Publications by authors named "Hafid O Al-Hassi"

28 Publications

  • Page 1 of 1

The impact of treatment with bile acid sequestrants on quality of life in patients with bile acid diarrhoea.

BMC Gastroenterol 2022 Jul 2;22(1):325. Epub 2022 Jul 2.

The Royal Wolverhampton NHS Trust, Wolverhampton Road, Wolverhampton, WV10 0QP, UK.

Background: Bile acid diarrhoea (BAD) can be severely debilitating and negatively affect patients' quality of life (QoL). We carried out a multi-centre prospective study exploring QoL outcomes in patients with BAD after treatment with colesevelam.

Methods: Patients with or without a positive 23-seleno-25-homotaurocholic acid (SeHCAT) scan were recruited and categorised into four groups: SeHCAT negative control group (CG), idiopathic BAD, post-cholecystectomy (PC) and post-terminal ileal resection for Crohn's disease (CD). Patients with a positive SeHCAT were treated with colesevelam and dosing was titrated to symptomatic response. Patients were reviewed at 4- and 8-weekly intervals and QoL was evaluated by EQ-5D-3L, SF-36, IBDQ-32 at each visit (where relevant). Patients with a negative SeHCAT (CG cohort) completed one set of questionnaires before being discharged from the study.

Results: 47 patients (BAD = 24, PC = 12, CD = 11) completed paired QoL questionnaires before and after treatment and 30 CG patients completed a baseline questionnaire. There was a significant improvement in IBDQ-32 mean scores before and after treatment in CD patients [134.6 (95%CI 112.5-156.6) and 158.4 (136.1-180.6), respectively (p = 0.007). Following treatment, BAD patients had significantly improved mean SF-36 scores in the "Role limitation due to physical health" dimension (p = 0.02) and in the overall mental component summary (p = 0.03). Prior to starting treatment, BAD patients had the lowest scores in the 'activity' dimension of the EQ-5D-3L (p = 0.04), which improved significantly after treatment (p = 0.002). Overall, the BAD and CD cohort showed improved mean scores with treatment in all components of the SF-36 and EQ-5D-3L, while the PC cohort showed a general decline in mean scores after treatment. 55% of patients clinically responded to treatment of which 41.7%, 58.3% and 81.8% responded from the BAD, PC and CD groups respectively. Correlations between those deemed as responders with improvements on the SF-36 and EQ-5D dimensions were not statistically significant.

Conclusion: Our results demonstrate improved QoL in the BAD and CD cohort with treatment. Further larger studies are recommended specifically investigating the PC cohort and whether patients may improve with newer treatments such as FXR agonists. Trial registration Ethical approval REC Ref: 16/LO/1325.
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http://dx.doi.org/10.1186/s12876-022-02404-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250209PMC
July 2022

Variability in the Pre-Analytical Stages Influences Microbiome Laboratory Analyses.

Genes (Basel) 2022 Jun 15;13(6). Epub 2022 Jun 15.

Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK.

Introduction: There are numerous confounding variables in the pre-analytical steps in the analysis of gut microbial composition that affect data consistency and reproducibility. This study compared two DNA extraction methods from the same faecal samples to analyse differences in microbial composition.

Methods: DNA was extracted from 20 faecal samples using either (A) chemical/enzymatic heat lysis (lysis buffer, proteinase K, 95 °C + 70 °C) or (B) mechanical and chemical/enzymatic heat lysis (bead-beating, lysis buffer, proteinase K, 65 °C). Gut microbiota was mapped through the 16S rRNA gene (V3-V9) using a set of pre-selected DNA probes targeting >300 bacteria on different taxonomic levels. Apart from the pre-analytical DNA extraction technique, all other parameters including microbial analysis remained the same. Bacterial abundance and deviations in the microbiome were compared between the two methods.

Results: Significant variation in bacterial abundance was seen between the different DNA extraction techniques, with a higher yield of species noted in the combined mechanical and heat lysis technique (B). The five predominant bacteria seen in both (A) and (B) were spp. and spp. ( NS), followed by ( 0.005), ( 0.0001), spp. ( 0.0001) and ( 0.0001).

Conclusion: As microbial testing becomes more easily and commercially accessible, a unified international consensus for optimal sampling and DNA isolation procedures must be implemented for robustness and reproducibility of the results.
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http://dx.doi.org/10.3390/genes13061069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223004PMC
June 2022

A single faecal bile acid stool test demonstrates potential efficacy in replacing SeHCAT testing for bile acid diarrhoea in selected patients.

Sci Rep 2022 05 18;12(1):8313. Epub 2022 May 18.

Clinical Chemistry, Black Country Pathology Services, The Royal Wolverhampton NHS Trust, Wolverhampton, UK.

