Enteric glial cells as regulators of the gut-brain axis: hormonal signaling, stress responses and progenitor potential

It is important to distinguish between the directly established, the emerging, and the largely hypothetical aspects of enteric glial biology discussed in this review. While stress-induced reactive gliosis is comparatively well documented, hormonal regulation of EGCs remains supported by only a small number of direct studies, and the integrative model proposed below is therefore a conceptual hypothesis rather than an established mechanism. The studies discussed throughout this review suggest that enteric glial cells occupy a unique position within the gut-brain axis, acting simultaneously as regulators of neuroimmune communication, stress-responsive cells, and facultative progenitors ( Figure 2 ). Although these functions have traditionally been investigated separately, accumulating evidence indicates that they may represent interconnected aspects of enteric glial biology. Graphic summary of the key factors that interact with enteric glial cells. Generated with napkin.AI. Inflammatory and oxidative stress induce profound changes in enteric glial phenotype, including reactive gliosis, cytokine secretion, altered neurotrophic support, and modulation of epithelial barrier function. At the same time, hormonal signaling pathways influence neuroinflammatory responses, cellular survival, and tissue plasticity throughout the nervous system. Emerging evidence further suggests that enteric glia express hormone receptors and respond to endocrine signals, although direct mechanistic studies remain scarce. The convergence of these pathways raises the possibility that enteric glia function as central integrators of environmental and systemic signals within the ENS. Under physiological conditions, EGCs contribute to neuronal maintenance and gastrointestinal homeostasis. Following injury or stress, however, activation of inflammatory, endocrine, and neurotrophic pathways may shift glial cells toward adaptive phenotypes that support tissue repair and, under specific circumstances, neuronal regeneration. We therefore propose a conceptual framework in which hormonal signaling and stress-related pathways act as upstream regulators of enteric glial plasticity. In this model, EGCs integrate signals derived from the immune system, intestinal microbiota, and endocrine organs and translate them into coordinated responses affecting neuronal survival, barrier integrity, and regenerative capacity. While substantial experimental work will be required to validate this hypothesis, such a framework may help explain how systemic physiological states influence ENS adaptation and gut-brain axis function across the lifespan.

Enteric glial cells (EGCs) are increasingly recognized as active regulators of gastrointestinal physiology and essential components of the gut-brain axis (GBA). Traditionally regarded as supportive cells of the enteric nervous system (ENS), EGCs are now known to participate in a broad range of functions, including the maintenance of intestinal epithelial barrier integrity, modulation of immune responses, regulation of neurotransmission, and bidirectional communication with the gut microbiota ( Neunlist et al., 2014 ; Grubišić and Gulbransen, 2016 ). Through these diverse activities, EGCs integrate neural, immune, microbial, and endocrine signals and thereby contribute to the maintenance of intestinal homeostasis and gut-brain communication. Growing evidence suggests that enteric glia are critically involved in disorders associated with GBA dysfunction. Alterations in EGC activity have been described in inflammatory bowel disease, irritable bowel syndrome, and neurodegenerative disorders such as Parkinson’s disease. In Parkinson’s disease, reactive EGCs have been implicated in the regulation of intestinal motility, visceral sensory signaling, and immune polarization, highlighting their potential contribution to both local gastrointestinal pathology and systemic neuroimmune processes ( Thomasi et al., 2023 ). Despite these advances, the mechanisms by which EGCs integrate environmental and systemic signals to influence gut-brain communication remain incompletely understood. One emerging area of research concerns the role of EGCs as stress-responsive cells. Experimental studies have demonstrated that chronic stress alters enteric glial activity and disrupts intestinal homeostasis. In a rat model of chronic water-avoidance stress, pharmacological inhibition of enteric glia reversed stress-induced alterations in microbiota composition and restored the expression of the tight junction proteins occludin and claudin-1 ( Lu et al., 2024 ). Furthermore, EGCs have been proposed to participate in microbiota-brain communication through the sensing of microbial metabolites and the modulation of neuroinflammatory pathways ( Blair et al., 2025 ). These findings