Reconceptualizing regional anesthesia as a systemic modulator: a hypothesis-driven gut-brain axis perspective

The gut-brain axis is an integrated physiological system comprising multiple, interconnected components, not a single structure (Carabotti et al., 2015). Its core architecture consists of four main elements (Holzer and Farzi, 2014). First, the central nervous system acts as the primary command and integration center (Mayer et al., 2015). Second, the autonomic nervous system—specifically its sympathetic and parasympathetic branches—provides a rapid, bidirectional communication channel (Mayer et al., 2015). Third, the enteric nervous system, an extensive neural network within the gut wall often called the “second brain,” can orchestrate local digestive functions independently (Furness, 2012). Fourth, the gut microbiota, a vast community of intestinal microorganisms, generates numerous bioactive compounds through metabolic activity (He et al., 2024). These components communicate continuously through neural, endocrine, and immune signaling pathways, forming a complex, dynamic network (Figure 1).

Direct neural connections are fundamental to the gut-brain axis's bidirectional communication. The vagus nerve is the principal parasympathetic pathway, transmitting the majority of sensory information from the gut to the brain and carrying regulatory commands back to the viscera (Bonaz et al., 2018). In contrast, spinal-sympathetic pathways are chiefly activated during stress, suppressing gastrointestinal motility and blood flow (Teff, 2008). Visceral afferent nerve fibers, distributed throughout the gut, detect local mechanical, chemical, and noxious stimuli and relay this sensory input to the central nervous system via the spinal cord (Furness, 2012; Yu et al., 2020). Together, these neural circuits enable the brain to monitor gut status in real time and modulate its function accordingly.

Signaling within the gut-brain axis also depends heavily on circulating biochemical and immune mediators. Pro-inflammatory and anti-inflammatory cytokines can, during systemic inflammation, cross the blood-brain barrier or signal via nerves to influence central nervous system activity, thereby affecting mood and cognition (Zhang H. et al., 2025). Neuropeptides—such as gut-derived peptide YY and glucagon-like peptide-1, along with brain-derived corticotropin-releasing hormone—coordinate appetite, stress responses, and gut function (Holzer and Farzi, 2014). Additionally, short-chain fatty acids, produced by gut bacteria fermenting dietary fiber, serve as crucial microbial messengers that influence host immunity and neurology both locally and systemically after entering circulation (Silva et al., 2020).

Surgery and the associated perioperative stress represent a potent disruptor of gut-brain axis homeostasis (Danehower, 2021). The trauma of surgery initiates a systemic inflammatory response, characterized by the release of cytokines that can disrupt central nervous system function (Danehower, 2021). Concurrently, neuroendocrine stress responses and reduced splanchnic perfusion can compromise the intestinal epithelial barrier, increasing its permeability (Morys et al., 2024). This “leaky gut” may allow bacterial products to translocate into the bloodstream, potentially exacerbating systemic inflammation (Lange et al., 2025). Furthermore, factors like opioids, fasting, and antibiotics can induce a rapid shift in microbial community structure and function, known as dysbiosis (Klingensmith and Coopersmith, 2016). These three perturbations—systematic inflammation, intestinal barrier dysfunction, and gut dysbiosis—frequently interact in a synergistic and often self-perpetuating manner, establishing a pathophysiological vicious cycle. Clinically, this cycle manifests directly as postoperative gastrointestinal dysfunction, encompassing conditions such as ileus, feeding intolerance, and delayed bowel recovery (Mazzotta et al., 2020). Such complications not only prolong hospitalization but also perpetuate systemic inflammation and critically hinder functional recovery, particularly following major abdominal or colorectal procedures (Harnsberger et al., 2019; Bain et al., 2023). Collectively, these findings underscore the pivotal role of gastrointestinal physiology and gut-brain axis integrity in determining overall surgical outcomes, linking molecular and systemic perturbations to concrete clinical morbidity (Lubbers et al., 2010).