This study examines the validity of measuring faecal bile acids (FBA) in a single stool sample as a diagnostic tool for bile acid diarrhoea (BAD) by direct comparison to the selenium-homotaurocholic acid (SeHCAT) scan. A prospective observational study was undertaken. Patients with chronic diarrhoea (> 6 weeks) being investigated for potential BAD with SeHCAT scan provided stool samples for measurement of FBA, using an enzyme-linked immunosorbent assay. Patients were characterised into four groups: SeHCAT negative control group, post-cholecystectomy, idiopathic BAD and post-operative terminal ileal resected Crohn's disease. Stool samples were collected at baseline and 8-weeks post treatment to determine whether FBA measurement could be used to monitor therapeutic response. 113 patients had a stool sample to directly compare with their SeHCAT result. FBA concentrations (μmol/g) and interquartile ranges in patients in the control group (2.8; 1.6-4.2), BAD (3.6; 1.9-7.2) and post-cholecystectomy cohort 3.8 (2.3-6.8) were similar, but all were significantly lower (p < 0.001) compared to the Crohn's disease cohort (11.8; 10.1-16.2). FBA concentrations in patients with SeHCAT retention of < 15% (4.95; 2.6-10.5) and < 5% (9.9; 4.8-15.4) were significantly higher than those with a SeHCAT retention > 15% (2.6; 1.6-4.2); (p < 0.001 and p < 0.0001, respectively). The sensitivity and specificity using FBA cut-off of 1.6 μmol/g (using ≤ 15% SeHCAT retention as diagnostic of BAD) were 90% and 25% respectively. A single random stool sample may have potential use in diagnosing severe BAD or BAD in Crohn's patients. Larger studies are now needed to confirm the potential efficacy of this test to accurately diagnose BAD in the absence of SeHCAT testing.
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http://dx.doi.org/10.1038/s41598-022-12003-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117305PMC
May 2022

Bile Acids and the Microbiome: Making Sense of This Dynamic Relationship in Their Role and Management in Crohn's Disease.

Can J Gastroenterol Hepatol 2022 22;2022:8416578. Epub 2022 Mar 22.

Department of Gastroenterology, The Royal Wolverhampton NHS Trust, New Cross Hospital, Wolverhampton, UK.

Background: Bile acids help maintain the physiological balance of the gut microbiome and the integrity of the intestinal epithelial barrier. Similarly, intestinal bacteria play a major role in bile acid metabolism as they are involved in crucial biotransformation steps in the enterohepatic circulation pathway. Understanding the relationship between bile acid signalling and the gut microbiome in Crohn's disease can help target new and innovative treatment strategies.

Aims: This review summarises the relationship between bile acids and the microbiome in Crohn's disease and discusses potential novel therapeutic options.

Methods: We performed a literature review on bile acid signalling, its effect on the gut microbiome, and therapeutic applications in Crohn's disease.

Results: Current research suggests that there is a strong interplay between the dysregulated microbiota, bile acid metabolism, and the mucosal immune system that can result in a changed immunological function, triggering the inflammatory response in Crohn's disease. Recent studies have demonstrated an association with altering the enterohepatic circulation and activating the farnesoid X receptor signalling pathway with the use of probiotics and faecal microbial transplantation, respectively. Bile acid sequestrants have been shown to have anti-inflammatory, cytoprotective, and anti-apoptotic properties with the potential to alter the intestinal microbial composition, suggesting a possible role in inducing and maintaining Crohn's disease.

Conclusions: Active Crohn's disease has been correlated with changes in bacterial concentrations, which may be associated with changes in bile acid modification. Further research should focus on targeting these areas for future therapeutic options.
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http://dx.doi.org/10.1155/2022/8416578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964223PMC
April 2022

Intravenous iron is non-inferior to oral iron regarding cell growth and iron metabolism in colorectal cancer associated with iron-deficiency anaemia.

Sci Rep 2021 07 1;11(1):13699. Epub 2021 Jul 1.

Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK.

Oral iron promotes intestinal tumourigenesis in animal models. In humans, expression of iron transport proteins are altered in colorectal cancer. This study examined whether the route of iron therapy alters iron transport and tumour growth. Colorectal adenocarcinoma patients with pre-operative iron deficiency anaemia received oral ferrous sulphate (n = 15), or intravenous ferric carboxymaltose (n = 15). Paired (normal and tumour tissues) samples were compared for expression of iron loading, iron transporters, proliferation, apoptosis and Wnt signalling using immunohistochemistry and RT-PCR. Iron loading was increased in tumour and distributed to the stroma in intravenous treatment and to the epithelium in oral treatment. Protein and mRNA expression of proliferation and iron transporters were increased in tumours compared to normal tissues but there were no significant differences between the treatment groups. However, intravenous iron treatment reduced ferritin mRNA levels in tumours and replenished body iron stores. Iron distribution to non-epithelial cells in intravenous iron suggests that iron is less bioavailable to tumour cells. Therefore, intravenous iron may be a better option in the treatment of colorectal cancer patients with iron deficiency anaemia due to its efficiency in replenishing iron levels while its effect on proliferation and iron metabolism is similar to that of oral iron treatment.
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http://dx.doi.org/10.1038/s41598-021-93155-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249613PMC
July 2021

Oral and Intravenous Iron Therapy Differentially Alter the On- and Off-Tumor Microbiota in Anemic Colorectal Cancer Patients.

