The enteric nervous system (ENS) is a network of neurons and glia that controls ongoing gastrointestinal (GI) functions. Damage or injury to the ENS can lead to functional GI disorders. Current data support the conclusion that many functional GI disorders are caused by an imbalance between gut microbes and the immune system, but how the ENS is involved in these interactions is less understood. Because of the proximity of the ENS to bacteria and other foreign antigens in the GI tract, it is important to prevent the passage of these antigens through the GI epithelium. If any foreign compounds manage to pass through the GI epithelium, an immune response is triggered to prevent injury to the ENS and underlying structures. However, careful modulation of the inflammatory response is required to allow for adequate elimination of foreign antigens while avoiding inappropriate overactivation of the immune system as in autoimmune disorders. Enteric neurons and glial cells are capable of performing these immunomodulatory functions to provide adequate protection to the ENS. We review recent studies examining the interactions between the ENS and the immune system, with specific focus on enteric glial cells and their ability to modulate inflammation in the ENS.
the enteric nervous system (ENS) is the largest division of the autonomic nervous system and it is housed entirely within the walls of the gastrointestinal (GI) tract. Neural reflexes mediated through the ENS are responsible for coordinating most ongoing activities of the GI tract, such as patterns of motility, secretions, and local blood flow. Like the brain, the ENS is composed of neurons and glial cells that are housed within ganglia in two ganglionated plexuses. The neural circuitry in the submucosal plexus is responsible for coordinating gut secretions, absorption, and local blood flow, while the myenteric plexus is primarily responsible for coordinating contractions and relaxations of gut smooth muscle involved in patterns of gut motility. Proper orchestration of GI functions requires that both plexuses are intact and maintain healthy interactions with target cells. Injuries inflicted on the ENS during local inflammation disrupt the functional connectivity of enteric neural networks and create long-lasting changes in ENS function (13). These changes in the local control of gut reflexes contribute to a broad range of common functional GI disorders, such as irritable bowel syndrome and functional constipation, and contribute to persistent intestinal dysmotility during remission in inflammatory bowel disease (IBD).
Clearly, cells within the innate and adaptive arms of the immune system are the main drivers of gut inflammation. In general, inflammation is a protective response to invading pathogens that evade the first line of defense posed by the intestinal epithelial barrier and defects in the balanced immune response to intestinal bacteria represent a major contributing factor to gut disease. The acute inflammatory response predominantly involves recruitment and activation of the innate arm of the immune system (29) while chronic inflammation involves both innate and adaptive components. An overly aggressive adaptive immune response can attack native antigens in the gut and contribute to the development of inflammation (27). Current animal models used to study bowel inflammation are based on these principles and act to increase epithelial permeability, such as the dextran sodium sulfate colitis model, or to enhance T cell stimulation, such as the trinitrobenzene sulfonic acid (TNBS), dinitrobenzene sulfonic acid, oxazolone, T cell adoptive transfer, and interleukin (IL)-10 knockout models (37). The understanding of the immune response in colitis is becoming increasingly refined and has led to many important breakthroughs in therapies. However, how inflammation produces long-lasting changes in gut function through effects on the ENS is still poorly understood. New data suggest that bidirectional interactions between cells in the ENS and immune cells may actively participate in the modulation of inflammatory responses. Here, we provide a short review of recent studies that highlight potential roles for the ENS in the regulation of gut inflammation and, in particular, focus on the key roles of enteric glial cells.
Contribution of Enteric Neurons to Inflammation
Many immunomodulatory effects of the parasympathetic and sympathetic branches of the autonomic nervous system have emerged in recent years and the general picture is that vagal parasympathetic innervation is anti-inflammatory while α-adrenergic sympathetic innervation is proinflammatory (6, 10). However, far less is known about how intrinsic enteric neurons influence immune responses in the gut. The current evidence strongly suggests that enteric neurons have major immunomodulatory capabilities. The relative contributions of direct neuron-immune cell communication and indirect communication via intermediary cells, such as enteric glia, are largely unknown. It is likely that many neuroimmune interactions at the ganglionic interface are mediated through enteric glia because enteric glia delineate the boundaries of enteric ganglia and largely surround enteric neuron cell bodies. However, neuronal processes extending outside the ganglia have a high potential for direct interactions with various immune cells. The capacity of neurons to influence immune responses through both direct and indirect pathways likely accounts for the observation that enteric neuron number and density influence intestinal inflammation (47). Margolis et al. found that transgenic mice with a hyperplastic ENS and higher density of enteric neurons developed greater colonic inflammation when exposed to TNBS than wild-type animals (47). These results must be interpreted with caution since the genetic mutation in this model could affect the development of numerous systems that could contribute to disease susceptibility. However, the fact that this study used a transgenic animal model characterized by high neuronal density before administration of TNBS strongly suggests that neuronal hyperplasia is not merely a response to induced colonic inflammation but could, in fact, be a risk factor for the development of colitis. These findings are particularly interesting in light of the discovery that enteric glia kill a significant portion of neurons during acute inflammation (14). Given the proinflammatory effect of enteric neurons, it is tempting to speculate that glia-driven neurodegeneration functions to protect against the neuronal potentiation of inflammation, but this concept remains unproven.
