgrowth of putrefactive bacteria by nutritional competition and niche exclusion, maintaining gut microbiota homeostasis, and enhancing the immune function of gut-associated lymphoid tissue. By activating relevant intracellular signaling pathways, probiotics can also suppress the synthesis and release of multiple inflammatory mediators, thereby further reducing endotoxin levels (103). Widely used probiotics for endotoxin clearance primarily include conventional strains such as lactic acid bacteria, streptococci, bifidobacteria, yeasts, and bacilli. For example, Lactobacillus plantarum, Lactobacillus delbrueckii subsp. lactis, and Bacillus licheniformis help modulate the gut microbiota, reduce LPS levels, and enhance intestinal epithelial barrier function (104). Wu et al. found that Lactobacillus rhamnosus activates the Wnt/β-catenin pathway, which stimulates the proliferation of intestinal epithelial cells, repairs epithelial damage, protects the intestinal mucosal barrier from inflammatory injury, reduces intestinal endotoxin leakage, and consequently suppresses elevated blood endotoxin levels (97).

Research indicates that specific probiotic strains, such as Lactobacillus reuteri and Lactobacillus rhamnosus, can ameliorate social behavioral deficits and alleviate anxiety in LPS-exposed rats (105). The underlying mechanism may involve probiotic cell wall components that mitigate LPS-induced systemic inflammation by modulating immune-inflammatory responses and oxidative stress (106). Furthermore, in vitro experiments have demonstrated that Lactobacillus reuteri and its metabolite gamma-aminobutyric acid (GABA) confer protection against acute ischemic cardiac injury induced by ischemia/reperfusion (I/R) surgery, primarily through the suppression of cardiac inflammation during the I/R process (107). Specifically, GABA inhibits lysosomal leakage and NLRP3 inflammasome activation, thereby blocking the polarization of macrophages toward the pro-inflammatory M1 phenotype and exerting anti-inflammatory effects. In summary, preventive oral administration of Lactobacillus reuteri effectively attenuates acute cardiac injury following I/R surgery by inhibiting myocardial inflammatory responses.

As a biological therapeutic agent, probiotics are widely used in clinical practice and functional foods. However, their live-microbial nature entails poor stability, susceptibility to environmental factors, and inconsistent efficacy across numerous clinical trials (108–110). Therefore, the adoption of probiotics as a routine treatment strategy requires further investigation.

Colchicine, an alkaloid derived from Colchicum autumnale, is a well-established treatment for gout and familial Mediterranean fever (111). Owing to its potent anti-inflammatory properties, it has been incorporated into clinical guidelines as a standard therapy for pericarditis (112). Given the central role of inflammation in the pathogenesis of numerous cardiovascular diseases, including atherosclerosis and AF (113), anti-inflammatory strategies have emerged as a promising therapeutic approach for these conditions (114). Colchicine, in particular, has attracted significant interest as a potential oral cardiovascular agent due to its low cost, straightforward extraction, favorable patient tolerability, and direct action on inflammatory pathways (115, 116).

As one of the most extensively studied NLRP3 inflammasome inhibitors, colchicine acts by inhibiting microtubule polymerization, thereby preventing the assembly and activation of the NLRP3 inflammasome (117). The NLRP3 inflammasome serves as a critical downstream hub for LPS signaling; its activation triggers caspase-1-mediated maturation and release of potent pro-inflammatory cytokines such as IL-1β and IL-18 (118). By inhibiting this pathway, colchicine effectively reduces inflammatory infiltration and fibrosis in atrial tissue. Animal studies have demonstrated that colchicine improves survival and left ventricular systolic function in mice following coronary artery ligation, concurrently reducing myocardial mRNA expression of NLRP3 inflammasome components (119).

Clinically, low-dose colchicine is associated with reduced long-term AF recurrence after ablation (120). Initiating colchicine from 7 days pre-ablation to 1 month post-procedure significantly diminishes the incidence of acute pericarditis and related hospitalizations, with higher survival rates observed in patients with paroxysmal AF receiving this treatment (121). Furthermore, multiple clinical trials consistently show that colchicine reduces the risk of ischemic cardiovascular events in patients with acute or chronic coronary artery disease (122–126). In summary, colchicine directly targets the downstream inflammatory cascade triggered by LPS, representing a key mechanism for controlling AF progression. However, its potential gastrointestinal side effects and risk of myelosuppression warrant careful clinical consideration.