Cancers (Basel) 2021 Mar 16;13(6). Epub 2021 Mar 16.

Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK.

Iron deficiency anemia is a common complication of colorectal cancer and may require iron therapy. Oral iron can increase the iron available to gut bacteria and may alter the colonic microbiota. We performed an intervention study to compare oral and intravenous iron therapy on the colonic tumor-associated (on-tumor) and paired non-tumor-associated adjacent (off-tumor) microbiota. Anemic patients with colorectal adenocarcinoma received either oral ferrous sulphate ( = 16) or intravenous ferric carboxymaltose ( = 24). On- and off-tumor biopsies were obtained post-surgery and microbial profiling was performed using 16S ribosomal RNA analysis. Off-tumor α- and β-diversity were significantly different between iron treatment groups. No differences in on-tumor diversity were observed. Off-tumor microbiota of oral iron-treated patients showed higher abundances of the orders Clostridiales, Cytophagales, and Anaeroplasmatales compared to intravenous iron-treated patients. The on-tumor microbiota was enriched with the orders Lactobacillales and Alteromonadales in the oral and intravenous iron groups, respectively. The on- and off-tumor microbiota associated with intravenous iron-treated patients infers increased abundances of enzymes involved in iron sequestration and anti-inflammatory/oncogenic metabolite production, compared to oral iron-treated patients. Collectively, this suggests that intravenous iron may be a more appropriate therapy to limit adverse microbial outcomes compared to oral iron.
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http://dx.doi.org/10.3390/cancers13061341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002270PMC
March 2021

Patients with gastrointestinal irritability after TGN1412-induced cytokine storm displayed selective expansion of gut-homing αβ and γδT cells.

Cancer Immunol Immunother 2021 Apr 13;70(4):1143-1153. Epub 2020 Oct 13.

Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, London, UK.

Following infusion of the anti-CD28 superagonist monoclonal antibody TGN1412, three of six previously healthy, young male recipients developed gastrointestinal irritability associated with increased expression of 'gut-homing' integrin β7 on peripheral blood αβT cells. This subset of patients with intestinal symptoms also displayed a striking and persistent expansion of putative Vδ2 γδT cells in the circulation which declined over a 2-year period following drug infusion, concordant with subsiding gut symptoms. These data demonstrate that TGN1412-induced gastrointestinal symptoms were associated with dysregulation of the 'gut-homing' pool of blood αβ and γδT cells, induced directly by the antibody and/or arising from the subsequent cytokine storm.
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http://dx.doi.org/10.1007/s00262-020-02723-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552579PMC
April 2021

Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm.

Cancer Immunol Immunother 2021 Apr 8;70(4):1127-1142. Epub 2020 Oct 8.

Antigen Presentation Research Group, Imperial College London, Northwick Park & St. Mark's Campus, London, UK.

Cytokine storm can result from cancer immunotherapy or certain infections, including COVID-19. Though short-term immune-related adverse events are routinely described, longer-term immune consequences and sequential immune monitoring are not as well defined. In 2006, six healthy volunteers received TGN1412, a CD28 superagonist antibody, in a first-in-man clinical trial and suffered from cytokine storm. After the initial cytokine release, antibody effect-specific immune monitoring started on Day + 10 and consisted mainly of evaluation of dendritic cell and T-cell subsets and 15 serum cytokines at 21 time-points over 2 years. All patients developed problems with concentration and memory; three patients were diagnosed with mild-to-moderate depression. Mild neutropenia and autoantibody production was observed intermittently. One patient suffered from peripheral dry gangrene, required amputations, and had persistent Raynaud's phenomenon. Gastrointestinal irritability was noted in three patients and coincided with elevated γδT-cells. One had pruritus associated with elevated IgE levels, also found in three other asymptomatic patients. Dendritic cells, initially undetectable, rose to normal within a month. Naïve CD8 T-cells were maintained at high levels, whereas naïve CD4 and memory CD4 and CD8 T-cells started high but declined over 2 years. T-regulatory cells cycled circannually and were normal in number. Cytokine dysregulation was especially noted in one patient with systemic symptoms. Over a 2-year follow-up, cognitive deficits were observed in all patients following TGN1412 infusion. Some also had signs or symptoms of psychological, mucosal or immune dysregulation. These observations may discern immunopathology, treatment targets, and long-term monitoring strategies for other patients undergoing immunotherapy or with cytokine storm.
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http://dx.doi.org/10.1007/s00262-020-02725-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543968PMC
April 2021

Influence of Iron on the Gut Microbiota in Colorectal Cancer.

