Contributions of Intestinal Stress Peptides to Inflammation and Motility

COMMENTARY

The stressed gut: Contributions of intestinal stress peptides to inflammation and motility

Nigel W. Bunnett* Departments of Surgery and Physiology, University of California, 521 Parnassus Avenue, Room C317, San Francisco, CA 94143-0660

ost of us have experienced at first hand the effects of stress on our digestive systems. As early as 1833, BeaumontM (1) described that fear and anger influenced acid secretion from the stomach of his patient Alexis St. Martin, a Canadian trapper with a permanent gastric fistula caused by a gunshot wound. The impact of psychological, physical, and immunological stressors on gastrointestinal secretion, motility, epithelial permeability, and inflammation is now thoroughly documented, and stress has a major influence on digestive diseases (refs. 2–4 and references therein). Most studies concern central mechanisms whereby a stressful event per- ceived by the brain triggers neuronal and hormonal reflexes that influence the gut. However, a report by la Fleur et al. in this issue of PNAS (5) makes the Fig. 1. Stress-induced alterations in gastrointestinal functions. Central stressors induce release of CRF, exciting observation that the intestine ACTH, and glucocorticoids, which have antiinﬂammatory actions. Centrally released CRF and Ucns activate produces the same stress peptides that parasympathetic nerves, which in turn innervates enteric neurons within the gut wall to stimulate or are present in the central nervous sys- inhibit motility (depending on the region) and stimulate secretion. Peripheral stressors induce local release tem. A local stressor, in this case a bac- of CRF and Ucns, possibly from enteric neurons and immune cells. Peripherally derived CRF may act on terial toxin that is the principal cause of enteric nerves, mast cells, and enterocytes to induce inﬂammation and control motility and secretion. antibiotic-induced colitis and diarrhea, results in the local generation and action of stress peptides that mediate inflam- behavior, and gastrointestinal functions. One of the obstacles to determining mation without involving the central During stress, CRF from the hypothala- the specific role of gut-derived CRF and nervous system (Fig. 1). These peptides mus stimulates secretion of adrenocorti- Ucns is the difficulty of selectively an- also regulate the transit of digested cotrophic hormone (ACTH) from the tagonizing these peptides within the in- material through the intestine under pituitary, which in turn releases glu- testinal wall. When injected centrally or normal conditions. This intrinsic stress cocorticoids from the adrenal gland. systemically, agonists or antagonists response mechanism may mediate al- CRF is thus a crucial link in the hypo- could affect many cell types expressing tered digestive processes that accom- thalamic–pituitary–adrenal axis that me- CRF-Rs, and the generation of mice pany physical and chemical insults to the diates neuroendocrine stress responses that lack CRF, Ucns, or their receptors intestine and could contribute to poorly (Fig. 1). Central CRF and Ucns also in particular populations of intestinal understood disorders, such as inflamma- control activity of autonomic nerves and cells is a daunting task. To circumvent tory bowel disease and irritable bowel thereby mediate the effects of central these difficulties, la Fleur et al. (5) used syndrome, for which stress exacerbates stressors on gastrointestinal motility and RNA interference (RNAi) to silence the the symptoms. secretion (Fig. 1). However, the gut has expression of CRF and UcnII. RNAi The study focuses on the corticotrop- its own nervous system, the enteric ner- depends on the cellular uptake and in-releasing factor (CRF) and urocortin vous system or “little brain,” which can processing of double-stranded RNA (Ucn) family of neuropeptides (reviewed regulate gastrointestinal functions inde- (dsRNA) into small interfering RNAs in refs. 3, 4, and 6). CRF and UcnI, -II, pendently of central control. Enteric (siRNAs) of 21–23 nt by the RNase III and -III are structurally related peptides nerves and other cells in the gut express enzyme Dicer. siRNAs pair with cog- that interact with two CRF receptors CRF, Ucns, and their receptors, al- nate mRNA, resulting in degradation (CRF-Rs). CRF preferentially interacts though in some cases the precise sites and gene silencing (7). Injection of long with CRF-R1 over CRF-R2, UcnII in- remain to be determined. Systemically sequences of CRF or UcnII dsRNA into teracts similarly with both receptors, and administered CRF and Ucns also affect the wall of the rat ileum led to a promi- UcnII and UcnIII interact only with gastrointestinal motility and mucosal nent down-regulation of peptide and CRF-R2. These peptides and their re- functions presumably by activating re- mRNA within 4–6 days. The down- ceptors are expressed in distinct regions ceptors in the gut wall. Because the of the brain, where they mediate the intestine expresses stress peptides and effects of psychological, physical, and receptors, could an intrinsic stress re- See companion article on page 7647. immunological stressors on hormonal sponse system mediate the effects of *E-mail: [email protected]. responses, anxiety, mood, feeding local stressors on the digestive tract? © 2005 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0503092102 PNAS ͉ May 24, 2005 ͉ vol. 102 ͉ no. 21 ͉ 7409–7410 Downloaded by guest on September 24, 