eRapport

Er irritabel tarm en stamcelle sykdom?

Prosjekt
Prosjektnummer
911978
Ansvarlig person
Magdy El-Salhy
Institusjon
Helse Fonna HF
Prosjektkategori
Åpen prosjektstøtte
Helsekategori
Oral and Gastrointestinal
Forskningsaktivitet
5. Treatment Developement
Rapporter
2017 - sluttrapport
We have shown reduced stem cell clonogenic and differentiation progeny activities not only in the proximal small intestine, but also in the distal small intestine and large intestine of IBS patients. These three segments of the gut have different physiological activities and different endocrine cell populations. Patients with irritable bowel syndrome (IBS) in Asia show distinctive differences from those in the Western world (USA and Europe). These differences include the prevalence, gender, clinical presentation and. The prevalence of IBS in Asia is 5%-9% compared with the reported prevalence of 5–20% in western countries. Furthermore, no female predominance has been found in Asian IBS patients as in those in the West. The clinical presentation of IBS in Asian patients is different from that in Western countries. Abdominal bloating is more common complaints than pain and the abdominal pain is localized to the upper abdomen rather than in the lower abdomen as in Western patients. Moreover, alteration in bowel habits is much less prominent in Asian IBS patients than in Western patients. We have demonstrated that Asian patients with IBS have normal intestinal stem cell activities indicating that IBS in Asia has probably different pathophysiology than that of the Western world. This in turn may explain the contradictory results in studies done on these two different patient populations. IBS is a common disorder affecting between 8-22 of the Norwegian population. Although IBS is not mortal, it reduces the patients’ quality of life considerably and is economically burden to both the patients and society. IBS lack an effective treatment. The present findings suggest that stem cell transplantation may be an effective treatment for this disorder. Stem cell transplantation has been tried in other gastrointestinal diseases with success. Both genetic and environmental factors seem to play important roles in the pathophysiology of IBS. Our preliminary results show that change in environmental factors such as diet, intestinal microbiota and treatment of inflammation restore the stem cells to normal level. These results suggest that controlling the environmental factors in IBS may be as effective as stem-cell transplantation?

Helse Fonna har et Brukerpanel som vil bli brukt som et rådgivende organ og til å drøfte problemstillinger underveis i prosjektet.

2016
We have shown 2 abnormalities in the stem cell activities in the small intestine of IBS patients: the ability of stem cell to make a copy of itself and to differentiate into endocrine cells is decreased. This would explain the low density of small intestinal endocrine cells in these patients, which is believed to be the cause of IBSWe have extended our research to include the distal small intestine (ileum), which contains other types of endocrine cells than the proximal small intestine (duodenum). Thus, 94 patients with IBS including all the 3 types and 31 controls underwent standard colonoscopy and biopsy samples were taken from the ileum during the procedure. The tissue samples were immunostained for markers for stem cells and endocrine cell progenitors. The immunostained sections were quantified by computer-image analysis. This study showed that the density of stem cells as detected by Musashi 1 and the Neurogenin3 (progenitor for endocrine cells) were decreased. Furthermore, the decrease in the densities of stem cells and endocrine cell progenitor were closely correlated to the decrease in enteroendocrine cells. The abnormalities in the enteroendocrine cells in patients with IBS are believed to play a major role in the pathophysiology of IBS. Our results point to the possibility that the abnormalities in the enteroendocrine cells is caused by abnormalities in the stem cell activity. Low-grade inflammation is one of the factors that proved to play a role in the pathophysiology of IBS. We tested therefor whether inflammation causes similar changes in enteroendocrine cells and in stem cells as in IBS. We studied the enteroendocrine cells in 2 animal models of human ulcerative colitis and Crohn`s disease, namely TNBS- and DSS-induced colitis in rats. We found in both animal models changes in the enteroendocrine cells, and stem cells and their progenitors toward endocrine cells. The changes in enteroendocrine cells and the changes in the stem cell activities were closely correlated.
2015
203 pasienter med irritabel tarm (IBS) og 86 kontroller har gjennomgått en gastroskopi med biopsi prøvetaking. Vi har studert tettheten av alle endokrine celletyper i tynntarmen, samt markører for stamceller (Msi-1) og for endokrine forstadie celler (neurog 3). Tettheten av endokrine Msi-1 og Neurog 3 var redusert. Dette kan tyde på at forstyrrelse i stamceller kan være årsaken til utvikling av IBS.Årsaken til IBS er ikke klarlagt, men forstyrrelser i de gastrointestinale endokrine cellene antas å spille en viktig rolle i utviklingen av IBS. Årsaken til reduksjon av tarm endokrine cellers tetthet i pasienter med IBS, er ukjent. Vi har nylig studert Musashi 1 (MSI 1), som er en markør for tarm stamceller, og neurogenin 3 (Neurog 3), som er en markør for første stadiet for intestinale endokrine celler i tynntarmen, hos IBS-pasienter. Tettheten av Msi-1 og Neurog 3 celler er redusert i tynntarmen hos pasienter med IBS, uavhengig av subtype, noe som indikerer forstyrrelse i både klonogen fornyelse og differensiering av stamceller. Disse forstyrrelsene i tynntarmens stamceller er ledsaget av en reduksjon av endokrine cellers tetthet. Dette tyder på en sammenheng mellom avvik av stamceller og reduksjon av tynntarmens endokrine celler hos IBS pasienter. Identifiseringen av forstyrrelser i tarm stamceller gir en ny tilnærming i forskningen av utviklingen av IBS, og kan gi et effektivt verktøy for behandling. Derfor bør forskning rundt årsaken til forstyrrelser i stamceller i IBS gjennomføres, og stamcelle stimulering/transplantasjon kan være et nytt verktøy for behandling av IBS i nær fremtid. I tillegg til arbeidet som er beskrevet, har vi rekruttert 101 IBS-pasienter og 62 kontroller, der kjønn og alder er tilpasset, for å undersøke videre sammenheng mellom forstyrrelser i nedre del av tynntarmen (ileum) og i tykktarmens endokrine celler og stamceller. Pasienter og kontroller har gjennomgått en koloskopi med biopsi prøvetaking fra ulike deler av tynntarm, tykktarm og endetarm. Endokrine celletyper i den nedre delen av tynntarmen og tykktarmen er helt forskjellige enn i tynntarmen. I øvre del av tynntarmen finnes det Chromogranin A, Secretin, Cholecystokinin (CCK), Gastric Inhibitory Peptide (GIP), Serotonin og Somatostatin. I nedre del av tynntarmen og i tykktarmen finnes det Chromogranin A, Peptide YY (PYY), Enteroglucagon, Pancreatic Polypeptide (PP), Serotonin og Somatostatin.
Vitenskapelige artikler
El-Salhy M, Patcharatrakul T, Hatlebakk JG, Hausken T, Gilja OH, Gonlachanvit S