suggest that enteric glia may represent an important cellular interface through which environmental stressors influence GBA function. However, current knowledge is derived predominantly from animal models and mechanistic studies, and translation to human physiology remains limited. In parallel, increasing attention has been directed toward endocrine regulation of the ENS. Steroid hormones and stress-related endocrine pathways are established modulators of gastrointestinal physiology and gut-brain communication, influencing intestinal permeability, immune responses, and neuronal function. Nevertheless, their specific effects on enteric glial biology remain poorly characterized. Emerging evidence suggests that EGCs may respond to hormonal and neuroendocrine signals and thereby contribute to the integration of systemic endocrine cues within the ENS. Understanding these mechanisms may provide important insights into how physiological states such as aging, stress, and hormonal fluctuations influence intestinal and neurological health. Another rapidly evolving area of research concerns the remarkable cellular plasticity of enteric glia. Although EGCs are generally quiescent under physiological conditions in mammals, accumulating evidence indicates that they retain progenitor-like properties and may contribute to neuronal regeneration following injury. In zebrafish, enteric glia actively proliferates and generates new enteric neurons under homeostatic conditions through mechanisms involving Notch signaling ( McCallum et al., 2020 ). In mammals, lineage-tracing and single-cell transcriptomic studies have demonstrated that subsets of EGCs maintain accessibility at neurogenic loci, supporting their capacity for neuronal differentiation under specific pathological conditions ( McCallum et al., 2020 ; Laddach et al., 2023 ). These findings position enteric glia as promising candidates for endogenous ENS repair and regeneration ( Boesmans et al., 2022 ; Lefèvre et al., 2023 ). Although substantial progress has been made in characterizing enteric glial biology, the fields of hormonal regulation, stress responsiveness, and progenitor potential have largely developed independently. To date, no comprehensive synthesis has integrated these emerging properties of EGCs within the broader framework of gut-brain axis regulation. Yet, accumulating evidence suggests that these processes may be closely interconnected. Hormonal and stress-related signals influence cellular plasticity and neuroimmune function in multiple tissues, raising the possibility that similar mechanisms shape enteric glial behavior and adaptive responses within the ENS. In this review, we summarize current knowledge on enteric glial cells as regulators of the gut-brain axis, with particular emphasis on hormonal signaling, stress responses, and progenitor potential. We discuss how these interconnected functions may contribute to ENS homeostasis, adaptation, and disease and highlight key challenges and future directions for understanding the role of enteric glia in gut-brain axis physiology.

Despite substantial advances in enteric glial biology, major knowledge gaps (see Table 4 ) remain regarding the mechanisms by which hormones, stress-related signaling pathways, and regenerative programs interact within EGCs. Future studies should prioritize the identification of hormone receptor expression patterns across distinct glial subpopulations and determine whether endocrine signaling directly regulates enteric glial phenotype, neuroimmune function, and neurogenic potential. Major knowledge gaps and future research priorities. Recent developments in single-cell transcriptomics, spatial transcriptomics, lineage tracing, and organoid-based ENS models provide powerful tools to address these questions. In particular, integrating these approaches with experimental models of stress, aging, and neurodegeneration may reveal previously unrecognized mechanisms governing enteric glial plasticity. From a translational perspective, enteric glia represent attractive therapeutic targets ( Table 5 ). Their accessibility within the gastrointestinal tract, combined with their roles in barrier maintenance, immune regulation, neuronal support, and tissue repair, positions them as potential mediators of interventions aimed at restoring gut-brain axis homeostasis. Pharmacological modulation of glial signaling pathways, neurotrophic support mechanisms, or hormone-responsive pathways may therefore offer novel therapeutic opportunities for gastrointestinal disorders, neurodegenerative diseases, and age-associated ENS dysfunction. Potential therapeutic targets in enteric glial cells. Ultimately, a deeper understanding of how enteric glia integrate hormonal, inflammatory, and environmental signals may not only redefine current concepts of ENS biology but also uncover new strategies to promote regeneration and resilience within the GBA.

