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

TL;DR

The paper suggests that regional anesthesia may have systemic effects by influencing the gut-brain axis, offering new insights for perioperative care.

Contribution

It proposes a novel perspective of regional anesthesia as a systemic modulator via the gut-brain axis.

Findings

Regional anesthesia may modulate the gut-brain axis through neural, immune, and endocrine pathways.

This modulation could impact perioperative stress and inflammation.

The paper calls for clinical trials to explore systemic benefits of regional anesthesia.

Abstract

Traditionally, regional anesthesia has been considered a local analgesic technique with benefits limited to the site of blockade. However, emerging preclinical and clinical evidence indicates that it may produce systemic effects by modulating the gut-brain axis. The gut-brain axis is a bidirectional regulatory system that integrates neural, immune, endocrine, and microbial signaling and is crucial for managing perioperative stress, inflammation, and physiological balance. This perspective article examines how regional anesthesia influences the gut-brain axis through several interconnected pathways, including neural modulation, immune regulation, endocrine effects, and indirect alterations in gut microbiota. We argue for reconceptualizing regional anesthesia as a systemic modulator and discuss its potential applications in perioperative recovery and chronic disease management. We conclude by calling for interdisciplinary research and mechanism-focused clinical trials to integrate this perspective into a more holistic model of perioperative medicine.

Figures

Anatomical and physiological components of the gut-brain and their potential interactions in the perioperative context.

Multi-pathway modulation of the gut-brain axis by regional anesthesia.

Full text

Introduction

1

Regional anesthesia, especially peripheral nerve blocks and neuraxial anesthesia, is a cornerstone of perioperative care primarily due to its potent local analgesic effects (Hutton et al., 2018; Schug et al., 2006). Its mechanism of action has been traditionally understood as the reversible pharmacological blockade of specific nerve pathways by local anesthetics (Taylor and McLeod, 2020). By preventing nociceptive signals from reaching the central nervous system, it provides excellent targeted pain relief, thereby reducing the need for systemic opioids and associated side effects like postoperative nausea and respiratory depression (Bingham et al., 2012). Consequently, this conventional view frames regional anesthesia primarily as a localized intervention, with its benefits considered largely confined to the anesthetized anatomical region (Liu and Wu, 2007).

In addition to this mechanistic and physiological relevance, regional anesthetic techniques offer distinct clinical advantages that have strengthened their role in contemporary practice. Local anesthetics are inherently cost-effective and widely accessible (Graff et al., 2023). Their regional application limits systemic drug exposure, enhancing safety (Hutton et al., 2018). Furthermore, within multimodal analgesic strategies, these techniques substantially decrease the dependency on general anesthetics and opioids, thereby lowering the overall risks of postoperative nausea, respiratory depression, and delirium (Li et al., 2022).

However, accumulating evidence from both clinical and basic research suggests that the impact of regional anesthesia extends well beyond localized neural blockade (Sessler et al., 2019). A growing body of evidence demonstrates that regional anesthesia confers systemic benefits across diverse surgical settings, including major abdominal, thoracic, orthopedic, and oncologic procedures (Reysner et al., 2024). These systemic benefits encompass areas such as immune modulation, attenuation of the neuroendocrine stress response, and enhancement of overall postoperative recovery (Reysner et al., 2024; Grosu and Lavand'homme, 2015). A clinically and mechanistically significant example is the facilitation of gastrointestinal recovery following abdominal surgery (Shi et al., 2014). This specific effect underscores the involvement of sophisticated gut-brain signaling pathways, which are central to maintaining perioperative homeostasis (Costes et al., 2014). This broader impact is further evidenced by documented associations with modulated immune responses and potential effects on long-term outcomes like cancer recurrence and cardiovascular events, all pointing to the involvement of systemic regulatory pathways (Dubowitz et al., 2018; Myles et al., 2011).

In this context, the gut-brain axis—a bidirectional communication network integrating the central nervous, autonomic, enteric, and immune systems along with gut microbiota—has emerged as a critical systemic regulatory hub (Wang et al., 2021). This axis plays a fundamental role in pain perception, stress responses, inflammation, and maintaining visceral homeostasis (Cryan et al., 2019).

Building on this, a compelling hypothesis posits that regional anesthesia may modulate systemic physiology by directly or indirectly influencing the gut-brain axis (Schäper et al., 2013). For example, by attenuating surgical stress and nociceptive signaling, nerve blockade can reduce sympathetic nervous system hyperactivity (Schäper et al., 2013). This sympathetic suppression can, in turn, improve intestinal blood flow, regulate gut barrier function, and influence local and systemic immune activity (Reysner et al., 2024). Furthermore, by blunting the surgical stress and inflammatory response, regional anesthesia may create a systemic milieu that favorably alters gut-brain communication (Schäper et al., 2013; Hahnenkamp et al., 2004). Thus, a local nerve block might initiate a cascade of events through the gut-brain axis, leading to widespread physiological effects.

This perspective article, therefore, argues for a paradigm shift in understanding regional anesthesia: from a focus on local analgesia to its recognition as a modulator of systemic physiology. We aim, first, to explore the evidence linking regional anesthesia to systemic effects mediated via the gut-brain axis. Second, we will synthesize current knowledge into a coherent mechanistic framework explaining this local-to-systemic translation. Finally, we will explore the clinical implications of this paradigm for perioperative strategy design and future research directions. Through this perspective, we seek to provide a deeper mechanistic rationale for its use and highlight its potential as a broader therapeutic tool in perioperative medicine.