Nutrients 2020 Aug 20;12(9). Epub 2020 Aug 20.

Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK.

Perturbations of the colonic microbiota can contribute to the initiation and progression of colorectal cancer, leading to an increase in pathogenic bacteria at the expense of protective bacteria. This can contribute to disease through increasing carcinogenic metabolite/toxin production, inducing inflammation, and activating oncogenic signaling. To limit disease progression, external factors that may influence the colonic microbiota need to be considered in patients with colorectal cancer. One major factor that can influence the colonic microbiota is iron. Iron is an essential micronutrient that is required by both prokaryotes and eukaryotes for cellular function. Most pathogenic bacteria have heightened iron acquisition mechanisms and therefore tend to outcompete protective bacteria for free iron. Colorectal cancer patients often present with anemia due to iron deficiency, and thus they require iron therapy. Depending upon the route of administration, iron therapy has the potential to contribute to a procarciongenic microbiota. Orally administered iron is the common treatment for anemia in these patients but can lead to an increased gut iron concentration. This suggests the need to reassess the route of iron therapy in these patients. Currently, this has only been assessed in murine studies, with human trials being necessary to unravel the potential microbial outcomes of iron therapy.
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http://dx.doi.org/10.3390/nu12092512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551435PMC
August 2020

Iron deficiency, immunology, and colorectal cancer.

Nutr Rev 2021 01;79(1):88-97

O. Phipps, M.J. Brookes, and H.O. Al-Hassi are with the Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, United Kingdom.

Excessive gut luminal iron contributes to the initiation and progression of colorectal cancer. However, emerging evidence suggests that reduced iron intake and low systemic iron levels are also associated with the pathogenesis of colorectal cancer. This is important because patients with colorectal cancer often present with iron deficiency. Iron is necessary for appropriate immunological functions; hence, iron deficiency may hinder cancer immunosurveillance and potentially modify the tumor immune microenvironment, both of which may assist cancer development. This is supported by studies showing that patients with colorectal cancer with iron deficiency have inferior outcomes and reduced response to therapy. Here, we provide an overview of the immunological consequences of iron deficiency and suggest ensuring adequate iron therapy to limit these outcomes.
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http://dx.doi.org/10.1093/nutrit/nuaa040DOI Listing
January 2021

Pilot study of immunological factors in non-inflammatory bowel disease enterocutaneous fistulas.

Int J Surg 2017 May 30;41:127-133. Epub 2017 Mar 30.

Colorectal Surgery and Lennard-Jones Intestinal Failure Unit, St. Mark's Hospital and Academic Institute, Watford Road, Harrow, Middlesex, HA1 3UJ, UK.

Background: Tumour necrosis factor alpha (TNF-α) is a cytokine elevated in inflammatory bowel disease enterocutaneous fistula (IBD ECF). Dendritic cells are antigen presenting cells that orchestrate the immune responses and regulate the production of cytokines by immune cells including T cells. No study to date has assessed the level of TNF-α or the presence of dendritic cells in non-IBD ECF. The aim of this study was to assess the inflammatory activity, with a particular emphasis on TNF-α in non-IBD ECF when compared with control small bowel tissue.

Methods: Tissue biopsies were obtained from ECF at operation from non-IBD patients and from terminal ileum in normal colonoscopy control patients. After overnight culture, accumulation of intracellular TNF-α was measured by flow cytometry in cells treated with monensin to assess the on-going cytokine production. Data were acquired using FACS Canto II. Unpaired Student's t-test was used to compare variables between groups and p < 0.05 was regarded as significant.

Results: The on-going production of TNF-α from dendritic cells (p = 0.0007), putative monocyte and B cell populations (p = 0.04) and CD3 T cells (p = 0.04) was significantly higher in non-IBD ECF tissue than that from control tissue.

Conclusions: This study reveals results which provide evidence for the potential use of anti-TNF-α agents in the treatment of non-IBD ECF. A pilot study to evaluate this treatment as an alternative option in an already surgically challenging group of patients is planned. Positive findings would be a major medical advance with a new use for anti-TNF-α agents.
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http://dx.doi.org/10.1016/j.ijsu.2017.03.079DOI Listing
May 2017

Body composition of the host influences dendritic cell phenotype in patients treated for colorectal cancer.

Tumour Biol 2016 Aug 10;37(8):11359-64. Epub 2016 Mar 10.

Antigen Presentation Research Group, Imperial College London, North West London Hospitals Campus, Watford Road, Harrow, HA1 3UJ, UK.