Among the most intriguing properties of EGCs is their capacity to act as facultative progenitor cells. Although traditionally viewed as terminally differentiated support cells, accumulating evidence suggests that subsets of EGCs retain developmental programs that enable neuronal differentiation under specific physiological or pathological conditions. Early studies identified EGCs as potential neuronal and glial progenitors within the ENS. Neunlist et al. (2014) described enteric glia as a cellular population capable of generating both neuronal and glial lineages, while Bondurand et al. (2003) demonstrated that progenitor cells isolated from fetal and postnatal mouse intestine could generate mature neurons and glia and successfully colonize aganglionic gut tissue. More recently, mechanistic insights from lineage-tracing and single-cell sequencing studies have revealed that EGCs maintain accessibility at key neurogenic loci despite their differentiated phenotype. This permissive chromatin landscape may allow glial cells to re-enter developmental programs and generate neurons in response to specific stimuli ( Laddach et al., 2023 ). Beyond their neurogenic potential, recent single-cell analyses suggest that enteric glial populations actively regulate intestinal stem cell niches. Baghdadi et al. (2022) demonstrated that transcriptionally distinct EGC populations occupy specific microenvironments and contribute to local niche signaling, further supporting the concept that enteric glia participate in tissue maintenance and regeneration beyond their classical neuro-supportive functions. However, the neurogenic capacity of EGCs remains highly context dependent. As emphasized by Gulbransen and Sharkey (2012) , enteric glia appear capable of generating neurons only under restricted conditions. Likewise, Gershon (2011) noted that although enteric glia can function as neuronal precursors in vitro and under experimental conditions in vivo, they do not constitutively replace neurons during normal tissue homeostasis. Consequently, spontaneous neurogenesis appears to be limited in the healthy mammalian ENS. Interestingly, substantial species differences have been reported. In zebrafish, enteric glia actively proliferate and continuously generate new enteric neurons under physiological conditions through Notch-dependent mechanisms ( McCallum et al., 2020 ). In contrast, mammalian EGCs generally remain quiescent and require injury, inflammation, or experimental manipulation to activate neurogenic programs. These findings suggest that the regenerative potential of enteric glia is evolutionarily conserved but differentially regulated across species. Importantly, the emerging concepts discussed in the previous chapters raise the possibility that neurogenic plasticity is not an isolated property of EGCs but may be closely linked to their stress-responsive and hormone-sensitive nature. In other nervous systems, inflammatory mediators, steroid hormones, and growth factors are well-established regulators of stem cell activity and cellular plasticity. Whether similar mechanisms govern the activation of neurogenic programs in enteric glia remains largely unknown. Understanding how stress- and hormone-dependent signaling pathways influence EGC plasticity may therefore represent an important step toward harnessing endogenous regenerative mechanisms within the ENS. Translational Limitations: From Rodent Models to Human ENS: The vast majority of findings summarized in this review derive from mouse, rat, or zebrafish models. Direct human data remain scarce and are largely limited to receptor-expression studies (e.g., Kallabis et al., 2026 ) or descriptive immunohistochemical analyses. Important species differences further complicate translation: for example, GFAP expression is a near-universal marker of rodent enteric glia but is only detectable in a subset of glial cells in the healthy human gut, becoming more prominent under pathological conditions (Le Berre-Scoul et al., cited via Enteric Glia: S100, GFAP, and Beyond). Access to viable human enteric tissue is additionally constrained by the invasiveness of full-thickness biopsies, limiting functional and mechanistic studies to surgical specimens, organoid models, or post-mortem tissue. These constraints should be considered when interpreting the mechanistic conclusions drawn from animal studies discussed throughout this review.”