Theoretical basis: gut-brain axis integration in anatomy and physiology

2

Components of the gut-brain axis

2.1

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).

Anatomical and physiological components of the gut-brain and their potential interactions in the perioperative context.

Key neural pathways of gut-brain axis

2.2

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.

Humoral and Immune Mediators

2.3

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).

Surgical and stress-induced perturbation of the gut-brain axis

2.4

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).

Potential regulatory mechanisms of nerve block on the gut-brain axis

3

The systemic benefits of regional anesthesia may arise primarily from its multi-faceted modulation of the integrated gut-brain axis (Figure 2). Importantly, we do not attribute all systemic effects of regional anesthesia to gut-brain axis pathways. Instead, we hypothesize that some of its systemic benefits may involve—directly or indirectly—gut-brain interactions, operating in conjunction with broader autonomic and neuroimmune mechanisms.

Multi-pathway modulation of the gut-brain axis by regional anesthesia.

However, regional anesthesia encompasses a diverse range of techniques that vary in their anatomical targets, duration, and neural specificity, such as neuraxial versus peripheral nerve blocks (Axelsson and Gupta, 2009; Jeng et al., 2010). This inherent variability complicates the attribution of specific physiological effects—particularly those involving systemic or gut-brain pathways—to a singular mechanism (Reysner et al., 2024). Consequently, extrapolating findings across different techniques requires careful and contextual interpretation.

While regional anesthesia broadly suppresses sympathetic activity and enhances vagal tone, only part of this autonomic shift directly engages enteric neural pathways (Introna et al., 1995). The specific role of the enteric nervous system (ENS) in these processes remains incompletely understood, with current evidence supporting its plausible, rather than definitive, involvement (Heiss and Olofsson, 2019). Beyond its role within autonomic pathways, the ENS may also perform distinct, locally autonomous regulatory functions independent of vagal signaling (Fung and Vanden Berghe, 2020). Studies suggest that the ENS modulates enteric reflexes governing peristalsis and secretion, interacts bidirectionally with intestinal macrophages in the lamina propria, and influences epithelial barrier function via enteric glial cells (Spencer and Hu, 2020; Meroni et al., 2019). Additionally, ENS regulation of enteroendocrine signaling may alter local hormone release, potentially affecting systemic neuroendocrine and immune responses (Vergnolle and Cirillo, 2018; Latorre et al., 2016). Although direct evidence linking these ENS-specific mechanisms to the systemic effects of regional anesthesia remains limited, their functional and anatomical independence supports their plausible contribution within the broader gut-brain axis. Similarly, influences from the microbiota are more appropriately viewed as secondary or permissive modulators within this regulatory network (Geng et al., 2022). Advances in local anesthetic formulations have further reinforced the clinical value of these systemic benefits by optimizing pharmacodynamic profiles (Skolnik and Gan, 2014). For instance, liposome-encapsulated bupivacaine offers extended postoperative analgesia through sustained drug release, enabling prolonged modulation of these pathways (Hu et al., 2013; Gorfine et al., 2011; Hamilton et al., 2022). Meanwhile, the growing preference for ropivacaine leverages its lower cardiotoxicity and milder motor block to support earlier and safer postoperative mobilization and rehabilitation (Mather and Chang, 2001; Tai et al., 2022). The underlying mechanisms of gut-brain axis modulation can be organized into four interconnected categories.

Neural pathway intervention

3.1

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.

Immune and inflammatory modulation

3.2

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).

Endocrine and metabolic effects

3.3

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).

Indirect modulation of microbiota-host interaction

3.4

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.

Evidence synthesis: insights from preclinical and clinical research

4

The integration of evidence from preclinical and clinical studies is crucial for understanding the gut-brain axis effects of regional anesthesia. This synthesis supports the proposed systemic mechanisms and highlights current knowledge gaps (Supplementary Table 1).

Animal studies

4.1

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 observations

4.2

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.

Evidence from veterinary medicine

4.3

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.

Limitations

4.4

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.

Translational prospects

5

Moving beyond its traditional role as a local analgesic, regional anesthesia should be recognized as a perioperative intervention with significant potential for systemic modulation via the gut-brain axis. This reconceptualization opens new avenues for translating this understanding into clinical practice and research.

Optimization of perioperative application

5.1

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).

Potential role in chronic disease management

5.2

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.

Personalized medicine

5.3

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 directions

5.4

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.

Summary

6

This perspective has argued that regional anesthesia exerts effects far beyond local pain control by modulating the gut-brain axis. Based on the presented evidence, we conclude with the following key points and a call to action. Regional anesthesia should be conceptualized as a systemic modulator, influencing physiology through neural, immune, endocrine, and microbial pathways linked to the gut-brain axis. This broader understanding elevates its role from a perioperative analgesic to a potential cornerstone of holistic recovery strategies.

In practice, clinicians should consider nerve blocks as a key intervention for regulating the body's integrated stress and recovery responses to surgery. Utilizing this multi-system perspective can optimize patient management, aiming not only for analgesia but also for improved gastrointestinal function, reduced inflammation, and enhanced overall recovery.

Advancing this field requires dedicated collaboration across multiple disciplines. Experts in anesthesiology, gastroenterology, neuroscience, microbiology, and surgery should work together to design targeted clinical trials and develop practical monitoring tools. This collaborative effort is essential to translate the gut-brain axis paradigm into effective, personalized patient care and to foster a more integrative model of perioperative medicine.