How higher numbers of enteric neurons translate to worsening inflammation is not immediately clear but likely occurs through the neuronal release of cytokines and neurotransmitters/neuromodulators. For example, enteric neurons from patients with Crohn’s disease demonstrate high expression of proinflammatory prostaglandin D2 (43). Enteric neurons are also capable of secreting leukocyte chemoattractive factors that include tumor necrosis factor-α (TNF-α), IL-6, monocyte chemoattractant protein-1, and, possibly, IL-8, when challenged with pathogenic bacteria (15, 60) (Fig. 1). Interestingly, enteric neurons do not increase their secretion of these chemoattractive factors in response to gram-positive bacteria, despite the ability of gram-positive and gram-negative bacteria to activate NF-κB signal transduction pathways in neurons (15). This may be achieved through the effects of concurrent Wnt signaling within enteric neurons because stimulation of the Wnt pathway in the presence of LPS confers an anti-inflammatory phenotype in enteric neurons in vitro (40) (Fig. 1). These findings suggest that neurons are capable of differentiating between beneficial and harmful bacteria and participate in defensive responses to clear potentially pathogenic species. However, the inherent ability of neurons to recruit leukocytes could be potentially detrimental when additional neurons are present and may contribute to enteric ganglionitis. Although untested at this point, aberrant neuronal chemoattractant secretion under these conditions could be an important mechanism that contributes to a proinflammatory environment and a predisposition to GI disease.
In addition to their proinflammatory potential, enteric neurons may also contribute to anti-inflammatory effects via the synthesis and secretion of factors such as netrin-1. Netrin-1 is typically known for its role in neuronal development but its expression is also induced during hypoxia-induced tissue damage (59) and the secretion of this molecule can induce angiogenesis, activate tissue stem cells, and bind neutrophil cell surface receptors such as A2B-adenosine receptors (3, 35). The main effect of netrin-1 on neutrophils is to inhibit their migration and accumulation and netrin-1 may induce an egress from the source of netrin-1 (3). As such, enteric neurons could theoretically synthesize and secrete netrin-1 in response to inflammatory damage for neuronal survival and promote regeneration, and a loss in netrin-1 secretion could theoretically contribute to inappropriate leukocyte recruitment (4) (Fig. 1). However, other major sources of netrin-1 in the GI system include the colonic epithelium. Therefore, further studies are required to elucidate the extent to which the ENS contributes to netrin-induced anti-inflammatory effects.
Although activation of the Wnt pathway and secretion of prostaglandin D2 can induce inflammation, they can also inhibit the progression of inflammation. As described earlier, activation of the Wnt pathway with a concurrent LPS costimulatory signal on enteric neurons causes anti-inflammatory effects via the release of IL-10 (40). Neuronal prostaglandin D2 can be metabolized into 15-deoxy-Δ12,14-prostaglandin J2, an anti-inflammatory compound (43). The dual functioning of the Wnt pathway and prostaglandin release suggests that enteric neurons may be important for the selective activation and “fine-tuning” of inflammatory responses in the ENS. In addition to cytokines and chemokines, neurotransmitters in the ENS such as ATP, acetylcholine, norepinephrine, vasoactive intestinal peptide (VIP), neuropeptide Y, calcitonin gene-related peptide, substance P, and serotonin can modulate the activities of intestinal leukocytes (1, 28, 33, 48) (Fig. 1). These neurotransmitters yield both pro- and anti-inflammatory effects and likely have a major influence on inflammatory processes in the ENS. In a recent review, Margolis and Gershon provide an excellent summary of the roles of several neurotransmitters in the regulation of intestinal inflammation (46). To summarize, the ability of immune cells to interact with neurotransmitters suggests a close relationship and frequent communication between enteric neurons and the immune system.