Enteric glial cells (EGCs) exhibit marked morphological, regional, and functional heterogeneity within the ENS ( Table 1 ). Whether this heterogeneity reflects stable cellular subtypes or dynamic functional states remains a matter of ongoing debate ( Valès et al., 2018 ). Based on combined morphological, molecular, and functional analyses, four major EGC subtypes can be distinguished ( Figure 1 ). Enteric glial heterogeneity across functional levels. Topo-morphological and functional heterogeneity of enteric glial cells. Four major EGC subtypes have been described in the mouse ENS, differing in morphology, location and molecular/function profiles. ADP, adenosine diphosphate; CCK, cholecystokinin; ENS, enteric nervous system; EGC, enteric glial cells. Figure generated with assistance of ChatGPT (OpenAI, GPT-5.3-mini). Type I (protoplasmic, intraganglionic glia) are located within myenteric and submucosal ganglia. They are characterized by multiple highly branched processes with end-foot-like structures and establish extensive contacts with enteric neurons and neighboring glial cells. These cells are considered highly integrated within intraganglionic signaling networks. Type II (fibrous, interganglionic glia) are primarily located along thick interganglionic nerve fiber tracts. They exhibit elongated, parallel processes that extend along nerve fibers without fully ensheathing them, suggesting a role in long-range structural and signaling support within enteric plexuses. Type III (extraganglionic, vascular/neuronal-associated glia) are positioned outside ganglia and interganglionic fiber bundles but within the same tissue plane. They display several major processes with secondary branching and are closely associated with small nerve fibers and blood vessels, indicating potential involvement in neurovascular and metabolic coupling. Type IV (bipolar, muscularis-associated glia) are located in the muscularis propria and are associated with thin nerve fibers. They typically exhibit two unbranched processes extending parallel to nerve fibers, suggesting a specialized role in neuromuscular regulation. Functional studies indicate that these EGC subtypes display distinct calcium signaling profiles in response to neuromodulators such as adenosine diphosphate (ADP) and cholecystokinin (CCK), supporting functional heterogeneity across intestinal regions ( Seguella et al., 2022 ). Recent transcriptomic analyses have further refined, and in part challenged, the concept of discrete enteric glial subtypes. A comprehensive single-cell study identified transcriptionally distinct mucosal and muscularis glial populations and demonstrated that TACR3 marks a specialized subset of enteric glia responsive to Neurokinin-B signaling. Tachykinin signaling was further shown to actively regulate glial diversification, indicating that enteric glial heterogeneity is not solely developmental in origin but remains dynamically regulated throughout life, and may better be described as a continuous transcriptional landscape rather than a set of discrete, fixed subtypes ( Muppirala et al., 2026 ). Consistent with this view, molecular analyses show that a substantial fraction of extraganglionic glia lack canonical markers such as glial fibrillary acidic protein (GFAP), S100β, and Sox10, pointing to dynamic transcriptional regulation rather than fixed lineage identity ( Boesmans et al., 2014 ). Developmental studies further demonstrate that Schwann cell-derived progenitors contribute differentially to specific glial subtypes during postnatal ENS maturation ( Lefèvre et al., 2023 ). Despite the extensive characterization, the functional consequences of enteric glial heterogeneity remain only partially understood. A plethora of functions have been described or postulated for subtypes I–III, including the regulation of oxidative stress ( Abdo et al., 2010 ), neuroinflammation ( Ibiza et al., 2016 ), neurogenesis ( Laranjeira et al., 2011 ; Belkind-Gerson et al., 2017 ), and gliogenesis ( Rao and Gershon, 2015 ), whereas the functions of some Type III subpopulations and Type IV cells have received comparatively little attention. Collectively, these findings support the concept that EGCs represent a highly heterogeneous and dynamically regulated cellular network with region-specific specialization and functional diversity within the ENS, though the underlying classification remains incompletely resolved. In this regard, it should be emphasized that the four-subtype classification introduced above is based primarily on morphological and topographical criteria and should not be interpreted as a definitive molecular taxonomy; the boundaries between this morphological framework and the continuous transcriptional heterogeneity described above remain to be reconciled and warrant further investigation.

