Current Molecular Medicine - Volume 8, Issue 4, 2008

During the second half of the nineteenth and the first decades of the twentieth century the separation of medical and psychiatric disorders started to be reconsidered by a number of physicians and scientists, leaded by Ivan Pavlov and Walter Cannon that inherited the legacy of Hippocrates and Galen who, more than two thousand years ago support the notion that psychosomatic disorders were abnormal physical reactions to stressful emotions or situations. Soon after, Hans Selye defined the physiological responses to stressors and adapted the term stress from physics and engineering to introduce it in the medical vocabulary: “in the biological sense stress is the interaction between damage and defense, just as in physics tension or pressure represents the interplay between a force and the resistance offered to it”, [1]. Selye described a uniform array of sequential, adaptive responses - termed the “General Adaptation Syndrome” - that, through the years, have been universally accepted as direct consequences of stress exposure: enlargement of the adrenal glands, atrophy of immune organs such as thymus, spleen and lymph nodes, and gastrointestinal ulcers [2, 3]. Eighty years later, the definition of stress remains to be subject of debate. In biological systems, the classical definition is any condition that seriously perturbs the physiological/psychological homeostasis of an organism. Indeed, biological stress occurs every day to organisms in their relation with other organisms and also with themselves, provoking a double-faced response: it can be an adaptive mechanism, allowing the organism to survive or fight to the stressful experience, but stress have also a negative impact on the individual, mainly after very intense, long lasting stressful stimuli. Several decades after the seminal works cited above, McEwen extended the term of homeostasis to explain that these mechanisms of stability are continuously changing and called it allostasis [4]. The price the organisms pay to maintain (or try to maintain) the stability is called allostatic load, many times clear diseases. The development of possible permanent changes depends on factors such as chronicity, controllability, predictability and habituation, in part because they are influencing the way an organism can reduce the impact of stressors (coping strategies). The current terminology distinguishes between the stimulus (stressful stimulus or stressor), the state generated in the organism (stress) and the response to the situation (stress response) [5]. Nowadays physical and psychological stresses are widely accepted as triggers and / or modifiers of the clinical course of a variety of gastrointestinal diseases such as functional gastrointestinal disorders, peptic ulcers, and inflammatory bowel diseases [6]. It has been shown that patients with functional gastrointestinal disorders, gastroduodenal ulcers, and relapsing IBD are more frequently exposed to stressful stimuli [7]. On the other hand, stress is involved in the subjective perception of gastrointestinal symptoms - which is often a challenge for the specialist - by patients [8], and psychological factors could be related with the high rate of placebo responses observed in IBD and IBS clinical trials. But although the relationship is often recognized both by patients and physicians, obvious methodological pitfalls of clinical studies make the demonstration of a casual nexus difficult. During the last years, growing evidence from experimental studies supports the ability of psychosocial stress to induce a wide variety of disturbances on the gastrointestinal tract such as gastric erosions and ulcers, increased gastrointestinal motility, altered ion secretion, increased intestinal permeability and enteric neurons dysfunction, to increase the severity of experimental colitis, and even to reactivate a quiescent colitis [9]. In this volume of Current Molecular Medicine, several scientists from some of the most productive groups worldwide in this topic write theirs reflections on different aspects of the effects of stress on the gastrointestinal function. Throughout these pages the possibility that consequences of stress provoke or predispose to disease, and the molecular and cellular basis of gut damage will be reviewed. Maunder and Levenstein, from Toronto and Rome, systematically review the published epidemiological evidence about the role of stress in the development and clinical course of IBD. Interestingly, whereas evidence of a contribution of stress to the onset of the disease is very weak, longitudinal studies on stress or depression and IBD disease course (based on inflammatory parameters) showed a significant relationship between UC and stress and CD and depression. Although possible therapeutic benefits of psychological interventions are limited by methodological weaknesses in these studies, both psychological and pharmacological interventions may be taken into account in IBD patients.

