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Gastrointestinal Permeability and Motility in Inflammatory Bowel Disease
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Gastroenterologi/hepatologi. (Gastroenterology and Hepatology)ORCID-id: 0000-0002-4842-3227
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Synchronized motility, permeability and secretory (hormones and enzymes) events are integral to normal physiology. Smooth muscle syncytium operates with enteric nervous system (ENS) and endocrine signalling to accommodate, mix and control passage of ingested materials. The intestinal epithelial cells (IECs) drive digestion and absorption while repelling harmful compounds.

This thesis investigated GI barrier function (permeability, mucosal integrity), motility and hormonal patterns in inflammatory bowel disease (IBD) by: 1) assessing GI motility using a wireless motility capsule (WMC, SmartPill®) and video capsule endoscopy (VCE, Pillcam®), 2) investigation of intestinal fatty acid binding protein (I-FABP) as a biomarker of Crohn’s disease (CD) disease activity, 3) evaluation of small intestinal permeability in IBD, 4) investigating meal-related WMC motility and simultaneous hormonal (e.g., Ghrelin, GLP-1, GIP, PYY) patterns in IBD. Reference WMC motility values for transit times for gastric emptying, small bowel, orocecal, small+large bowel, colon and whole gut were established. Software-generated estimates and visually determined values were nearly identical. Compared with VCE estimates (represents fasting conditions), the WMC records longer GET and SBTT. Variations in intra-subject reproducibility must be considered in clinical investigations. This data was then used to investigate IBD patients. I-FABP was primarily expressed in the epithelium of the small bowel and to lesser extent also in the colon and stomach. Circulating I-FABP was elevated in active CD with a magnitude comparable to TNFα. I-FABP lowers and rises again in parallel with TNFα and HBI during infliximab treatment. I-FABP can be used as a jejunum and ileum selective prognostic biomarker for monitoring disease activity. Increased small intestine mucosal barrier permeability to lactulose in both CD and UC was found. Sucralose can serve a dual purpose in quantifying small and large intestinal permeability. Small intestinal hyper-permeability was not revealed as a transporter dependent nutrient (riboflavin) malabsorption. Using the WMC, consistent motility disturbances in IBD were limited, as were differences in pH. However, disturbances within many individuals were found. As part of the investigation, defects in gut peptide and metabolic hormone meal responses were found, typically higher plasma levels. No clear associations between hormones and motility were found. Effects on hunger/satiety signaling in IBD are anticipated.

The present thesis shows the utility of the WMC and gut barrier tests in monitoring IBD patients.

Abstract [sv]

Mag-tarmkanalens glatta muskulatur är funktionellt integrerad med enteriska nervsystemet och endokrin signalering för ackommodation, blandning och passage genom mag-tarmkanalen. De intestinala epitelcellerna upprätthåller digestion och absorption, samtidigt med barriärfunktion mot skadliga agens.

Avhandlingen utvärderar patofysiologiska barriärmekanismer vid inflammatorisk tarmsjukdom (IBD) beträffande permeabilitet, förändrad motilitet och hormonella mönster vid Crohns sjukdom (CD) och ulcerös colit (UC) genom att, 1) utvärdera mag-tarmkanalens motilitet med trådlös motilitetskapsel (WMC) och videokapsel endoskopi (VCE), 2) studera I-FABP som biomarkör vid CD avseende distribution i mag-tarmkanalen, samband med sjukdomsktivitet, parallellitet med  TNFα och Harvey-Bradshaw index (HBI) under anti-TNFα-behandling, 3) utvärdera intestinal permeabilitet vid IBD, 4) studera användning av WMC för att registrera motilitet vid måltidssvar och hormonella mönster.

WMC registrerade pH, tryck och temperatur längs hela mag-tarmkanalen. Referensvärden för  ventrikeltömningstid och transittider för tunntarm, colon och totala mag-tarmkanalen etablerades. Dessa värden har använts för utvärdering av IBD. Mjukvaruberäknade värden var lika visuellt avlästa värden. Mätvärden för VCE under fasta visade snabb transit, medan WMC hade längre ventrikeltömningstid och transittid för tunntarm. Intra-individuell variation måste bedömas särskilt vid kliniska undersökningar.