Compared with the growing body of literature addressing inflammatory and oxidative stress responses in enteric glia, remarkably little is known about the direct hormonal regulation of EGC function. Nevertheless, accumulating evidence suggests that endocrine signaling represents an important but underexplored component of enteric glial biology. Sex-specific differences observed in gastrointestinal disorders, neurodegenerative diseases, and gut-brain axis dysfunction strongly suggest that hormonal signaling contributes to ENS regulation. However, whether EGCs serve merely as downstream responders or act as direct targets of hormonal signaling remains largely unresolved. Steroid Hormones: Among endocrine regulators, estrogens have received the greatest attention within the broader context of gut-brain axis physiology. Estrogen signaling influences intestinal permeability, immune responses, visceral sensitivity, and microbiota composition. In a spontaneous rat model of disorders of gut-brain interaction, estrogen was shown to directly contribute to colonic hypersensitivity in both males and females ( Accarie et al., 2022 ). Furthermore, sex-dependent differences in gastrointestinal disorders such as irritable bowel syndrome have long suggested a role for fluctuating estrogen levels in ENS regulation ( Hogan et al., 2009 ). Direct evidence linking estrogens to EGC function remains scarce. However, several observations support a potential interaction. Estrogen receptors ERα, ERβ, and GPER have been identified throughout the murine gastrointestinal tract, with receptor expression exhibiting sex-specific patterns ( Liu et al., 2019 ). Furthermore, ERβ signaling promotes proliferation and differentiation of enteric neuronal progenitor cells, enhancing the generation of both enteric neurons and glia in vitro ( D’Errico et al., 2018 ). These findings suggest that estrogen signaling may influence enteric glial development, maintenance, or plasticity, although direct mechanistic studies are currently lacking. Similar knowledge gaps exist regarding progesterone. While the neuroprotective effects of progesterone are well established in the central nervous system, relatively few studies have examined its role within the ENS. Stegemann et al. (2023) demonstrated that enteric neurons express multiple progesterone receptors, including PR-A/B, mPRα, mPRβ, and PGRMC1. In a rotenone-induced model of Parkinson-like neurotoxicity, progesterone significantly reduced neuronal cell death, with PGRMC1 acting as a key mediator of this protective effect. Likewise, Jarras et al. (2019) reported neuroprotective and anti-inflammatory actions of progesterone in the myenteric plexus of MPTP-treated mice. More recently, Kallabis et al. (2026) identified progesterone receptor expression throughout the human gastrointestinal tract and demonstrated receptor localization not only in neurons but also in Sox10- and GFAP-positive enteric glial cells. Importantly, receptor expression differed between males and females, providing some of the strongest evidence to date for direct progesterone responsiveness of human EGCs. Compared with estrogens and progesterone, even less is known about androgen signaling in enteric glia. Nevertheless, sexual dimorphism of enteric glial phenotypes has been reported, and early-life stress has been shown to induce sex-specific glial alterations in experimental models ( Gonzales et al., 2024 ). While androgen receptor signaling clearly regulates gastrointestinal motility and ENS function, current evidence suggests that these effects are primarily mediated through enteric neurons rather than glia ( Rastelli et al., 2022 ). Whether androgens directly influence enteric glial physiology remains unknown. Neurotrophic Signaling: Beyond classical steroid hormones, enteric glia both respond to and produce neurotrophic factors that are essential for ENS maintenance and repair. The physiological importance of glial-derived trophic support is highlighted by studies demonstrating that ablation of GFAP-positive enteric glia results in severe intestinal pathology and loss of gastrointestinal homeostasis ( von Boyen and Steinkamp, 2006 ). Primary cultures of rat EGCs secrete biologically relevant concentrations of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF), all of which promote neuronal survival and neurite outgrowth ( Hansebout et al., 2012 ). In the developing human ENS, neurotrophin receptors TrkA and TrkB are expressed in both enteric neurons and glia, whereas TrkC expression appears restricted to neurons ( Hoehner et al., 1996 ). Furthermore, BDNF has been shown to inhibit apoptosis of enteric glia during intestinal inflammation, suggesting a protective role in maintaining ENS integrity under pathological conditions ( Steinkamp et al., 2012 ). Similarly, inflammatory stimuli increase NGF secretion from EGCs, linking neurotrophic signaling to inflammatory adaptation and visceral sensitivity ( von Boyen and Steinkamp, 2006 ). Taken together, current evidence supports the concept that enteric glia participate in endocrine and neurotrophic signaling networks that influence ENS homeostasis, stress adaptation, and potentially regenerative responses (summarized in Table 3 ). However, direct mechanistic studies remain surprisingly limited. Most available data derive from neuronal analyses, animal models, or indirect observations, whereas investigations specifically targeting EGCs are rare. Consequently, it remains unclear whether hormonal signaling directly regulates enteric glial phenotype, stress responsiveness, and progenitor potential or whether these effects occur secondarily through neuronal or immune pathways. Hormonal regulation of enteric glial cells. Addressing these questions represents an important challenge for future research. Given the established influence of hormones on neuroinflammation, cellular plasticity, and regeneration in other nervous systems, hormonal regulation of enteric glia may represent a previously underappreciated mechanism linking sex, aging, stress, and GBA function.