Nerve blockade exerts its most direct effect through physical interruption of neural signaling pathways. Firstly, by blocking nociceptive afferent signals from the surgical site, it significantly dampens the activation of the hypothalamic-pituitary-adrenal (HPA) axis, thereby reducing the systemic neuroendocrine stress response at its source (Abram, 2000). Secondly, regional anesthesia, especially neuraxial blocks, modulates the autonomic nervous system balance. It inhibits sympathetic outflow while potentially promoting a relative dominance of vagal (parasympathetic) tone (Li et al., 2003). This shift toward parasympathetic predominance favors gastrointestinal motility, improves gut mucosal blood flow, and promotes an anti-inflammatory systemic environment (Tracey, 2002; de Jonge et al., 2005). The autonomic influence on gut function is likely mediated via direct modulation of enteric neural circuits, although the precise signaling integration within the ENS warrants further elucidation.

Through these neural effects, nerve blockade induces significant immunomodulatory changes. Locally, by limiting nociceptive signaling and sympathetic activity, it suppresses the release of pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha, interleukin-6) from the surgical site (Occhinegro et al., 2023). Systemically, the attenuated stress response and reduced sympathetic tone help preserve intestinal immune homeostasis (Populin et al., 2021; Mallesh et al., 2022). This may involve a shift toward an anti-inflammatory phenotype in gut-resident immune cells and helps maintain the integrity of the intestinal mucosal barrier, reducing bacterial translocation and subsequent systemic inflammation (Populin et al., 2021; Mallesh et al., 2022).

Nerve blockade also has bidirectional effects on the endocrine system. By suppressing HPA axis activation, it directly lowers circulating levels of stress hormones like cortisol and catecholamines (Carli et al., 2002). Normalizing these hormone levels alleviates associated metabolic disturbances and removes their suppressive effects on gut function and immunity (Carli et al., 2002). Furthermore, the improved autonomic balance may positively influence enteroendocrine cell function (Furness et al., 2013). This could modulate the secretion of gut hormones such as ghrelin and glucagon-like peptide-1, thereby impacting broader metabolic homeostasis and nutrient signaling (Holst, 2007).

Finally, nerve blockade can indirectly influence the gut microbiota by altering the intestinal environment. Enhancing intestinal motility and perfusion supports a favorable niche for commensal bacteria, helping to maintain a stable and diverse microbial community (Huang et al., 2022; Xie et al., 2025). Concurrently, the neuro-immunologically mediated anti-inflammatory state may alter, the functional output of the microbiota (Xie et al., 2025). A key example is the potential modulation in the production of microbially derived metabolites, particularly short-chain fatty acids like butyrate, which have recognized anti-inflammatory and neuroactive properties (Bruning et al., 2020; Pang et al., 2026). This establishes a feedback loop where microbial metabolites further contribute to systemic physiological regulation. The microbiota likely functions as a responsive consortium within this system, whose composition and metabolic activity can be modulated by, and in turn modulate, host physiology altered by nerve blockade.

In summary, regional anesthesia acts as a powerful multi-system modulator rather than a purely local analgesic. By simultaneously targeting neural, immune, endocrine, and microbial communication pathways, it helps restore perioperative gut-brain axis homeostasis. This integrative mechanism underpins its potential to provide systemic protective effects beyond pain control.

Animal models offer valuable insights into the direct mechanisms of nerve blocks (Wu et al., 2022). Studies in abdominal surgery models show that neuraxial or regional blocks, compared to general anesthesia, significantly improve postoperative gastrointestinal recovery and reduce ileus (Boeckxstaens and Jonge, 2009; De Winter, 2003). These benefits appear linked to the modulation of neuroinflammation, such as reduced microglial activation in the brain (Wu et al., 2022; Zou et al., 2024). Furthermore, nerve blockade in animals helps preserve a healthier gut microbial balance after surgery, preventing severe dysbiosis and maintaining levels of beneficial metabolites like butyrate (Zou et al., 2024; Glynn et al., 2025). These findings provide experimental support for the interconnected neural, immune, and microbial pathways proposed in the gut-brain axis hypothesis.

