Symptom science is emerging as an important opportunity to meld nursing science conducted at the bedside or ambulatory care centers with that conducted at the bench. Clinically nurses play key roles in symptom prevention and management including designing and implementing strategies to enhance self-management strategies for patients and their caregivers. Using clinical observations and careful description as well as randomized clinical trials, the field of nursing science has contributed importantly to each of these components. At this time we are poised to delve even further as we test the links between basic science, pathobiology, behavior, and symptoms using newer techniques including genomics, proteomics, and metabolomics. Although the study of symptoms and clinical phenotype have long been the focus of nursing research, the label of 'symptom science' offers the opportunity for nursing scientists to view the work we do within a broader framework and to incorporate additional tools from other disciplines. In this paper we present an update on our work focused on a common functional gastrointestinal (FGID) disorder, irritable bowel syndrome (IBS).

Approximately 10-20% of adults in the United States (US) and 6.6-9.0% in South Korea (Park et al., 2010) experience chronic abdominal symptoms (abdominal pain/discomfort and associated bowel changes [constipation and/or diarrhea]) compatible with a diagnosis of IBS (Drossman et al., 2006). In the US as well as other western countries, women seek health care services disproportionately more than men. The public health impact of IBS in the US is enormous with direct costs totaling approximately $1.35 billion/year and indirect costs about 205 million/year (Inadomi et al., 2003) . In South Korea, the direct medical costs were approximately $96 million (108 billion KRW) in 2007 by the National Health Insurance Statistical Yearbook (Jung et al., 2011) and it is increasing.

Despite the public health importance of FGIDs, progress defining the mechanism (s) accounting for symptoms (particularly pain) and delineating effective pain interventions has been slow. In part, because the definition of the disorder has changed over time (Rome criteria), is symptom-based, and is open to interpretation (Camilleri & Talley, 2004; Gwee & Ghoshal, 2010). Although phenotype-based diagnosis in IBS has been suggested to be valid, studies have questioned these findings (Camilleri & Talley; Gwee & Ghoshal; Moayyedi & Ford, 2011). Our work to date underscores the challenges with phenotype-based diagnosis (Cain et al., 2006; Cain, Jarrett, Burr, Hertig, & Heitkemper, 2007; Goo et al., 2012). Yet, phenotype-based categorization commonly dictates what is done clinically for these patients. For example, the lack of non-invasive biomarkers that discriminate among IBS, inflammatory bowel disease (IBD), cancer, and celiac disease in patients and healthy individuals contributes to the number of diagnostic procedures and clinical burden of chronic GI pain condition (Halpert, 2010). Thus, as noted by leaders in IBS, use of clinical phenotyping alone is not enough (Camilleri & Talley; Gwee & Ghoshal; Moayyedi & Ford). They advocate development of biomarkers to identify pathophysiological mechanisms in IBS to elucidate the etiology, define the diagnosis, predict the prognosis, speed up development of treatment/management strategies, and reduce IBS-related costs.

The primary hypothesis of our on-going studies is that factors contributing to the experience of pain and life disruption in IBS vary among subgroups distinguished by factors other than stool pattern. Understanding those factors and how they interact concurrently is central and essential to development of interventions to reduce or alleviate pain and disability and enhance quality of life (Chitkara, van Tilburg, Blois-Martin, & Whitehead, 2008). By improving knowledge of the pathobiology operative in IBS, our results will likely impact future therapeutic efforts and symptom management.

Studies suggest an interplay among increased GI permeability ('leaky gut'), abnormalities in the composition of the GI microbiota (bacteria, their genomes and interaction with the host), altered immune responses, autonomic dysfunction, altered bile acid metabolism, and psychological distress lead to the symptoms and the subsequent functional impact of IBS (Camilleri, Lasch, & Zhou, 2012). Recent studies of pathobiological markers support the hypotheses that IBS can develop from centrally dominant factors such as early adverse events/stress (Bradford et al., 2012), significant life events with moderate stress in adults (Alonso et al., 2008), luminal factors (infection, alterations in the GI microbiota [dysbiosis]) triggering immune activation (Hughes et al., 2013), or all three. In some these occur concurrently or interactively. For example, stress can increase or slow GI motility (Konturek, Brzozowski, & Konturek, 2011) thereby modifying the microbiota with subsequent immune activation that generates symptoms. Increased permeability may be due to genetic susceptibility in the inflammatory response and/or dysbiosis leading subsequent host immune responses and symptoms. Based on preliminary data and the literature, our group has started to focus on additional mechanisms that may distinguish groups, clarify pathophysiology, and lead to more personalized care.