In addition to their direct action on immune cells, these neurotransmitters can act on intestinal mucosa and alter epithelial barrier permeability. For example, in vitro experiments demonstrate that neuropeptide Y increases the epithelial barrier permeability and exposes the ENS to potential pathogens (17), whereas cholinergic and VIPergic signaling maintains barrier integrity and decreases permeability (18, 38, 55) (Fig. 1). Control of intestinal epithelial barrier function and exposure of the ENS to potential pathogens can modulate the inflammatory state of the ENS. This may represent an indirect means by which enteric neurons exert their influence on the immune system, further reinforcing the involvement of the ENS in immunomodulation.
Glia in the Healthy Intestine
Enteric glial cells are historically regarded as a network of cells that establish the homeostatic environment within enteric ganglia and function to provide structural and nutritional support for enteric neurons. They are found primarily in the submucosal and myenteric plexuses of the ENS but they are also present outside the ENS in the muscularis and in the mucosal lamina propria. Enteric glia are a heterogeneous group of cells that can be subdivided into several types based on morphology and expression profiling (8, 56). These glial cell subtypes respond differently to purinergic signaling, suggesting activation of different glial subtypes in varying situations. However, specific roles for the distinct glial populations have yet to be elucidated. Beyond structural and nutritional support, subsets of enteric glial cells also exert influence over other nearby cells of the GI tract and have local immunomodulatory effects. These functions largely resemble those of astrocytes in the central nervous system (CNS) and it is thought that certain groups of enteric glia fulfill astrocyte-like roles in the ENS.
The relationship between enteric neurons and enteric glial cells begins early and new data show that glial cells are necessary for the proper maturation of neurons in the ENS (7). Glial cell guidance of neuronal development occurs through purinergic signaling between the two cell types and impaired signaling can lead to decreased enteric neuron density and complexity (7). Purinergic signaling between enteric glia and neurons continues into adulthood and plays an important role in neural circuits that coordinate GI motility (32, 50, 51). These exciting discoveries suggest that alterations in purinergic intercellular signaling between neurons and glia could contribute to gut dysfunction by impairing the development and maturation of enteric neurons or by altering neuronal activity. Consistent with these discoveries, impairment of glial purinergic signaling in adult mice hinders coordinated contractions of the GI tract and slows colonic transit time (51).
Mucosal enteric glial cells also interact with nonneuronal cells such as enterocytes and enteroendocrine cells that are important in the maintenance of GI homeostasis. Glial cells influence the development and maturation of enterocytes and these roles contribute to the maintenance of an intact GI epithelial barrier (52). Less is known about mucosal glia-enteroendocrine interactions but specialized connections between the two cell types suggest that glia may have the potential to influence GI hormone release (9). The fundamental roles of barrier regulation and hormone release in GI physiology suggest that defective interactions between enteric glia and enterocytes or enteroendocrine cells could contribute to GI inflammation and possibly even metabolic diseases such as diabetes and obesity (9, 65).
Glial Cells Are Activated by Cytokines and Immunomodulatory Signals
The ability of enteric glial cells to respond to immunomodulatory signals such as cytokines, bacteria, and neurotransmitters in the extracellular milieu suggests that glia mediate a significant amount of the cross talk between the ENS and the immune system. For example, glial cells can detect local levels of the proinflammatory cytokines IL-1, IL-4, and TNF-α (12) (Fig. 2). Binding of these cytokines can elicit glial cell activation similar to reactive gliosis in the CNS, and contribute to inflammation and GI dysfunction (61). Similarly, the activation of glial Toll-like receptors 2 and 4 by LPS and other bacterial components drives proinflammatory pathways that are important in the protective response against bacteria that successfully bypass the gut epithelial barrier (58, 62). Eposito et al. demonstrated that LPS-activated glial cells play a crucial role in the creation of a robust inflammatory response in the local ENS environment and that inhibition of the NF-κB pathway in glia can effectively ameliorate colonic inflammation in mice and cultured human biopsies (23). However, LPS-activated cultured human glia can also increase transcription of growth factors and several anti-inflammatory genes (41). This paradoxical elevation of the transcription of growth factors and anti-inflammatory genes with simultaneous expression of proinflammatory genes hints at a complex regulation of expression that likely involves negative-feedback pathways. Interestingly, Turco et al. showed that cultured human enteric glial cells are able to distinguish pathogenic from probiotic bacteria and modulate their expression of Toll-like receptors accordingly (62). Similarly, di Liddo et al. showed that exposure of mixed cultures of rat enteric neurons and glia to a combination of LPS and Wnt3a induces the secretion of anti-inflammatory agents and inhibits NF-κB activity in vitro (40). These findings suggest that the glial response to bacterial components in the ENS and the decision of whether to undertake pro- or anti-inflammatory pathways depend on the identity of the bacteria and which signaling molecules are being coexpressed.