I-FABP lokaliserades till epitelet i tunntarmen, i mindre omfattning i ventrikel och colon. Cirkulerande I-FABP var förhöjt vid aktiv CD, som TNFα. Plasmanivåer av I-FABP följde parallellt TNFα och HBI under behandling och uppföljning. I-FABP kan användas som selektiv prognostisk markör för CD i jejunum och ileum vid monitorering av CD patienter.

Ökad tunntarmspermeabilitet sågs både vid CD och UC med hyperpermeabilitet för laktulos, medan sukralos, som ersättning för laktulos, kunde mäta permeabilitet i både tunntarm och colon. Hyperpermeabiliteten medför ingen generell malabsorption eftersom absorptionen av riboflavin var normal, och beror av specifika transportmekanismer i tunntarmen.

Med hjälp av WMC kunde endast begränsade avvikelser i motiliteten vid IBD registreras, även för pH. Hos enskilda individer kunde tydliga avvikelser ses. Dessutom noterades generellt förhöjda gastrointestinala och metabola peptidhormoner samtidigt med ett bevarat måltidssvar. Samband mellan hormonnivåer och motilitetsavvikelser saknades, men sannolikt har hormonnivåerna betydelse för hunger och mättnad.

Den sammantagna bilden visar användbarheten av WMC och permeabilitetstest för att bedöma patofysiologiska funktioner i mag-tarmkanalen. I-FABP kan spåra sjukdomsaktivitet i tunntarmen, medan permeabilitetstest ger information selektivt om sjukdom i tunntarm och colon. Användning av WMC tillsammans med mönster av hormonfrisättning kan ge information om motilitetsstörningar och sannolikt förändrad aptitreglering.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. , s. 62
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1577
Nyckelord [en]
Gastrointestinal motility, intestinal permeability, Mucosal, Ghrelin
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Medicinsk vetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-382486ISBN: 978-91-513-0671-1 (tryckt)OAI: oai:DiVA.org:uu-382486DiVA, id: diva2:1307132
Disputation
2019-06-14, Enghoffsalen, Ing 50 bv, Akademiska sjukhuset, Uppsala, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-05-23 Skapad: 2019-04-25 Senast uppdaterad: 2019-06-17
Delarbeten
1. Validation of SmartPill® wireless motility capsule for gastrointestinaltransit time: Intra-subject variability, software accuracy and comparison with video capsule endoscopy
Öppna denna publikation i ny flik eller fönster >>Validation of SmartPill® wireless motility capsule for gastrointestinaltransit time: Intra-subject variability, software accuracy and comparison with video capsule endoscopy
Visa övriga...
2017 (Engelska)Ingår i: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 29, nr 10, artikel-id e13107Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND: There is interest in ultimately combining endoscopy and motility assessments. Gastric emptying (GET), small bowel (SBTT), colon (CTT) and whole gut transit (WGTT) times are conveniently obtained by SmartPill® wireless motility capsule (WMC) that records luminal pH, temperature and pressure. Reproducibility within same subjects and accuracy of software derived times (MotiliGI® ) were investigated for diagnostic application. GET and SBTT were separately measured using video capsule endoscopy (VCE). The aim of this investigation was to assess same subject reproducibility of WMC, accuracy of software derived transit times and relate to Pillcam® SB (small bowel) VCE motility data.

METHODS: Seventy three healthy adults ingested a 260 kcal mixed meal followed by WMC tests. Food intake was permitted after 6 hours. Regional transit data was obtained for GET, SBTT and CTT, the sum yielding WGTT. Nineteen subjects repeated WMC tests 2 or 4 weeks later; a separate 70 underwent VCE while fasted.