Dendritic cells (DCs) are antigen-presenting cells that can acquire tumour antigens and initiate cytotoxic T cell reactions. Obesity has been proposed as a cause for tumours escaping immune surveillance, but few studies investigate the impact of other body composition parameters. We examined the relationship of DC phenotype with computer tomography (CT)-defined parameters in patients with colorectal cancer (CRC). DCs were identified within peripheral blood mononuclear cells by flow cytometry as HLA-DR positive and negative for markers of other cell lineages in 21 patients. Analysis of CT scans was used to calculate lumbar skeletal muscle index (LSMI) and mean muscle attenuation (MA). Positive correlation between the LSMI and expression of CD40 in all DCs (r = 0.45; p = 0.04) was demonstrated. The MA was positively correlated with scavenger receptor CD36 [all DCs (r = 0.60; p = 0.01) and myeloid DCs (r = 0.63; p < 0.01)]. However, the MA was negatively correlated with CCR7 expression in all DCs (r = -0.46, p = 0.03.) and with CD83 [all DCs (r = -0.63; p = 0.01) and myeloid DCs (r = -0.75; p < 0.01)]. There were no relationships between the fat indexes and the DC phenotype. These results highlight a direct relationship between muscle depletion and changes in stimulatory, migratory and fatty acid-processing potential of DC in patients with CRC.
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http://dx.doi.org/10.1007/s13277-016-5009-yDOI Listing
August 2016

Age-related alterations in blood and colonic dendritic cell properties.

Oncotarget 2016 Mar;7(11):11913-22

Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK.

Background: Dendritic cells (DC) determine initiation, type and location of immune responses and, in adults, show decreased Toll-like receptors and some increased cytokine levels on ageing. Few studies in children have characterised DC or explored DC-related mechanisms producing age-related immune changes.

Results: The pDC marker BDCA2 (but not CD123) was absent in pre-pubertal children and numbers of pDC decreased with age. Blood and colonic DC were more mature and activated in adults. Decrease in pDC numbers correlated with reduced GM-CSF levels with aging, but increasing IL-4 and IL-8 levels correlated with a more activated DC profile in blood. CXCL16 levels decreased with age.

Methods: Blood and colonic DC phenotypes were determined in healthy adults and children by flow cytometry and correlated with aging. Blood DC were divided into plasmacytoid (pDC) and myeloid (mDC) while only mDC were identified in colon. Serum cytokine levels were determined by multiplex cytokine assays and correlated with DC properties.

Conclusions: In children, lack of BDCA2, a receptor mediating antigen capture and inhibiting interferon induction, may be immunologically beneficial during immune development. Conversely, reduced pDC numbers, probably secondary to decreasing GM-CSF and increasing cytokine-induced maturation of DC are likely to determine deteriorating immunity with ageing.
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http://dx.doi.org/10.18632/oncotarget.7799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914258PMC
March 2016

Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon.

Cell Mol Gastroenterol Hepatol 2016 Jan 3;2(1):22-39.e5. Epub 2015 Sep 3.

Antigen Presentation Research Group, Imperial College London, Harrow, United Kingdom.

Background & Aims: Most knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103 DC specialize in generating immune tolerance with the functionality of CD11b subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon.

Methods: Paired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing.

Results: Colonic DC identified were myeloid (mDC, CD11cCD123) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103SIRPα DC were the major population and with CD103SIRPα DC were CD1cILT3CCR2 (although CCR2 was not expressed on all CD103SIRPα DC). CD103SIRPα DC constituted a minor subset that were CD141ILT3CCR2. Proximal colon samples had higher total DC counts and fewer CD103SIRPα cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4CD45RA T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c, but not CD141 mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments.

Conclusions: Proximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.
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http://dx.doi.org/10.1016/j.jcmgh.2015.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705905PMC
January 2016

The prognostic significance and relationship with body composition of CCR7-positive cells in colorectal cancer.

J Surg Oncol 2015 Jul 14;112(1):86-92. Epub 2015 Jul 14.

Department of Surgery St. Marks Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK.

Background And Objectives: The host local immune response (LIR) to cancer is a determinant of cancer outcome. Regulation of this local response is largely achieved through chemokine synthesis from the tumor microenvironment such as C-Chemokine-Receptor-7 (CCR7). We examined the LIR measured as CCR7 expression, in colorectal cancers (CRC) and explored relationships with body composition (BC) and survival.

Methods: A study of paraffin-embedded tissue specimens was carried out in 116 patients with non-metastatic CRC. CCR7 expression was determined by immunohistochemistry. Analysis of computer tomography scans was used to calculate BC parameters. Survival analyses and multivariate regression models were used.

Results: High CCR7(+) cell density within the tumor stroma and at the margin was significantly associated with increased age, the presence of lymphovascular invasion, higher tumor stage, lymph node metastasis, high Klintrup-Makinen immune score, and myosteatosis. High CCR7(+) cell density in the tumor margin was significantly associated with shorter disease-free (DFS) and overall survival (OS) (P < 0.001). This was also significantly associated with shorter survival in multivariate analysis (HR = 8.87; 95%CI [2.51-31.3]; P < 0.01 for OS and HR = 4.72; 95%CI (1.24-12.9); P = 0.02 for DFS).