Background: It is unclear whether psychological stress contributes to the inflammatory process in the inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease (CD). This review assesses the epidemiological evidence regarding a causal link between stress and gut inflammation in IBD. Methods: A Medline search identified prospective studies of the effects of stress on subsequent disease activity and randomized controlled studies of the effects of psychological interventions on disease course in IBD. Controlled retrospective studies were included in the review of aspects of the stress-inflammatory relationship for which few prospective studies are available (e.g. the link between stress and disease onset). Studies were assessed qualitatively. Results: Among 9 longitudinal studies of stress or depression and disease course, a significant stressinflammation relationship has been found when UC and CD are studied independently (4 of 4 studies positive) but studies of mixed samples of CD and UC have mostly had negative results (1 of 5 studies positive). Evidence of a contribution of stress to disease onset is very weak. The results of 5 studies of psychological interventions in IBD have been negative or modestly supportive of benefit. Confidence in therapeutic benefits of psychological interventions results is limited by methodological weaknesses in these studies. Discussion: There is consistent evidence for a contribution of psychological factors to IBD disease course, especially stress in UC and depressive symptoms in CD. More rigorous tests of psychological interventions in IBD are needed.

Stress is often considered a risk factor for upper gastrointestinal tract disease, as any acute threat to homeostasis evokes an adaptive or allostatic response. Various types of stress may play a role in the onset and modulation of acute or chronic peptic ulcer disease. When upper endoscopy is employed, stress-related acute mucosal damage is found to develop shortly after admission to an intensive care unit in 60 to 100 percent of patients. However, the epidemiology of chronic peptic damage has not been accurately described by type of stressor, and any association is controversial. The incidence of chronic peptic ulcer disease is falling; the proportion of chronic peptic ulcers that are Helicobacter pylori negative appears to be between 5% and 20%, and some have suggested that stress or other psychological factors may play a role here. Therefore, our objective is to provide an overview of the epidemiology and clinical presentation of stress-related peptic damage, in order to shed insights into the current understanding of the pathophysiology and treatment.

Inflammatory bowel disease (IBD) and the irritable bowel syndrome (IBS) are common causes of medical consultation and the most frequent diagnosis raised by gastroenterologists. Recent years have witnessed considerable advances in the understanding of the mechanisms involved in the initiation and perpetuation of these chronic and recurrent disorders. However, particularly in IBS, the success of the “bench-to thebedside medicine” has been rather poor since many affected individuals still experience significant bother and negative impact in their quality of life despite growing investigative and sanitary costs. Besides IBD, several subgroups of IBS patients have been lately identified as carriers of mucosal inflammation throughout the gut. Although multifactorial, life stress has emerged as a critical factor for mucosal inflammation in these conditions. Due to the clinical and biological heterogeneity of IBD and IBS patients, the simplistic hypothesis of a stress-related stepwise progression of gut inflammation may be useful to gain operative knowledge and render better and specific diagnostic markers and improved therapeutic options. Therefore, in this review, we have consciously admitted the possibility of linear evolution of gut inflammation, from the mucosa to the serosa, and assumed a bidirectional progression, from physiological to pathological inflammation. Thus, we have outlined the stress neurocircuitry implicated in the regulation of gut inflammation and the participating pathways (mechanisms, receptors and molecules) and provided with both, evidence and a theoretical-based approach to present and potential drugs that, alone or in combination, might help to prevent, control or regress the stress-induced inflammatory process at different stages.

Stress has been shown to have both central and peripheral effects, promoting psychological illness (such as anxiety and depression), as well influencing peripheral disease in the intestine. Stress in humans can exacerbate symptoms of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), lowering visceral pain thresholds and decreasing mucosal barrier function. Studies in rodents have revealed that both acute and chronic exposure to stressors can lead to pathophysiology of the small and large intestine, including altered ion secretion and increased epithelial permeability (by both transcellular and paracellular pathways). Prolonged exposure to stress can induce low-grade inflammation, cause ultrastructural epithelial abnormalities, and alter bacterial-host interactions allowing greater microbial translocation. In this review, we discuss the stress response and the effects of both acute and chronic stress to induce pathophysiological damage to the gut. We present the potential pathways involved, and the proposed mechanisms of action mediating the effects. Furthermore, we explore the impact of early life stress on colonic physiology in neonatal rodents and the implications for gut dysfunction in adulthood.

