1. Översiktlig projektbeskrivning

Engelsk titel

Mechanisms behind symptoms in functional and inflammatory gastrointestinal diseases.

Sammanfattning av projektet

Vi avser att fortsätta våra studier där betydelsen av olika patofysiologiska avvikelser för symtombilden hos patienter med funktionella och inflammatoriska gastrointestinala (GI) sjukdomar undersöks. Vår modell med systematisk utvärdering av koppling mellan patofysiologi och symtom hos patienter med irritable bowel syndrome (IBS), som rönt stor internationell uppskattning, kommer nu att appliceras på flera stora patientgrupper där kunskapen om mekanismer bakom symtom är bristfälliga. Tre huvudgrupper av patienter kommer att undersökas: 1.IBS patienter, 2.patienter med icke kardiell bröstsmärta (non-cardiac chest pain, NCCP), 3.patienter med inflammatorisk tarmsjukdom med pågående symtom trots avsaknad av aktiv inflammation. Interaktion mellan avvikelser i klassiska patofysiologiska avvikelser, såsom visceral hypersensitivitet, avvikande GI motorik och sekretion, och avvikelser i tarmflora, GI barriärfunktion och inflammation/immun-aktivering kommer att värderas och sättas i relation till symtombilden. Resultaten från dessa undersökningar kan förväntas optimera behandling, utredning och omhändertagande av dessa stora patientgrupper med idag ofta oförklarade symtom. Vår hypotes är att definition och gruppering av funktionella magtarmsjukdomar baserat på patofysiologi i stället för som idag på symtombilden kommer att leda till bättre behandling. Vi kommer också att fortsätta våra studier som värderar effekten på kort och lång sikt av olika terapiformer, samt mekansimer bakom dess effektivitet. I projektet ingår även undersökningar avseende mekanismer bakom symtomupplevelse, coping strategier och faktorer av betydelse för ett optimerat omhändertagande av patienter med olika GI och hepatologiska sjukdomar.

Typ av projekt

Forskningsprojekt

MeSH-termer för att beskriva ämnesområdet

Inlagda MeSH-termer

Irritable Bowel Syndrome

A disorder with chronic or recurrent colonic symptoms without a clearcut etiology. This condition is characterized by chronic or recurrent ABDOMINAL PAIN, bloating, MUCUS in FECES, and an erratic disturbance of DEFECATION.

Colonic Diseases, Functional

Chronic or recurrent colonic disorders without an identifiable structural or biochemical explanation. The widely recognized IRRITABLE BOWEL SYNDROME falls into this category.

Colonic Diseases

Pathological processes in the COLON region of the large intestine (INTESTINE, LARGE).

Intestinal Diseases

Pathological processes in any segment of the INTESTINE from DUODENUM to RECTUM.

Gastrointestinal Diseases

Diseases in any segment of the GASTROINTESTINAL TRACT from ESOPHAGUS to RECTUM.

Digestive System Diseases

Diseases in any part of the GASTROINTESTINAL TRACT or the accessory organs (LIVER; BILIARY TRACT; PANCREAS).

Stomach

An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the ESOPHAGUS and the beginning of the DUODENUM.

Gastrointestinal Tract

Generally refers to the digestive structures stretching from the MOUTH to ANUS, but does not include the accessory glandular organs (LIVER; BILIARY TRACT; PANCREAS).

Digestive System

A group of organs stretching from the MOUTH to the ANUS, serving to breakdown foods, assimilate nutrients, and eliminate waste. In humans, the digestive system includes the GASTROINTESTINAL TRACT and the accessory glands (LIVER; BILIARY TRACT; PANCREAS).

Upper Gastrointestinal Tract

The segment of GASTROINTESTINAL TRACT that includes the ESOPHAGUS; the STOMACH; and the DUODENUM.