KEY RESULTS: Visually derived data from WMC yielded GET 3.46±0.27, SBTT 5.15±0.21, CTT 20.76±1.19 and WGTT 29.53±1.28 hours (mean±SEM). Pearson's correlation coefficients (r) against software derived results were: GET 0.78 (P<.0001), SBTT 0.28 (P<.05), CTT 0.96 (P<.0001), WGTT 0.99 (P<.0001). VCE yielded lower GET (0.71±0.08 hours) and SBTT (4.15±0.13 hours).

CONCLUSIONS AND INFERENCES: GET, SBTT, CTT and WGTT obtained by WMC are commensurate with literature values, including by other methods. Visually and software derived transit times have strongest correlations for CTT and WGTT. WMC yields longer GET and SBTT than VCE, perhaps due to meal related effects on motility.

Nationell ämneskategori
Gastroenterologi
Identifikatorer
urn:nbn:se:uu:diva-322579 (URN)10.1111/nmo.13107 (DOI)000410149700014 ()
Forskningsfinansiär
Svenska läkaresällskapet, SLS-503131Jerringfonden
Tillgänglig från: 2017-05-26 Skapad: 2017-05-26 Senast uppdaterad: 2019-04-29
2. Parallel Changes in Harvey-Bradshaw Index, TNFα, and Intestinal Fatty Acid Binding Protein  in Response to Infliximab in Crohn’s Disease
Öppna denna publikation i ny flik eller fönster >>Parallel Changes in Harvey-Bradshaw Index, TNFα, and Intestinal Fatty Acid Binding Protein  in Response to Infliximab in Crohn’s Disease
Visa övriga...
2017 (Engelska)Ingår i: Gastroenterology Research and Practice, ISSN 1687-6121, E-ISSN 1687-630X, s. 1-8, artikel-id 1745918Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Intestinal fatty acid binding protein (I-FABP) indicates barrier integrity. Aims: determine if I-FABP is elevated in active Crohn's disease (CD) and if I-FABP parallels anti-TNF alpha antibody (infliximab) induced lowering of TNF alpha and Harvey-Bradshaw Index (HBI) as potential indicator of mucosal healing. I-FABP distribution along human gut was determined. Serum from 10 CD patients collected during first three consecutive infliximab treatments with matched pretreatment and follow-up samples one week after each treatment and corresponding HBI data were analyzed. I-FABP reference interval was established from 31 healthy subjects with normal gut permeability. I-FABP and TNF alpha were measured by ELISA; CRP was measured by nephelometry. Healthy tissue was used for I-FABP immunohistochemistry. Pretreatment CD patient TNF alpha was 1.6-fold higher than in-house reference interval, while I-FABP was 2.5-fold higher, which lowered at follow-ups. Combining all 30 infusion/follow-up pairs also revealed changes in I-FABP. HBI followed this pattern; CRP declined gradually. I-FABP was expressed in epithelium of stomach, jejunum, ileum, and colon, with the highest expression in jejunum and ileum. I-FABP is elevated in active CD with a magnitude comparable to TNF alpha. Parallel infliximab effects on TNF alpha, HBI, and I-FABP were found. I-FABP may be useful as an intestine selective prognostic marker in CD.

Ort, förlag, år, upplaga, sidor
Egypt: Hindawi Publishing Corporation, 2017
Nationell ämneskategori
Gastroenterologi
Identifikatorer
urn:nbn:se:uu:diva-334232 (URN)10.1155/2017/1745918 (DOI)000413557400001 ()
Forskningsfinansiär
Vetenskapsrådet, 7916Karolinska Institutets ForskningsstiftelseSveriges läkarförbund, SLS-411921; SLS-503131
Anmärkning

Title in WoS: Parallel Changes in Harvey-Bradshaw Index, TNF alpha, and Intestinal Fatty Acid Binding Protein in Response to Infliximab in Crohn's Disease