Purines are a major component of the “inflammatory soup” generated during tissue injury and purines contribute to the pathophysiology of many inflammatory diseases of the intestine. Enteric glia are highly responsive to purines and express receptors for ATP and derivatives such as ADP and adenosine. The glial response to ADP through the activation of P2Y1 receptors is the most well characterized and is involved in the coordination of neural circuits and the promotion of neuronal maturation under normal conditions (7, 50, 51). However, glial P2Y1 receptors also play an important role in the glial response to neuronal danger cues released during inflammation, and the activation of glia in this context causes neurodegeneration (14). The cause of the vastly different glial responses to P2Y1 receptor activation appears to primarily involve the influence of proinflammatory mediators, such as nitric oxide, on downstream effectors that include connexin-43 hemichannels (14). Therefore, the response of glia to purinergic agonists depends heavily on the context in which they are activated. How the activation of glia by other purines influences their response to inflammation is much less clear. For example, cultured human enteric glia express adenosine receptors that primarily couple to intracellular signal transduction pathways that utilize cAMP (41). Given the potent anti-inflammatory effect of adenosine in the gut, it is likely that adenosine has similar anti-inflammatory actions on glia but how the activation of glia by adenosine influences gut physiology and pathophysiology is unknown.
Finally, enteric glial cells are innervated by both sympathetic and parasympathetic neurons of the autonomic nervous system (31, 63) (Fig. 2). Stimulation of glial cells via parasympathetic vagal innervation confers an anti-inflammatory and neuroprotective effect, similar to the effects of parasympathetic vagal stimulation on intestinal macrophages (48). Specifically, the activation of glial cholinergic receptors in vitro promotes increased epithelial barrier function and inhibits the transcription of the proinflammatory factor NF-κB (18). These findings support previous data showing that the beneficial effects of vagal nerve stimulation on the intestinal epithelium following burn injuries are mediated through effects on enteric glia (21). Conversely, sympathetic-mediated glia activation occurs through purinergic (31) and noradrenergic (54) signaling. As noted above, the activation of glia by ATP may contribute to a proinflammatory phenotype but how the activation of glia by norepinephrine influences glia is not known.
In summary, glia respond to a diverse array of immunomodulatory mediators that include proinflammatory cytokines, bacterial compounds, purines, and transmitters from the autonomic nervous system. Activated glial cells exhibit some characteristics similar to astrocytes undergoing reactive astrogliosis in the CNS such as an increase in calcium influx and signaling and an increase in glial acidic fibrillary protein or S100β expression (12, 18, 41). However, glial activation is context-specific and the outcome response of glia depends on integrative processing of all cues available at that particular time.
Glia Express and Secrete Cytokines and Proinflammatory Signals
Mounting evidence in recent years suggests that glial cells are not idle bystanders during injury and inflammation in the ENS. This evidence shows that, when activated, glia can contribute to a proinflammatory environment by secreting cytokines and other immunomodulatory signals. For example, one response of glia that are activated by inflammatory cues in the gut includes alterations in their morphology and expression and/or secretion of key proteins such as S100β and glial fibrillary acidic protein, similar to the process of reactive astrogliosis in the CNS (57). Increased secretion of S100β by glia contributes to inflammation by activating receptors for advanced glycation end products. This in turn leads to production of nitric oxide by inducible nitric oxide synthase, formation of reactive oxygen species, increased oxidative stress in the local environment, and neuronal damage in ex vivo and in vitro studies (22, 41, 45, 62). It is important to note that extracellular concentrations of S100β in the micromolar range are needed for proinflammatory effects and that basal S100β secretion in the nanomolar range yields neuroprotective effects (22) (Fig. 2). Interestingly, despite an increase in local S100β during inflammation of the GI tract, Celikbilek et al. show a counterintuitive decrease in serum levels of S100β in patients with ulcerative colitis (16), possibly due to damaged enteric glial cells secreting reduced S100β as a result of exposure to prolonged inflammatory stress. Serum S100β levels over time in IBD may show fluctuations depending on glial cell viability and may prove useful in determining chronicity of inflammation. The stimuli for glial S100β release are incompletely understood but include Toll-like receptor agonists (62) and also likely include purinergic signaling. Glial activation by purines during inflammation involves pathways similar to S100β such as inducible nitric oxide synthase and the release of ATP from activated glial cells (14). Glial S100β and ATP release have neurotoxic effects on enteric neurons and these mediators are key drivers of ENS damage during acute inflammation in vivo (14, 22) (Fig. 2).