Enteroendocrine, Musashi 1 and neurogenin 3 cells in the large intestine of Thai and Norwegian patients with irritable bowel syndrome.

Scand J Gastroenterol 2017 Dec;52(12):1331-1339. Epub 2017 aug 30

PMID: 28853300

El-Salhy M, Gilja OH

Abnormalities in ileal stem, neurogenin 3, and enteroendocrine cells in patients with irritable bowel syndrome.

BMC Gastroenterol 2017 Aug 01;17(1):90. Epub 2017 aug 1

PMID: 28764761

El-Salhy M, Umezawa K, Hatlebakk JG, Gilja OH

Abnormal differentiation of stem cells into enteroendocrine cells in rats with DSS-induced colitis.

Mol Med Rep 2017 Apr;15(4):2106-2112. Epub 2017 mar 1

PMID: 28259987

El-Salhy M, Mazzawi T, Umezawa K, Gilja OH

Enteroendocrine cells, stem cells and differentiation progenitors in rats with TNBS-induced colitis.

Int J Mol Med 2016 Dec;38(6):1743-1751. Epub 2016 okt 24

PMID: 27779708

El-Salhy M, Hatlebakk JG, Hausken T

Reduction in duodenal endocrine cells in irritable bowel syndrome is associated with stem cell abnormalities.

World J Gastroenterol 2015 Aug 28;21(32):9577-87.

PMID: 26327765

Mazzawi T, El-Salhy M, Lied GA, Hausken T.

The effects of faecal microbiota transplantation on small intestinal Musashi 1, neurogenin 3, and enteroendocrine cells in patients with irritable bowel syndrome

Manuscript.

El-Salhy, M, Gilja, OH

Abnormal stem cells and differentiation progeny into enteroendocrine cells in the colon of patients with IBS.

Meurogastroenterol Mot, 29, Supl 2, 68, 2017

EL-SALHY M, UMEZAWA K, HATLEBAKK JG, GILJA OH

Abnormal differentiation of stem cells into enteroendocrine cells in rats with DSS-induced colitis

Mol Med Rep, 2017, in press

Deltagere
  • Jan Gunnar Hatlebakk Prosjektdeltaker
  • Trygve Hausken Prosjektdeltaker
  • Magdy El-Salhy Prosjektleder
  • Tarek Mazzawi Prosjektdeltaker
  • Odd Helge Gilja Prosjektdeltaker

eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT

Alle henvendelser rettes til Faglig rapportering, Helse Vest

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