The Western diet (WD) is characterized by high intake of monosaccharides, refined flour, salt, processed meats, animal fats, and food additives, coupled with low consumption of fiber, minerals, vitamins, and antioxidants (127, 128). This dietary pattern influences host metabolism and health by promoting weight gain, activating immune responses, and facilitating the development of several chronic metabolic diseases—including obesity, type 2 diabetes, cardiovascular disease, neurodegenerative disorders, and autoimmune conditions (129). Under the metabolic stress imposed by a WD, profound alterations in gut bacterial composition occur, which compromise intestinal barrier integrity and may subsequently lead to endotoxemia and systemic inflammation (130). It has been suggested that chronic high-fat diets create favorable conditions for the proliferation of gram-negative bacteria (131) and are also considered a cause of impaired intestinal barrier function (132). A high-fat diet is widely thought to impair the intestinal barrier, leading to elevated circulating levels of LPS and the development of a pro-inflammatory state.

In contrast, the Mediterranean diet (MD) is rich in monounsaturated and polyunsaturated fatty acids (MUFAs and PUFAs). In addition to these lipids, it also provides considerable quantities of fiber, antioxidant vitamins, and phytochemicals (133). Research has found that, significantly increases the proportion of Firmicutes (134), which can produce butyric acid with anti-inflammatory effects, and plays an important role in maintaining microbial homeostasis and reducing LPS production (135). Clinical evidence indicates that long-term adherence to MD is associated with significantly lower plasma LPS levels in the elderly compared to a WD (136). This reduction in endotoxemia is linked to MD’s beneficial effects on overall metabolic health, gut microbiota, and inflammatory status (137).

Patients with cardiovascular disease, including those with AF, frequently exhibit intestinal barrier dysfunction and compromised integrity. This impairment allows LPS to translocate into the systemic circulation (138). Upon entry, LPS binds to TLR4 on immune cells and activates the release of pro-inflammatory cytokines, thereby initiating systemic inflammation. Specifically, via the TLR4/NF-κB pathway, LPS promotes the secretion of inflammatory mediators such as IL-1, IL-6, and TNF-α from macrophages and dendritic cells, which further exacerbates endotoxemia (139).

Given this cascade, directly blocking the interaction between LPS and its receptor represents the most upstream strategy for interrupting LPS signaling. TAK-242, a small-molecule inhibitor, selectively binds to the Cys747 residue in the intracellular domain of TLR4, thereby disrupting the interaction between TLR4 and its downstream adaptor proteins (TRAM/TRIF) (140). Animal studies have demonstrated that gut microbiota dysbiosis exacerbates cardiac dysfunction by activating the TLR4/NF-κB signaling pathway via LPS, which in turn drives myocardial inflammation and fibrosis (141). In this context, TAK-242 has been shown to significantly improve cardiac function and reduce fibrotic areas through a dual mechanism: inhibiting p65 phosphorylation and restoring microbial homeostasis. Another animal study confirmed that TAK-242 suppresses triggered activity induced by rapid pacing in both control and ischemia-related groups (30).

These findings not only enrich the theoretical framework of the gut-heart axis but also provide a novel rationale for targeting the intestinal microenvironment in the treatment of AF.

Traditional Chinese medicine (TCM) has a long history in China and, unlike some Western drugs known for adverse effects, exerts synergistic therapeutic actions through crosstalk between signaling pathways. Grounded in holistic philosophy and the theory that “the heart and small intestine are internally-externally connected,” TCM provides a unique perspective for the prevention and treatment of AF via multi-targeted, system-level regulation. According to TCM theory, pathological factors such as damp-heat and stagnation originating in the intestines—particularly the small intestine—may ascend to affect the heart, disturbing mental tranquility and thereby inducing palpitations. This view aligns closely with the modern concept of the “gut-heart axis.” In TCM, the pathogenesis of AF often involves heart meridian stasis and hyperactivity of heart fire. The systemic chronic inflammation and oxidative stress triggered by LPS entry into the bloodstream due to gut microbiota dysbiosis can be viewed as microscopic manifestations of TCM pathological factors like “stasis” and “fire”.

Both single herbs and TCM compound formulas can modulate LPS to reduce cardiovascular risk. Astragalus polysaccharides (APS), a macromolecular active component extracted from Astragalus membranaceus, exhibit multiple biological activities including immunomodulatory, antitumor, and antioxidant effects (142, 143). APS alleviates endothelial dysfunction by inhibiting LPS-induced macrophage polarization toward the M1 phenotype (144) and mitigating endothelial cell injury induced by H₂O₂, hyperglycemia, and TNF-α (145). Puerarin, derived from the root of Pueraria lobata, has been shown in vitro to significantly reverse the decline in H9C2 cell viability induced by LPS through inhibition of apoptosis (104). LPS markedly elevates ROS in H9C2 cells, while puerarin attenuates LPS-induced mitochondrial damage by regulating dynamin-related protein 1 (Drp1) and mitofusin-1 (MFN1). Moreover, puerarin and Torin1 significantly suppress the progression of sepsis by reversing LPS-induced inhibition of mitophagy in H9C2 cells via p62, LC3B, Pink1, and Parkin, thereby protecting cardiomyocytes (146). Zhuang et al. further demonstrated that puerarin activates GAS6 receptor agonists and targets the PGAM5–VDAC1 axis to regulate mitophagy, inhibiting LPS-induced necroptosis in cardiomyocytes and reversing mitochondrial pathway-related cardiac injury (147).

