Neuroimmunology of the gut: physiology, pathology, and pharmacology
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
References (55)
- et al.
Apposition of enteric nerve fibers to plasma cells and immunoblasts in the mouse small bowel
Neurosci Lett
(1998) - et al.
Glial-derived neurotrophic factor regulates apoptosis in colonic epithelial cells
Gastroenterology
(2003) - et al.
Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione
Gastroenterology
(2007) - et al.
Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn's disease?
Proc Natl Acad Sci U S A
(2001) - et al.
The value of myenteric plexitis to predict early postoperative Crohn's disease recurrence
Gastroenterology
(2006) A meta-analysis of the role of smoking in inflammatory bowel disease
Dig Dis Sci
(1989)- et al.
The effect of nicotine in vitro on the integrity of tight junctions in Caco-2 cell monolayers
Food Chem Toxicol
(2007) - et al.
The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation
Br J Pharmacol
(2007) - et al.
Smoking and ulcerative colitis
Br Med J (Clin Res Ed)
(1984) - et al.
Steroid-sparing effect of transdermal nicotine in ulcerative colitis
J Clin Gastroenterol
(1994)