The glial secretion of cytokines and chemokines is of specific interest among the repertoire of compounds secreted by enteric glia because of their direct immunologic effects. Specifically, recent in vivo and in vitro studies demonstrate that glia secrete a number of cytokines and chemokines including interferon-γ (IFN-γ), chemokine ligand 20, TNF-α, and prostaglandin D2 (25, 43, 58) (Fig. 2). However, conflicting data both support and refute the concept that enteric glia secrete TNF-α. Coquenlorge et al. showed that glial cell cultures are unable to secrete TNF-α even when stimulated with LPS (20). They concluded that TNF-α in the ENS originates from enteric neurons and not from glia. In contrast, Guedia et al. found that enteric glial cell lines are capable of secreting TNF-α when stimulated with LPS and that the effect is further enhanced when the cells are exposed to Tat protein derived from HIV (30). These conflicting results might suggest that multiple pathways can converge to induce inflammation and that there are various regulatory systems in place to restrict inappropriate inflammatory activation. Once activated, the glial secretion of cytokines and chemokines likely plays an important role in the activation and recruitment of immune cells and modulates inflammation. Beyond IFN-γ, chemokine ligand 20, and TNF-α, numerous other proinflammatory cytokines and chemokines undergo transcriptional changes in activated enteric glia in culture. However, detectable protein secretion of these compounds has not been measured from activated glia (41, 58).
Glial Cells Act as Antigen-Presenting Cells
The many similarities between enteric glial cells and astrocytes hint that enteric glia, like astrocytes, may function as antigen-presenting cells. New data show that enteric glia have phagocytic capabilities because glia transplanted from the ENS into the brain are capable of degrading preformed β-amyloid plaques in a manner similar to resident astrocytes (24, 64). In vivo and in vitro studies demonstrate that human enteric glial cells from the myenteric and submucosal plexuses are also capable of expressing major histocompatibility complex II molecules, especially after exposure to bacteria or parasites (5, 26, 62). In addition, enteric glia in patients with megacolon due to Chagas disease express the T cell costimulatory molecule cluster of differentiation (CD) 80 and CD86 on their cell surface (5). Together, these data show that enteric glia have the ability to engulf and, subsequently, present antigens to innate and adaptive immune cells and hint that enteric glial antigen presentation may play an important role at the neuroimmune interface. The role of glial antigen presentation in the gut is not understood but it could theoretically function to prime the adaptive immune system to bacteria in the ENS. By the same token, it would be possible for enteric glia to present neuronal debris to the adaptive immune system, thereby triggering enteric ganglionitis and an autoreactive immune response against ENS neurons similar to that in multiple sclerosis (44).