Projektets delaktighet i utbildning

Avhandling
D-uppsats / Magisterexamen
C-uppsats / Kandidatexamen
ST-läkarutbildning
Annan utbildning
Ej del i utbildning

3. Processen och projektets redovisning

Pågående aktiviteter

Planering och förberedelse före datainsamling
Datainsamling pågår
Analys av insamlade data pågår
Författande av skriftlig redovisning / publikation pågår
En eller flera publikationer från projektet är publicerade
Slutfört och inget mer görs inom ramen för detta projekt

Projektstart (när planeringen påbörjas och börjar dokumenteras skriftligt)

2008-01-01

Datum för påbörjande av datainsamling

2008-01-01

Datum då projektet är slutrapporterat

2013-12-31

4. Detaljerad projektbeskrivning

Bakgrundsbeskrivning

Major aims:
1.Unravel the link between “classical” pathophysiological factors (visceral hypersensitivity, altered gastrointestinal (GI) motility and secretion and psychological factors), abnormal gut immune and barrier function, alterations in gut microbiota, and symptoms in patients with irritable bowel syndrome (IBS).
2.Investigate underlying mechanisms for symptom generation in patients with non-cardiac chest pain.
3.Better understand why a large proportion of patients with inflammatory bowel disease (IBD) have ongoing GI symptoms, despite absence of active inflammation in the gut.
Background
In a large proportion of patients seeking health care for GI symptoms, the understanding of factors explaining these is poor. This holds true for patients with functional GI disorders, such as IBS, non-cardiac chest pain and functional dyspepsia, but also for patients with organic GI diseases, such as inflammatory bowel diseases (ulcerative colitis and Crohn’s disease), where symptoms, despite absence of active inflammation, is common. Recent progress in molecular techniques to study gut immune and barrier function, as well as the possibility to use culture independent methods to characterize the gut microbiota, will likely lead to enhanced understanding of mechanisms behind symptom generation. By combining these new molecular methods with assessment of classical pathophysiological alterations in these patients, and evaluate the association with the symptom pattern, progress can be made in order to improve our management of large patient groups within the field of gastroenterology.
Patients with functional GI disorders constitute the majority of patients seeking health-care for GI symptoms in primary and secondary care. Of these disorders IBS is one of the most common and affects 10-20% in the Western world and effective treatment alternatives are generally lacking. This is partly due to a lack of understanding of the aetiology of IBS and also of the importance of various pathophysiological alterations for the different symptoms in the patients. The pathophysiology of IBS is complex and most probably multifactorial (Öhman and Simrén Dig Liver Dis 2007). Alterations in motility and secretion in the gastrointestinal tract, visceral hypersensitivity, psychological disturbances and disturbances in autonomic nervous function are pathophysiological alterations known today. However, none of these are present in all patients with IBS, and the relationship with gastrointestinal and extraintestinal symptoms is not clear. Recently, a low-grade inflammation within the GI tract, abnormalities in gut microbiota, alterations in immune function and gut barrier defects have been proposed to be of importance in a subset of these patients. Also, for these “new” pathophysiological/pathogenetic factors the relevance for symptom generation is unclear and the link to the “classical” pathophysiological factors is not known.
Our group has demonstrated several pathophysiological alterations in groups of IBS patients, and established a relationship with the symptom pattern for some of these. However, the interplay between these factors is still incompletely known:
1.Altered intestinal motility, both in the small (Simrén et al Dig Dis Sci 2000) and large (Sadik et al Eur J Gastroenterol Hepatol 2010) intestine.
2.Enhanced secretory function of the small intestine (Larsson et al Neurogastroenterol Motil 2007).
3.Small intestinal bacterial overgrowth in a small number of IBS patients (Posserud et al Gut 2007).
4.Colorectal hypersensitivity in a large proportion of patients with IBS, which is exaggerated after nutrient intake (Simrén et al Gut 2001, Neurogastroenterol Motil 2007, Clin Gastroenterol hepatol 2007) and after/during mental stress (Posserud et al Gut 2004). The relevance of visceral hypersensitivity for pain and bloating in IBS has recently been demonstrated (Posserud et al Gastroenterology 2007).
5.Psychological disturbances, such as anxiety, depression and other psychological factors in a substantial proportion of IBS patients, especially in tertiary care (Simrén et al Scand J Gastroenterol 2001). In recent studies our group has established the importance of hypervigilance (Posserud et al J Psychosom Res 2009)) and GI specific anxiety (Jernsal et al Neurogastroenterol Motil 2010) in the generation of IBS symptoms.
6.A low-grade inflammation in the GI tract in a subset of IBS patients (Öhman et al Clin Gastroenterol 2005), as well as an activated immune system in peripheral blood (Öhman et al Neurogastroenterol Motil 2009, Am J Gastroenterol 2009).
Another large and poorly understood patient group is patients with non-cardiac chest pain (NCCP), which has been reported to occur in up to 25% of the population. These patients often visit the Emergency Room with severe pain in the chest and once a cardiac cause is ruled out they are reassured that “nothing is wrong” and no treatment or follow-up is offered. However, from recent studies it is clear that this management is not optimal, as the chest pain often recurs and the quality of life is severely reduced. Potential causes of NCCP include gastroesophageal reflux, muscular pain, oesophageal motility disorders, oesophageal/visceral hypersensitivity and psychological factors . Moreover, a defect barrier function in the oesophagus might lead to a “leaky epithelium”, increasing the possibility for acid reflux and other luminal factors to affect receptors and nerves within the oesophagus. A better understanding of the relative importance of these, the link to symptoms and the response to treatment is needed in order to improve the management of this large patient group.
The disease course in patients with inflammatory bowel diseases (IBD), i.e. ulcerative colitis and Crohn’s disease, differ substantially. In some patients there are frequent relapses or chronic active disease with severe symptoms due to active inflammation, whereas others have years of virtually complete remission with no signs of active inflammation . However, a significant proportion of IBD patients without signs of active inflammation have ongoing GI symptoms resembling those in patients with IBS. These patients with ongoing GI symptoms have reduced quality of life and poor psychological well-being, which has been demonstrated by our group (Simrén et al Am J Gastroenterol 2002). Moreover, the fact that these patients have continuous symptoms from the gut, sometimes lead to aggressive anti-inflammatory treatment with little effect on the symptoms and risk of adverse events. Therefore, it is of great importance to better clarify mechanisms behind the symptoms in these patients in order to be able to improve their well-being and to avoid the use of unnecessary treatment options with potential side effects.