2021 regulation was tissue-specific, being con- inflammatory because of the release silencing of CRF-R1 and CRF-R2 by fined to the ileum, and circulating levels of glucocorticoids, enteric CRF is RNAi could identify the functionally of corticosterone were unchanged, con- proinflammatory but by unknown mech- important receptors. One CRF target firming a lack of effect on central CRF. anisms. To study motility, the investiga- could be enteric nerves containing the A potential drawback is that long tors monitored the excretion of fecal neuropeptide substance P, an essential dsRNA can induce an IFN response and pellets and measured the transit of a mediator of toxin A ileitis (12). CRF exert nonspecific effects. However, CRF dye through the uninflamed intestine and substance P colocalize in ileal and UcnII dsRNA were specific for the (5). Silencing of ileal CRF increased the nerves, and CRF deletion prevents toxin selected peptide without affecting ex- frequency of defecation, and CRF and A-induced up-regulation of substance P pression of unrelated genes, and ␤- UcnII dsRNA accelerated intestinal (9). Thus, neuronal CRF secreted in globin or GFP dsRNA, used as controls, transit. Thus, under normal circum- response to toxin A could stimulate sub- had no effect (5). Cytokines, including stances, enteric CRF and UcnII dampen stance P release to induce inflammation. IFN, were at similar levels in peripheral intestinal motility, perhaps by modulat- CRF and UcnII may control release of blood in animals receiving CRF, UcnII, ing the peristaltic reflex. Indeed, periph- other enteric neurotransmitters to con- or GFP dsRNA or in animals treated eral CRF delays gastric emptying and trol peristalsis. CRF could also induce with a mixture of CRF siRNAs, arguing small intestinal transit and accelerates inflammation through effects on mast against a systemic inflammatory re- colonic transit, possibly by acting on en- cells, because mast cells mediate the sponse. This powerful approach could teric nerves (3, 4). effects of stress and CRF on intestinal be used for the tissue-specific silencing motility, secretion, and epithelial of other gut mediators, although it will permeability (13, 14). Perhaps the most be important to assess tissue cytokine Corticotropin-releasing intriguing question is whether these levels to exclude local inflammation. mechanisms contribute to gastrointesti- The effects of CRF and UcnII silenc- factor antagonists nal disorders. The study by La Fleur et ing on intestinal inflammation and mo- al. (5) adds to a body of evidence that tility were investigated (5). To induce a may be useful peripheral CRF is proinflammatory and local inflammatory stress, toxin A from CRF antagonists may be useful antiin- the bacterium Clostridium difficile, the antiinﬂammatory drugs. flammatory drugs (8, 9). Stress peptides cause of diarrhea and colitis after anti- may also contribute to irritable bowel biotic therapy, was injected into the ileal syndrome, a common disorder charac- lumen. In animals treated with control The discovery of a local stress re- terized by altered bowel habits and ab- dsRNA, toxin A caused up-regulation of sponse system in the gut not only adds dominal pain, which can be worsened by CRF in intestinal nerves, shedding of to our understanding of similar systems stress. Central and systemic CRF and enterocytes, massive neutrophil recruit- in other tissues, such as the skin (10), Ucns induce the symptoms of this syn- ment, and extensive fluid secretion into but also raises intriguing questions. Does drome, and antagonists blunt the effects the lumen. Remarkably, CRF dsRNA, the system mediate intestinal responses of stress on the gut (3, 4). A CRF-R1 which inhibited up-regulation of CRF, to other local stressors? What is the antagonist also suppresses the colonic prevented epithelial damage and inflam- source of intestinal CRF and what con- motility and pain responses to colonic mation and suppressed fluid secretion. trols its release? Although CRF is found distension and stimulation of the rectal UcnII dsRNA had no effect. Thus, a in enteric nerves, it is also produced by mucosa in patients with irritable bowel local stressor, toxin A, induces the syn- immune cells, which could be an impor- syndrome (15). Additional mechanistic studies, such as that of la Fleur et al., thesis and release of CRF by enteric tant source in inflamed tissues (9). How are clearly warranted to further our neurons, which acts within the gut itself does CRF exert its proinflammatory and understanding of the intestinal stress to cause inflammation. The results are antipropulsive effects? CRF-Rs are ex- response system in diseases and the in line with reports that CRF antago- pressed by enteric neurons and epithe- physiological regulation of digestion. nism and deletion prevent toxin A- lial cells and in the lamina propria (11), induced ileitis (8, 9). However, in those and the levels are up-regulated in the I thank M. Dallman (University of California, studies it was not possible to determine inflamed intestine (8). Additional stud- San Francisco), Y. Tache (University of Cali- whether CRF from the central or en- ies are required to define the precise fornia, Los Angeles), and C. Pothoulakis teric sources was involved. What is clear sites of receptor expression in normal (Harvard University, Cambridge, MA) for is that, whereas central CRF is anti- and diseased states, and tissue-specific helpful discussions.

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