Enteric Glia Exert Immunosuppressive and Anti-Inflammatory Effects
Consistent with the notion that glial cells play a neuroprotective role to maintain homeostasis, there is increasing evidence that glial cells are capable of immunosuppression and anti-inflammatory actions. These anti-inflammatory effects are controlled, in part, by the release of soluble glial compounds. Of specific interest are glia-related peptides and lipids including glial-derived neurotrophic factor (GDNF), glial-derived S-nitrosoglutathione (GSNO), and 15-deoxy-Δ12,14-prostaglandin J2 because these compounds have beneficial effects on intestinal epithelial permeability, inflammation, and neuron survival (2, 19, 34, 65) (Fig. 2). GDNF signals through the RET receptor and GDNF family receptor-α (GFRα) on innate immune cells and enterocytes of the gut to decrease expression of proinflammatory cytokines and help maintain and strengthen the intestinal epithelial barrier, respectively (34, 52, 65). Specifically, Ibiza et al. demonstrated via in vivo and in vitro mouse studies that ligands from the GDNF family act on type 3 innate lymphoid cells, leading to release of anti-inflammatory IL-22 and increased expression of repair genes in the gut epithelium (34). In addition, RET and GFRα expression has been demonstrated in B lymphocytes and CD4+ and CD8+ T lymphocytes (53) but the direct effects of GDNF on these cells have yet to be described. Recent studies with cultured human enteric glial cells derived from the myenteric plexus suggest that GDNF contributes to the inhibition of proliferation by previously activated CD8− and CD8+ T lymphocytes. However, it seems that direct cell-to-cell interactions, as opposed to secreted compounds, play a larger role in preventing T lymphocyte proliferation (36). Furthermore, Kermarrec et al. showed a greater immunosuppressant effect of enteric glia from patients with Crohn’s disease than control glia, suggesting that activated glial cells play an important role in immunomodulation (36). Similarly, von Boyen et al. reported increased glial fibrillary acidic protein and GDNF expression in activated mucosal glial cells from patients with Crohn’s disease (11). They further showed that proinflammatory cytokines are an effective stimulus for GDNF secretion in vitro (11). Together, the effects of GDNF contribute to an anti-inflammatory phenotype to reduce epithelial damage, prevent neuronal loss, suppress activated T lymphocytes, and improve gut function, potentially as a negative-feedback mechanism to limit the damage due to inflammation and proinflammatory cytokines (11, 36, 42) (Fig. 2). Similar to the actions of GDNF, in vitro and in vivo studies show that GSNO acts to promote a robust permeability barrier in the intestinal epithelium. This is achieved by induction of increased expression of zonula occludens-1 and occludin protein to form more tight junctions in the epithelium (19, 39). In addition, GSNO provides anti-inflammatory effects via the inhibition of NF-κB pathways that promote the expression of proinflammatory agents (39). Finally, secretion of 15-deoxy-Δ12,14-prostaglandin J2 from cultured rat myenteric glia elicits neuroprotective effects through the transcription factor nuclear factor erythroid 2-related factor 2 pathway, leading to neuronal synthesis of glutathione in vitro (2). Therefore, enteric glia can effectively modulate and control the extent of local inflammation and shift the local ENS environment back to homeostasis.
Enteric glial cells have gained increasing attention because of their diverse emerging roles in the modulation of gut health and disease. Increasing evidence supports the idea of cross talk between glial cells and enterocytes, neurons, and immune cells. Specifically, activated glial cells play a substantial role in the progression and inhibition of inflammation in the ENS. The seemingly contradictory actions may be due to the amount of secretion and extracellular concentration of glial products, as seen in S100β secretion, or the signaling pathway by which glial cells are activated, as demonstrated by cholinergic-induced vs. cytokine-induced activation. Regulation of glial activation has not been well studied but may give insights into the specific contexts by which certain activation pathways are chosen to yield either pro- or anti-inflammatory effects in the ENS. Furthermore, various pro- and anti-inflammatory genes are transcribed in parallel, although many upregulated genes never reach translation and expression. This suggests potentially complex expression regulation and self-regulation of enteric glial cells, to an extent, via negative feedback.
The possible phagocytic ability of enteric glia, along with their ability to induce oxidative stress in their local environment and secretion of cytokines, likens enteric glial cells to astrocytes and the innate immune system. Their ability to express major histocompatibility complex II and T cell costimulatory molecules suggests that glia play an important role in antigen presentation to T cells. Furthermore, the ability of enteric glial cells to modulate inflammation and immune activation shows that glia serve as an important mediator of neuroimmune interactions. An understanding of the specific contribution of glia to ENS injury and neuronal viability will offer important new insight into the pathogenesis of inflammatory and functional GI disorders.
This project was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK-103723 (to B. D. Gulbransen) and a Crohn’s and Colitis Foundation of America Senior Research Award (327058 to B. D. Gulbransen).
No conflicts of interest, financial or otherwise, are declared by the authors.
A.K.C. drafted the manuscript under the guidance of B.D.G; A.K.C. and B.D.G. reviewed and edited the manuscript; A.K.C. and B.D.G. approved the final version of the manuscript.
↵1 This article was invited as part of a series highlighting AJPGI-sponsored researchers at Experimental Biology 2016: San Diego, CA.
- Copyright © 2017 the American Physiological Society