Stress has a major impact on gut physiology and may affect the clinical course of gastro-intestinal diseases. In this review, we focus on the interaction between commensal gut microbiota and intestinal mucosa during stress and discuss the possibilities to counteract the deleterious effects of stress with probiotics. Normally, commensal microbes and their hosts benefit from a symbiotic relationship. Stress does, however, reduce the number of Lactobacilli, while on the contrary, an increased growth, epithelial adherence and mucosal uptake of gram-negative pathogens, e.g. E. coli and Pseudomonas, are seen. Moreover, intestinal bacteria have the ability to sense a stressed host and up-regulate their virulence factors when opportunity knocks. Probiotics are “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host”, and mainly represented by Lactic Acid Bacteria. Probiotics can counteract stress-induced changes in intestinal barrier function, visceral sensitivity and gut motility. These effects are strain specific and mediated by direct bacterial-host cell interaction and/or via soluble factors. Mechanisms of action include competition with pathogens for essential nutrients, induction of epithelial heat-shock proteins, restoring of tight junction protein structure, up-regulation of mucin genes, secretion of defensins, and regulation of the NFκB signalling pathway. In addition, the reduction of intestinal pain perception was shown to be mediated via cannabinoid receptors. Based on the studies reviewed here there is clearly a rationale for probiotic treatment in patients with stressrelated intestinal disorders. We are however far from being able to choose the precise combination of strains or bacterial components for each clinical setting.

Physical and psychological stresses are widely accepted as triggers and / or modifiers of the clinical course of diverse gastrointestinal disorders such as peptic ulcer, irritable bowel syndrome or inflammatory bowel disease. Growing experimental evidence from a variety of models such as immobilization, thermal injury or early maternal deprivation in laboratory animals uniformly supports the ability of stress to induce the development of gastric ulcers, altered gastrointestinal motility and ion secretion, and increased intestinal permeability leading to the passage of antigens to the lamina propria and bacterial translocation. Stress can also synergize with other pathogenic factors such as Helicobacter pylori, non-steroidal anti-inflammatory drugs or colitisinducing chemicals to produce gastrointestinal disease. The brain-gut axis provides the anatomical basis through emotions and environmental influences modulate the gastrointestinal function through the regulation of gastrointestinal immune system and mucosal inflammation; in this sense, mucosal mast cells - at cellular level - and corticotropin releasing factor (CRF) - at molecular level - seem to play a crucial role. On the other hand, an array of adaptive responses have been evolved in order to maintain the homeostasis and to ensure the survival of the individual. In the gut mucosa anti-inflammatory pathways counteract the deleterious effect of the stressful stimuli on the gastrointestinal homeostasis. In the present review we discuss the several experimental approaches used to mimic human stressful events or chronic stress in laboratory animals, the evidence of stress-induced gastrointestinal inflammation and dysfunction derived from them, and the involved cellular and molecular mechanisms that are being discovered during the last years.

The MST family of protein kinases plays a critical role in the regulation of cell death in diverse organisms including mammals. The intracellular signaling pathways that regulate MST-driven cell death in mammalian cells are the subject of intense investigation. Stress stimuli including oxidative stress and DNA damaging agents trigger the activity of MST in cells. Although the mechanisms by which oxidative stress and DNA damage trigger MST activation remain to be identified, MST activity can be regulated by caspase-induced cleavage as well as interactions with other proteins in cells. Once activated upon oxidative stress, MST induces cell death via phosphorylation and activation of the transcription factor FOXO3 or the histone protein H2B. This review focuses on the currently known upstream activating mechanisms for MST, and explores the downstream signaling pathways that mediate MST's principal function in cell death. Elucidation of MST functions and their regulatory mechanisms in cell death have important implications for our understanding of cellular homeostasis as well as the pathogenesis of diverse diseases.

The Transforming Growth Factor (TGF)-β-Smad signaling pathway regulates diverse biological processes essential for normal development and homeostasis. The Smad-interacting transcriptional modulator SnoN and its related homologs have emerged as important modulators of TGF-β signaling and responses. SnoN forms a physical complex with the TGF-β-regulated Smad2/Smad3 and co-Smad4 proteins and either represses or stimulates TGF-β-induced Smad-dependent transcription in a cell- and promoter-specific manner. In addition, the TGF-β-activated Smads recruit several ubiquitin ligases to SnoN and thereby promote the ubiquitination and consequent degradation of SnoN. Additional modifications of SnoN, including sumoylation, may contribute to the regulation of SnoN function and its role in TGF-β signaling. Collectively, these studies suggest that SnoN function is intimately linked to the TGF-β-Smad pathway in cellular signaling. Although the mechanisms by which SnoN modulates signaling in the TGF-β-Smad pathway are beginning to be characterized, the full range of SnoN functions and underlying mechanisms in normal development and disease processes remains to be elucidated.