Conclusions: Our results suggest that a specific immune microenvironment may be associated with altered host's BC and tumor behavior, and that CCR7 may serve as a novel prognostic biomarker.
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http://dx.doi.org/10.1002/jso.23959DOI Listing
July 2015

Prognostic Value of the Tumour-Infiltrating Dendritic Cells in Colorectal Cancer: A Systematic Review.

Cell Commun Adhes 2015 30;22(1):9-14. Epub 2015 May 30.

a Antigen Presentation Research Group, Imperial College London, North West London Hospitals Campus , Harrow, Middlesex , UK.

Dendritic cells (DCs) either boost the immune system (enhancing immunity) or dampen it (leading to tolerance). This dual effect explains their vital role in cancer development and progression. DCs have been tested as a predictor of outcomes for cancer progression. Eight studies evaluated tumour-infiltrating DCs (TIDCs) as a predictor for colorectal cancer (CRC) outcomes. The detection of TIDCs has not kept pace with the increased knowledge about the identification of DC subsets and their maturation status. For that reason, it is difficult to draw a conclusion about the performance of DCs as a predictor of outcome for CRC. In this review, we comprehensively examine the evidence for the in situ immune response due to DC infiltration, in predicting outcome in primary CRC and how such information may be incorporated into routine clinical assessment.
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http://dx.doi.org/10.3109/15419061.2015.1036859DOI Listing
June 2016

Human colon-derived soluble factors modulate gut microbiota composition.

Front Oncol 2015 13;5:86. Epub 2015 Apr 13.

Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Food Science and Technology Faculty, University of Vigo , Ourense , Spain.

The commensal microbiota modulates immunological and metabolic aspects of the intestinal mucosa contributing to development of human gut diseases including inflammatory bowel disease. The host/microbiota interaction often referred to as a crosstalk, mainly focuses on the effect of the microbiota on the host neglecting effects that the host could elicit on the commensals. Colonic microenvironments from three human healthy controls (obtained from the proximal and distal colon, both in resting conditions and after immune - IL-15- and microbiota - LPS-in vitro challenges) were used to condition a stable fecal population. Subsequent 16S rRNA gene-based analyses were performed to study the effect induced by the host on the microbiota composition and function. Non-supervised principal component analysis (PCA) showed that all microbiotas, which had been conditioned with colonic microenvironments clustered together in terms of relative microbial composition, suggesting that soluble factors were modulating a stable fecal population independently from the treatment or the origin. Our findings confirmed that the host intestinal microenvironment has the capacity to modulate the gut microbiota composition via yet unidentified soluble factors. These findings indicate that an appropriate understanding of the factors of the host mucosal microenvironment affecting microbiota composition and function could improve therapeutic manipulation of the microbiota composition.
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http://dx.doi.org/10.3389/fonc.2015.00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394693PMC
April 2015

Compartment-specific immunity in the human gut: properties and functions of dendritic cells in the colon versus the ileum.

Gut 2016 Feb 9;65(2):256-70. Epub 2015 Feb 9.

Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK.

Objective: Dendritic cells (DC) mediate intestinal immune tolerance. Despite striking differences between the colon and the ileum both in function and bacterial load, few studies distinguish between properties of immune cells in these compartments. Furthermore, information of gut DC in humans is scarce. We aimed to characterise human colonic versus ileal DC.

Design: Human DC from paired colonic and ileal samples were characterised by flow cytometry, electron microscopy or used to stimulate T cell responses in a mixed leucocyte reaction.

Results: A lower proportion of colonic DC produced pro-inflammatory cytokines (tumour necrosis factor-α and interleukin (IL)-1β) compared with their ileal counterparts and exhibited an enhanced ability to generate CD4(+)FoxP3(+)IL-10(+) (regulatory) T cells. There were enhanced proportions of CD103(+)Sirpα(-) DC in the colon, with increased proportions of CD103(+)Sirpα(+) DC in the ileum. A greater proportion of colonic DC subsets analysed expressed the lymph-node-homing marker CCR7, alongside enhanced endocytic capacity, which was most striking in CD103(+)Sirpα(+) DC. Expression of the inhibitory receptor ILT3 was enhanced on colonic DC. Interestingly, endocytic capacity was associated with CD103(+) DC, in particular CD103(+)Sirpα(+) DC. However, expression of ILT3 was associated with CD103(-) DC. Colonic and ileal DC differentially expressed skin-homing marker CCR4 and small-bowel-homing marker CCR9, respectively, and this corresponded to their ability to imprint these homing markers on T cells.

Conclusions: The regulatory properties of colonic DC may represent an evolutionary adaptation to the greater bacterial load in the colon. The colon and the ileum should be regarded as separate entities, each comprising DC with distinct roles in mucosal immunity and imprinting.
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http://dx.doi.org/10.1136/gutjnl-2014-307916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530083PMC
February 2016

Low Muscularity and Myosteatosis Is Related to the Host Systemic Inflammatory Response in Patients Undergoing Surgery for Colorectal Cancer.