Critically, although direct causal evidence is still limited, evidence from animal models converges with other lines of inquiry to suggest that the ENS may function as a key mediator in the gut-brain axis (Sharkey and Mawe, 2023). Current evidence supports a dual role for the ENS. First, it acts as a downstream responder, influenced by reduced sympathetic activity and attenuated inflammation (Progatzky and Pachnis, 2022; Progatzky et al., 2021). Second, it may actively regulate immune signaling, enteroendocrine pathways, and vagal afferent activity (Kaelberer et al., 2018). The ENS is anatomically and functionally situated to integrate neural, immune, and endocrine signals (Sharkey and Mawe, 2023). Within this framework, through these mechanisms, the ENS can amplify and integrate central nervous system effects, which helps explain how regional anesthesia may produce systemic benefits via the gut-brain axis (Matteoli et al., 2014).

Clinical research consistently shows associations between regional anesthesia and improved patient outcomes. Its use is correlated with a lower incidence of postoperative delirium, potentially due to reduced systemic inflammation and opioid use (Zhuang et al., 2022). Regional anesthesia is also associated with decreased risks of surgical site infections and pulmonary complications, suggesting a role in supporting immune function (Lee et al., 2011). Additionally, patients often experience faster return of bowel function, shorter hospital stays, and improved early mobility when regional techniques are employed (Zhuang et al., 2022; Levy et al., 2011). These clinical correlations align with the systemic benefits suggested by animal research and the gut-brain axis framework. Notably, perioperative clinical studies indicate that regional anesthesia has been consistently shown to modulate autonomic balance, inflammatory tone, stress signaling, and gastrointestinal function—processes in which the ENS is positioned to play an integrative role (Reysner et al., 2024; Li et al., 2003). Collectively, available clinical evidence suggests an indirect link between regional anesthesia and gut-brain axis physiology. However, this does not establish a central or required mediating role, underscoring the exploratory nature of the present perspective.

In addition to experimental models and human clinical studies, translational insights can also be drawn from veterinary medicine, where regional anesthesia has been widely practiced in diverse animal species. Regional anesthesia holds a long-established role in veterinary medicine and provides valuable translational insights (Edmondson, 2008). In large animals such as cattle and horses, surgical procedures—especially gastrointestinal and orthopedic interventions—are routinely performed under locoregional anesthesia alone (Román Durá et al., 2025). This preference stems from the increased risks of general anesthesia in these species. Standing abdominal procedures under nerve blocks, for instance, are particularly common in bovine practice (D'Anselme et al., 2022).

For small animals and equine surgery, regional anesthesia is a key element of multimodal analgesic strategies, supporting opioid-sparing approaches (Grubb and Lobprise, 2020). Its growing adoption has been accelerated in recent years by reduced opioid availability related to the human opioid crisis (Kogan et al., 2019). These veterinary applications highlight both the systemic relevance and practical utility of regional anesthesia across species, reinforcing its reconceptualization as a broadly applicable physiological modulator (Clarke et al., 2019). This body of veterinary research further contributes to the converging evidence suggesting a potential mediating role for the ENS, as the modulation of autonomic and gastrointestinal functions observed clinically is also a consistent feature of regional anesthesia in animal species.

It is important to critically acknowledge the limitations of the current evidence base. Most clinical data demonstrate association, not proven causation; benefits may be confounded by reduced opioid use and other perioperative factors (Tanios et al., 2025). Crucially, direct evidence in humans linking nerve blocks to specific gut-brain axis pathways remains largely absent (Minerbi and Shen, 2022). There is a significant lack of studies that track the complete mechanistic cascade from neural blockade to measurable changes in human immune markers, hormones, and gut metabolites (Ekatodramis, 2001). Therefore, while the hypothesis is well-supported and plausible, more direct translational research is needed to establish definitive causal mechanisms in patients.

The clinical application of regional anesthesia should be integrated into broader perioperative strategies, such as Enhanced Recovery after Surgery protocols (Mancel et al., 2021; Campoy, 2022). Its value should be assessed not only for pain relief but also for its potential to improve gastrointestinal recovery, modulate immune function, and provide neuroprotection (Zhang T. et al., 2025; Bosenberg and Flick, 2013). Anesthesia planning should therefore consider the systemic, gut-brain-mediated benefits of nerve blocks, shifting the focus from isolated analgesia to comprehensive rehabilitation support (Bosenberg and Flick, 2013).