With regard to developing diagnostic tools, our team has explored the utility of urine proteome characterization as a non-invasive biomarker. We used "shotgun" mass spectrometry to identify urine proteins in IBS and healthy control women. The differences in the urine proteome exist among symptomatically distinct groups of patients with IBS. However, like all body fluids there was large inter-and intra-individual variations (Jeffery et al., 2012). Several of the proteins that showed distinctive differences among IBS subgroups were ones involved in homeostasis of intestinal function. For example, mucin 1 (MUC1) and trefoil factor 3 (TFF3) are mucosal epithelial membrane-bound molecules synthesized by the intestinal goblet cells (Eutamene et al., 2007). Because the functional integrity of the intestine is important for defense against injury and pathogens, alterations in these proteins could result in mucosal inflammation and injury. As such the mucus layer and membrane-bound molecules such as TFF3 are the major components to protect/repair the epithelium. Thus, any change among these molecular components would affect the intestinal environment and result in increased permeability and subsequent inflammation. Increased permeability and elevations in tissue cytokines have been described in some patients with IBS (Aguilera et al., 2013). Research on the utility of urine proteomics as biomarkers for IBS is just beginning. Ideally, a proteomic biomarker would be one that distinguishes IBS subgroups from each other, healthy controls, and those with disease such as IBD. If such a biomarker can be found then samples from easily accessible body fluids such as urine, stool, or saliva could be collected non-invasively and tested.

Treatments for IBS include symptom-specific medications (ie, antispasmotic, antidiarrheal, anticonstipation, antidepressants, antibiotics), dietary management (e.g., fiber, elimination of trigger foods, probiotic) and psychological therapies (e.g., cognitive behavioral treatment [CBT], hypnosis, mindfulness meditation), herbal therapies, and acupuncture. Of these, only psychological therapies and a few drugs (e.g., lubiprostone, rifaximin, SSRIs) are recommended by national guidelines (e.g., American Gastroenterology Association [AGA], American College of Gastroenterology [ACG]) for select patient subgroups (American College of Gastroenterology Task Force on Irritable Bowel Syndrome et al., 2009). In 2012, the British Dietetic Association guideline for IBS recommended the dietary elimination of malabsorptive foods (e.g., lactose, fermentable carbohydrates) and use of probiotics for IBS (McKenzie et al., 2012). The recommendations for psychological treatment are based on in-person CBT delivered by well-trained physician, psychologist, or nurse in a specialty clinic. We have demonstrated in our preliminary work that an intervention including nurse-delivered CBT provided over the telephone (Jarrett et al., 2009) for most of the sessions is equally effective as a 9-session in-person delivery. Ljótsson et al. (2011) effectively delivered a similar intervention through an internet platform thus expanding the potential impact of CBTs.

We have developed a nurse therapist-delivered intervention, Comprehensive Self-Management (CSM). The sessions start with what IBS is and is not (e.g., cancer) followed by sessions on breathing-relaxation techniques for stress reduction, dietary assessment to identify trigger foods, and cognitive restructuring of negative thoughts, tailored to the individual. Our studies have evaluated CSM delivered in-person as well as delivered mostly by telephone, and demonstrated that both delivery methods are effective in reducing symptom distress and enhancing QOL (Heitkemper et al., 2004; Jarrett et al., 2009). Our results are consistent with the meta-analyses for CBT in that therapy from a well-trained therapist can help patients to reduce symptoms and stress, and increase QOL (Lackner, Mesmer, Morley, Dowzer, & Hamilton, 2004). A challenge to the dissemination of this evidenced-based CSM program is the lack of access to therapists qualified to provide nutritional counseling and CBT therapy as well as limited clinician time in primary and specialty clinics. This is particularly true in medically underserved areas where attendance at multiple appointments is not feasible, flexibility in scheduling is limited, and travel-related costs are expensive.

IBS should be viewed within a biopsychosocial model that considers pain, sleep, peripheral (luminal), immune activation, stress, autonomic nervous system dysregulation, genetics, as well as current and lifetime stress exposure. To date these measures have primarily been examined separately in patients' phenotypes using retrospective recall of bowel and discomfort symptoms. Such information is important to designing and tailor therapies.