Ann Surg 2016 Feb;263(2):320-5

*Department of Surgery, St Marks Hospital, Harrow, Middlesex, UK †Antigen Presentation Research Group of Imperial College, St Marks Hospital, Harrow, Middlesex, UK ‡Department of Clinical and Surgical Sciences, University of Edinburgh, Scotland §Department of Surgery and Cancer, Imperial College, Paddington, London, UK ¶Department of Colorectal Surgery, The Christie NHS Foundation Trust, Manchester, UK.

Objective: We examined the relationships between computed tomography (CT)-defined skeletal muscle parameters and the systemic inflammatory response (SIR) in patients with operable primary colorectal cancer (CRC).

Background: Muscle depletion is characterized by a reduced muscle mass (myopenia) and increased infiltration by inter- and intramuscular fat (myosteatosis). It is recognized as a poor prognostic indicator in patients with cancer, but the underlying factors remain unclear.

Methods: A total of 763 patients diagnosed with CRC undergoing elective surgical resection between 2006 and 2013 were included. Image analysis of CT scans was used to calculate Lumbar skeletal muscle index (LSMI), and mean muscle attenuation (MA). The SIR was quantified by the preoperative neutrophil to lymphocyte ratio (NLR) and albumin levels. Correlation and multivariate regression analysis was performed to identify independent relationships between patient SIR and muscle characteristics.

Results: Patients with NLR > 3 had significantly lower LSMI and lower MA than those with NLR < 3 [LSMI = 42.07 cmm vs 44.27 cmm (P = 0.002) and MA = 30.04 Hounsfield unit (HU) vs 28.36 HU (P = 0.016)]. Multivariate logistic regression analysis showed that high NLR [odds ratio (OR) = 1.78 (95% confidence interval [CI]: 1.29-2.45), P < 0.001] and low albumin [OR = 1.80 (95% CI: 1.17-2.74), P = 0.007] were independent predictors of reduced muscle mass. High NLR was significantly related with a low mean MA and hence myosteatosis [OR = 1.60 (95% CI: 1.03-2.49), P = 0.038].

Conclusions: These results highlight a direct association between myopenia, myosteatosis, and the host SIR in patients with operable CRC. A better understanding of factors that regulate muscle changes such as myopenia and myosteatosis may lead to the development of novel therapies that influence a more metabolically "healthy" skeletal muscle and potentially alter cancer outcomes.
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http://dx.doi.org/10.1097/SLA.0000000000001113DOI Listing
February 2016

Human gut dendritic cells drive aberrant gut-specific t-cell responses in ulcerative colitis, characterized by increased IL-4 production and loss of IL-22 and IFNγ.

Inflamm Bowel Dis 2014 Dec;20(12):2299-307

*Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, United Kingdom; †Gastrointestinal Division, Johns Hopkins University School of Medicine, Baltimore, Maryland; ‡Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Science, State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China; §Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom; ‖Department of Gastroenterology, St. Mark's Hospital, North West London Hospitals NHS Trust, Harrow, United Kingdom; ¶Yakult UK Ltd., South Ruislip, United Kingdom; and **Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

: The pathogenesis of inflammatory bowel disease is incompletely understood but results from a dysregulated intestinal immune response to the luminal microbiota. CD4 T cells mediate tissue injury in the inflammatory bowel disease-associated immune response. Dendritic cells (DC) generate primary T-cell responses and mediate intestinal immune tolerance to prevent overt inflammation in response to the gut microbiota. However, most information regarding function of intestinal DC has come from mouse models, and information in humans is scarce. We show here that intestinal DC subsets are skewed in ulcerative colitis (UC) in humans, with a loss of CD103 lymph-node homing DC; this intestinal DC subset preferentially generates regulatory T cells in mice. We show infiltrates of DC negative for myeloid marker CD11c, with enhanced expression of Toll-like receptors for bacterial recognition. After mixed leukocyte reaction, DC from the inflamed UC colon had an enhanced ability to generate gut-specific CD4 T cells with enhanced production of interleukin-4 but a loss of interferon γ and interleukin-22 production. Conditioning intestinal DC with probiotic strain Lactobacillus casei Shirota in UC partially restored their normal function indicated by reduced Toll-like receptor 2/4 expression and restoration of their ability to imprint homing molecules on T cells and to generate interleukin-22 production by stimulated T cells. This study suggests that T-cell dysfunction in UC is driven by DC. T-cell responses can be manipulated indirectly through effects of bacterial conditioning on gut DC with implications for immunomodulatory effects of the commensal microbiota in vivo. Manipulation of DC to allow generation of DC-specific therapy may be beneficial in inflammatory bowel disease.
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http://dx.doi.org/10.1097/MIB.0000000000000223DOI Listing
December 2014

Innate immune factors in the development and maintenance of pouchitis.

