Neuroimmunology of the gut: physiology, pathology, and pharmacology

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It has been increasingly appreciated that an intimate interaction between cells of the nervous and immune systems takes place in the gut, and may have a role in diverse inflammatory disorders. Thus, for instance, activation of the enteric nervous system may reduce intestinal epithelial permeability, via several mediators including S-nitrosoglutathione and vasoactive intestinal peptide (VIP). Moreover, ablation of glial cells instigated enterocolitis in murine models. These neuronal effects are particularly intriguing given our current understanding of the immunopathogenesis of Crohn's disease, in which intestinal barrier defect is suspected to at least partly drive the immune hyper-reactivity and ensuing inflammation. Parasympathetic nicotinic signaling, primarily via nicotinic acetylcholine receptor alpha7 (α7 nACHr), also exerts immunomodulatory effects, possibily underlaying the detrimental effects of smoking on Chron's disease, and its beneficial impact on ulcerative colitis. These, and others, neuro-immune interactions may pave the way to the design of novel therapeutic agents for the treatment of chronic inflammatory bowel disorders.

Introduction

The immune system plays a dominant role in diverse inflammatory disorders of the intestine, such as Crohn's disease (CD), ulcerative colitis, and celiac disease. The enteric nervous system (ENS) controls or modulates several important gut functions including, but not restricted to, peristalsis, fluid secretion, and the digestive processes. In recent years, an intricate interplay between the ENS and the intestinal immune system is increasingly appreciated. This research opens up new avenues for exploring potential pharmacological agents for treating inflammatory gut diseases. A comprehensive elaboration of this rapidly evolving field is beyond the scope of this concise review. Thus, we will not dwell on effects of inflammation on the ENS nor on neuro-endocrine effects on inflammatory processes. Rather, we will focus on how the ENS per se may modulate immune processes underlying chronic inflammatory disorders of the gut, as well as on related pharmacological agents investigated for a therapeutic potential in treating inflammatory diseases.

Section snippets

Anatomical considerations  immune system

The multitude of immune cells in the intestine is conveniently grouped under the term gastrointestinal-associated lymphoid tissue (GALT). Anatomically and functionally, the GALT is composed of scattered immune cells in the intestinal epithelium and the lamina propria, and of more organized structures in the gut wall. The latter consist of mesenteric lymph nodes (MLNs), Peyer patches (PPs), isolated lymphoid follicles (ILFs), and cryptopatches (CPs).

The diffusely scattered intraepithelial

Anatomical considerations  the nervous system

The abdominal viscera are innervated by sympathetic fibers arising from corresponding spinal nerves, and by parasympathetic fibers via the vagus nerve. The vagus also conveys afferent nerves from abdominal organs. The ENS is composed of three ganglionated plexuses, namely, the myenteric Aurebach plexus in the muscular layer of the gut, the submucosal Meissner plexus, and the mucus plexus innervating the mucosa [5]. Additional aganglionated plexuses innervating all the intestinal wall layers are

Neuro-immune crosstalk in the gut: epithelial barrier function

Inasmuch the gut is exposed to a myriad of potentially offensive pathogens and noxious dietary and environmental constituents, several immune and nonimmune, defense mechanisms have evolved to fence off these continuous luminal threats. These mechanisms include the intestinal epithelial barrier, gut motility, and the immune surveillance practiced by diverse populations of intestinal immunocytes.

The integrity of the intestinal epithelial barrier is paramount to the defense against invasion of

Neuro-immune crosstalk in the gut: intestinal motility

Intestinal motility is known to be regulated by the ENS. However, it is important to note that intact gut motility is also an additional mechanism of defense against potentially harmful luminal bacteria. In a novel study, Li and coworkers have shown that neuronal NO-synthase, but not the epithelial inducible NO-synthase, is essential for clearing infection with the parasite Giardia lamblia through increasing intestinal motility [21]. This observation may promote the hypothesis that deranged ENS

Neuro-immune crosstalk in the gut: cellular function of immunocytes

As noted, a fine balance exists between the chronic activation state of functional immune cells in the intestine and regulatory mechanisms that keep this low-grade inflammation controlled. The rate of immune cells migration into the gut, the secretion of cytokines and chemokines, and the proliferation and activation status of specific cell populations are the main determinants of this low-grade inflammatory state. Notably, evidence is mounting that these factors can be modulated by signals

The inflammatory bowel diseases  clinical and morphologic features

Despite the potent and protean interaction of the nervous system with the intestinal tract, few examples of pharmacological therapy for intestinal disorders based on this interaction are available. These therapeutic approaches have been most widely tested in IBDs, which are a cause of significant, often life-long, morbidity for patients. The two main forms of IBD are CD and UC. Although the pathogenesis of both diseases involves uncontrolled inflammation, the primary cause of which is unknown,

Therapeutic implications of neuro-immune interaction in IBD  the case of nicotine

Interestingly, although both CD and UC appear to respond to similar immune suppressing therapies, marked differences are notable in some of their epidemiological and environmental associations. One such difference is the association of disease with smoking. Smoking is considered to have an adverse effect on the clinical course of CD rendering the disease more aggressive. In addition, increased incidence of CD among smokers compared to nonsmokers (odds ratio of 2) was documented by several

Therapeutic implications of neuro-immune interaction in IBD  the case of local anesthetics

Another attempt of pharmacological therapy that may be based on the neuro-immunological interaction is the treatment of UC by local anesthetics.

Some trials demonstrated efficacy of local anesthetics following their rectal administration [50, 51]. In addition, a recent case report demonstrated clinical response and resolution of pain in a UC patient following systemic administration of lidocaine followed by mexilentine therapy [52]. These effects prompted studies in animal models in which the

Conclusion

From the above review it is apparent that there is a growing body of experimental evidence demonstrating potent and diverse neuroimmunomodulatory effects in the GI tract. Coupled with an unmet need for safe and effective therapeutic regimens for the down-regulation of the intestinal immune system, these interactions provide a stimulating opportunity for a novel approach toward rational drug design expanding the therapeutic armamentarium.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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