Tillgänglig från: 2017-11-21 Skapad: 2017-11-21 Senast uppdaterad: 2019-04-29Bibliografiskt granskad
3. Concurrent small and large intestinal permeability in inflammatory bowel disease: Hyper-permeability in IBD
Öppna denna publikation i ny flik eller fönster >>Concurrent small and large intestinal permeability in inflammatory bowel disease: Hyper-permeability in IBD
(Engelska)Manuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
Abstract [en]

Hyper-permeability in inflammatory bowel disease (IBD) has mostly been explored in the colon, where symptomatic inflammation is prevalent. Relationships between small and large intestine barrier function were examined. Fasted (4h) IBD (19 ulcerative colitis, 11 Crohn's disease) and 25 healthy control subjects’ were investigated. Lactulose (10g), mannitol (5g), riboflavin (0.05g) and sucralose (5g) were ingested with 500 mL water. Urine lactulose and mannitol were measured by enzyme assays, riboflavin by intrinsic fluorescence and sucralose by HPLC. CRP was measured by nephelometry. In IBD, small intestine lactulose and sucralose % recoveries were 1.77 and 2.73 fold higher than controls; combined data revealed the two probes were correlated (R2=0.6). In IBD, large intestine sucralose % recovery was 2.6 fold higher than controls and correlated with small intestine sucralose % recovery (R2=0.6). Conclusions: Sucralose yields similar result as lactulose for small intestine permeability, while having higher S:N, implying sucralose is more sensitive. No evidence was found for riboflavin malabsorption in IBD. There is concurrent small and large intestine hyper-permeability in IBD. Small intestine hyper-permeability is presumably related to inflammation in the large intestine, but without obvious deficiency in transporter mediated micronutrient absorption (i.e., riboflavin) in the small intestine.

Nyckelord
Crohn’s disease; Ulcerative colitis; Sucralose; Tight junction; Permeability; Intestine
Nationell ämneskategori
Klinisk medicin Gastroenterologi
Forskningsämne
Medicinsk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-383487 (URN)
Tillgänglig från: 2019-05-16 Skapad: 2019-05-16 Senast uppdaterad: 2019-05-17
4. Gastrointestinal motility examined by wireless motility capsule (SmartPill®) and gut hormone profiles in inflammatory bowel diseases: Motility and hormones inIBD
Öppna denna publikation i ny flik eller fönster >>Gastrointestinal motility examined by wireless motility capsule (SmartPill®) and gut hormone profiles in inflammatory bowel diseases: Motility and hormones inIBD
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Background: Inflammatory bowel disease (IBD) is associated with vague gastrointestinal (GI) discomfort even when inflammation is in clinical remission. In Crohn’s disease (CD) and ulcerative colitis (UC) motility disorders have been described throughout the GI tract. In clinics, considerable patient discomfort relates to symtoms of dysmotility (e.g., intestinal cramping, distension or diarrhea), which present in active and inactive disease. Treatment requires diagnostic methods to identify pathologies throughout the gut during meals while also evaluating gut peptide hormone changes.

Methods: SmartPill® wireless motility capsule (WMC) technique to identify pH and motility derangements along the GI tract. pH, luminal pressure, transit time and prandial peptide hormone changes were compared between either 10 CD patients or 10 UC patients relative 20 age- and sex-matched healthy controls.

Results: Motility index was significantly reduced in the stomach and contraction frequency and peak pressures were reduced in CD. Small bowel motility index was reduced in UC. In CD, meal responses of ghrelin, GIP, PYY and leptin, and to a lesser extent GLP-1, showed elevated plasma levels. In UC, ghrelin, GIP and GLP-1, but not PYY and leptin were elevated. Neither had a clear relationship to the motility discrepancies.

Conclusion: Enhanced endocrine meal responses may be a cause or result of motility disturbances in IBD, but cannot be broken down by individual peptides. These observations potentially give pathophysiological explanations for GI disturbances in IBD, opening the possibility for pharmacological treatment.

Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Medicinsk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-383491 (URN)
Tillgänglig från: 2019-05-16 Skapad: 2019-05-16 Senast uppdaterad: 2019-05-17

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