Syfte

Based on this, our research plan consists of three main projects, trying to better characterize factors of importance for symptom generation in these large patient groups:
I.Association between GI microbiota, low-grade inflammation, gut barrier function and classical pathophysiological factors in patients with irritable bowel syndrome (IBS). Relevance for symptoms?
II.Relative importance of different pathophysiological factors for patients with non-cardiac chest pain.
III.Mechanisms behind GI symptoms in patients with quiescent inflammatory bowel disease.

Referenser

Huvudreferenser av vikt för projektet:

1.Posserud I, Stotzer PO, Bjornsson ES, Abrahamsson H, Simren M. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut. 2007 Jun;56(6):802-8. (Impact factor 9,4)
2.Simrén M, Abrahamsson H, Björnsson ES. An exaggerated sensory component of the gastrocolonic response in patients with irritable bowel syndrome. Gut. 2001;48(1):20-7. (Impact factor 9,4)
3.Posserud I, Agerforz P, Ekman R, Bjornsson ES, Abrahamsson H, Simren M. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress. Gut. 2004 Aug;53(8):1102-8. (Impact factor 9,4)
4.Sadik R, Bjornsson E, Simren M. The relationship between symptoms, body mass index, gastrointestinal transit and stool frequency in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2010 Jan;22(1):102-8 (Impact factor 1,6)
5.Posserud I, Syrous A, Lindstrom L, Tack J, Abrahamsson H, Simren M. Altered rectal perception in irritable bowel syndrome is associated with symptom severity. Gastroenterology. 2007 Oct;133(4):1113-23. (Impact factor 12,9)
6.Jerndal P, Ringstrom G, Agerforz P, Karpefors M, Akkermans LM, Bayati A, et al. Gastrointestinal-specific anxiety: An important factor for severity of GI symptoms and quality of life in IBS. Neurogastroenterol Motil 2010 Jun;22(6):646-e179. (Impact factor 3,6)
7.Simrén M, Axelsson J, Gillberg R, Abrahamsson H, Svedlund J, Björnsson E. Quality of life in inflammatory bowel disease in remission: The impact of IBS-like symptoms and associated psychological factors. Am J Gastroenterol. 2002;97(2):389-96. (Impact factor 6,0)
8.Öhman L, Simrén M. Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol 2010 Mar;7(3):163-73. (Impact factor 4,5)
9.Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15064-9. (Impact Factor 9,4)
10.Simrén M, Silny J, Holloway R, Tack J, Janssens J, Sifrim D. Relevance of ineffective oesophageal motility during oesophageal acid clearance. Gut. 2003 Jun;52(6):784-90. (Impact factor 9,4)