Given the centrality of the gut-brain axis in chronic conditions, regional anesthesia may have therapeutic relevance beyond the operating room. For example, targeted nerve blocks could help manage refractory visceral pain in disorders like irritable bowel syndrome by modulating aberrant gut-brain signaling (Mayer et al., 2015). Furthermore, its modulatory effects on inflammation and metabolism suggest a potential adjuvant role in metabolic surgery perioperative care to improve long-term outcomes (Deer et al., 2014; Aron-Wisnewsky and Clément, 2016). This indicates a possible expansion of its utility into the management of select chronic diseases.

A personalized approach could optimize nerve block therapy by accounting for individual differences in gut-brain axis physiology. Preoperative profiling using biomarkers related to microbiota, inflammation, or stress response might help identify patients most likely to benefit from specific regional techniques (Lee et al., 2025; Pearse et al., 2011). This would enable a shift from standardized protocols to tailored strategies that select the optimal type, timing, and duration of blockade based on a patient's unique physiological profile (De Hert et al., 2011).

Future research should prioritize discovering and validating practical biomarkers to objectively assess gut-brain axis status before and after regional anesthesia (Dalile et al., 2019). Ideal biomarkers would reliably indicate key aspects such as intestinal permeability, systemic inflammation, or microbial metabolite levels. From a translational perspective, this aligns with a stepwise, testable framework wherein regional nerve blockade first alters autonomic and ENS activity, subsequently driving downstream immune, endocrine, and gut barrier responses to produce systemic clinical effects (Reysner et al., 2024; Schäper et al., 2013; Mahajan et al., 2017; Tracey, 2007). Accordingly, biomarker discovery should span these stages and include autonomic measures (e.g., heart rate variability), inflammatory markers, gut permeability indicators, and enteroendocrine hormones (Wells et al., 2017).

Rigorous, mechanistic clinical trials are needed to establish causality between nerve blocks and specific gut-brain axis outcomes. Future mechanistic studies should directly validate these proposed physiological pathways and clarify causal relationships beyond mere anatomical or physiological overlap. These studies should measure intermediate endpoints like neuroendocrine or inflammatory markers to directly test the proposed pathways (Evered et al., 2018).

Notably, a key limitation in current evidence is the lack of experimental studies that investigate the causal role of the ENS in mediating the systemic effects of regional anesthesia (Langness et al., 2017). Animal models employing chemical or genetic ENS ablation could offer a direct means to test whether—and to what extent—ENS integrity is necessary for regional anesthesia to modulate inflammation, endocrine signaling, and gut-brain communication (Grubišić et al., 2022; Yoneda et al., 2002). Addressing this gap would enhance mechanistic understanding and help differentiate ENS-mediated effects from those primarily driven by central autonomic pathways.

Despite its potential advantages, the broader implementation of regional anesthesia in such research and subsequent clinical translation faces significant challenges. Its successful application necessitates thorough anatomical knowledge, technical skill, and experience in ultrasound-guided procedures (Niazi et al., 2012). However, current variations in training quality and procedural exposure across anesthesiology programs can hinder consistent adoption and the reliable application required for high-quality study protocols and eventual widespread clinical use (Ardon et al., 2023). To overcome these barriers, parallel efforts are essential to develop standardized curricula, implement simulation-based training, and establish competency-based certification, thereby ensuring both the safety and methodological rigor necessary for its effective investigation and application (Sites et al., 2010; Udani et al., 2015).

Expanding on this, research should investigate whether regional anesthesia works synergistically with other gut-brain-targeted therapies, such as specific probiotics, dietary regimens, or neuromodulation techniques (Cryan et al., 2019). Such multimodal strategies may offer superior outcomes in modulating perioperative physiology and enhancing recovery.

The original contributions presented in the study are included in the article/, further inquiries can be directed to the corresponding author. Supplementary material