In addition, Xu et al. showed through in vivo and in vitro studies that ginseng effectively attenuates cardiac remodeling after myocardial infarction, with its protective effects closely associated with modulation of the SIRT1 signaling pathway (148). In vivo experiments indicated that ginseng improves cardiac function in a dose-dependent manner, reduces type I/III collagen deposition and IL-1β/IL-18 levels, and inhibits the NLRP3 inflammasome and TGFβ-1/Smads signaling pathways. In vitro experiments confirmed that ginseng similarly suppresses collagen production, inflammatory responses, and these key pathways in TGF-β1–induced cardiac fibroblasts and LPS-stimulated macrophages. The SIRT1-specific inhibitor EX-527 further verified SIRT1 as a critical upstream target of ginseng (148). Jingjie Fangfeng Decoction (JF), composed of Schizonepeta tenuifolia and Saposhnikovia divaricata, has been reported by Li et al. to significantly suppress LPS-induced inflammatory responses and oxidative stress in macrophages. Its key mechanism involves activation of the STAT3/p53/SLC7A11 signaling pathway, thereby inhibiting ferroptosis (149). The study also identified 5-O-methylquercetin, hesperidin, and luteolin as potential bioactive constituents of JF (149).

In summary, TCM demonstrates unique potential in modulating LPS-related mechanisms for the treatment of AF, guided by its holistic perspective and syndrome differentiation approach. TCM interventions act across multiple pathological stages. They work to reduce LPS production and intestinal translocation at the source, block midstream LPS signaling pathways, and alleviate downstream inflammatory and oxidative damage. This approach highlights the synergistic therapeutic advantage of multi-component, multi-target strategies.

Although numerous studies have revealed the substantial potential of single herbs and compound formulations in treating cardiovascular diseases via LPS modulation, the translation of TCM wisdom into outcomes that are comprehensible and broadly applicable within modern scientific frameworks still faces several core challenges. Foundational TCM theories, such as the concept that “the heart and small intestine are internally-externally related,” provide macro-level, holistic guidance for treating cardiac disorders from an intestinal perspective. However, a major bottleneck lies in the precise and systematic “translation” and cross-validation of TCM therapeutic methods—such as “clearing heat and drying dampness” or “promoting blood circulation and removing blood stasis”—with modern molecular pathways involved in “microbiota modulation, barrier repair, and LPS reduction.” Current evidence remains fragmented, lacking an integrated framework that bridges TCM principles, methods, formulas, and herbs with contemporary biomedical mechanisms. The prevailing reductionist research paradigm excels in deconstructing the effects of isolated components such as puerarin or astragalus polysaccharides. Yet, it falls short of capturing the essence of TCM compound formulas, which rely on the multi-target synergy among sovereign, minister, assistant, and messenger herbs. For instance, the anti-inflammatory effect of Jingjie Fangfeng decocation reflects its holistic efficacy; attributing this activity solely to a few identified constituents may not fully elucidate its therapeutic mechanism. Thus, developing a new research paradigm capable of integrating in-depth target analysis with holistic assessment of compound synergies represents an urgent and critical challenge in the field. Furthermore, the efficacy of TCM interventions stems from the combined actions of multiple constituents, making quality control far more complex than that of single-chemical drugs. Factors such as the geographical origin and processing methods of herbal materials directly influence the content and activity of key components—for example, the bioactivity of astragalus polysaccharides is affected by numerous variables. These issues pose significant challenges to the reproducible validation of research findings and the standardized production of TCM products.

In summary, as summarized in Table 2, intervention strategies for LPS-related AF exhibit a diverse landscape. Currently, colchicine can directly act upon the LPS-induced inflammatory cascade, representing a key mechanism potentially regulating the progression of AF (150). However, due to the drug’s potential gastrointestinal side effects (151) and risk of bone marrow suppression (152), its clinical utility must be carefully weighed. As foundational strategies for modulating the gut microenvironment and systemic inflammatory status, probiotics and anti-inflammatory diets offer benefits primarily focused on long-term risk management. However, they face challenges such as variable efficacy and patient compliance. In contrast, TLR4-targeting inhibitors and TCM represent promising research avenues. The former targets upstream precision blockade, while the latter emphasizes holistic multi-target regulation. Both demonstrate unique intervention potential, yet require further rigorously designed clinical studies to validate efficacy, safety, and to advance standardization before achieving widespread clinical application.