Inflamm Bowel Dis 2014 Nov;20(11):1942-9

*Department of Gastroenterology, St Mark's Hospital, London, United Kingdom; †Antigen Presentation Research Group, Imperial College London, Northwick Park and St Mark's Campus, London, United Kingdom; ‡Department of Gastroenterology, The Rayne Institute, St Thomas' Hospital, London, United Kingdom; and §Department of Surgery, St Mark's Hospital, London, United Kingdom.

Background: Tight junction proteins (TJPs) and dendritic cells (DC) are critical in the pathogenesis of inflammatory bowel diseases. The ileal pouch formed by restorative proctocolectomy provides a unique human model for studying the pathogenesis of inflammatory bowel diseases. Data implicate the microbiota in the pathogenesis of pouchitis, while the role of innate immune factors remains unclear. We performed longitudinal and cross-sectional studies of patients after restorative proctocolectomy and assessed TJP and DC characteristics in the ileal pouch.

Methods: Mucosal biopsies were taken from the ileal pouch of patients with ulcerative colitis (UC) and familial adenomatous polyposis (n = 8). Of patients with UC, one group (n = 5) was followed longitudinally over the first year after ileostomy closure, another group had pouchitis (n = 15), and another group no inflammation (n = 18). Dendritic cell phenotype and epithelial cell TJP expression were assessed using flow cytometric analysis.

Results: Increased epithelial expression of the "pore-forming" TJP claudin 2, and DC expression of gut-homing markers CCR 9 and integrin β7, occurred early after ileostomy closure. In patients with UC with pouchitis, epithelial expression of ZO-1 and claudin 1 were reduced, DC were activated with increased CD40, and Toll-like receptor 4 expression increased. In pouchitis, DC expressing CCR 9 were decreased, whereas DC expressing β7 increased.

Conclusions: Abnormalities were found in TJP expression in the pouch of patients with UC, in particular, increased expression of the pore-forming claudin 2 as an early event in the development of pouch inflammation and an aberrant DC phenotype was characterized in the ileal pouch of patients with UC.
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http://dx.doi.org/10.1097/MIB.0000000000000182DOI Listing
November 2014

Altered human gut dendritic cell properties in ulcerative colitis are reversed by Lactobacillus plantarum extracellular encrypted peptide STp.

Mol Nutr Food Res 2014 May 18;58(5):1132-43. Epub 2013 Dec 18.

Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, UK.

Scope: The human/microbiota cross-talk is partially mediated by bacteria-derived peptides like Serine-Threonine peptide (STp), which is resistant to gut proteolysis, is found in the human healthy colon and induces regulatory properties on gut dendritic cells (DCs); here we characterized human gut DC in ulcerative colitis (UC) patients and studied the effect of STp on their properties.

Methods And Results: Human colonic DC from healthy controls and UC patients were isolated, conditioned for 24 h +/- STp and characterized by flow cytometry, immunohistochemistry, and electron microscopy. Expression of immature DC markers DC-SIGN and ILT3, and Toll-like receptors were increased on gut UC-DC. Langerin (involved in phagocytosis), lymph node homing marker CCR7, and activation markers CD40/CD80/CD86 were decreased in UC. Gut DC had restricted stimulatory capacity for T-cells in UC. Conditioning of DC with STp in vitro reduced Toll-like receptor expression, increased CD40 and CD80 expression, and restored their stimulatory capacity.

Conclusion: Colonic DCs display an abnormal immature phenotype in UC, which was partially restored following STp treatment. Bacteria-derived metabolites, like STp, seem to have a role in gut homeostasis that is missing in UC so they might lead a new era of probiotic products setting the basis for nondrug dietary therapy in inflammatory bowel disease.
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http://dx.doi.org/10.1002/mnfr.201300596DOI Listing
May 2014

Mechanisms of action of anti-tumor necrosis factor α agents in Crohn's disease.

Inflamm Bowel Dis 2013 Jun;19(7):1546-55

Antigen Presentation Research Group, Imperial College, Northwick Park and St Mark's Hospital Campus, Watford Road, Harrow, Middlesex, United Kingdom.

Crohn's disease (CD) is characterized by inflammation that can affect any part of the gastrointestinal tract. It is a chronic destructive condition that follows a relapsing-remitting course and can lead to disability and a poor quality of life. Lifelong pharmacotherapy with systemic immunomodulator therapies remains the cornerstone of CD management. Advances in understanding of the immunopathogenic mechanisms underlying chronic gut inflammation in CD have led to the development of effective biological therapies for patients with CD. Tumor necrosis factor α (TNF-α) is a potent proinflammatory cytokine that plays a pivotal role in the development of Crohn's inflammation. Therapies designed to target this cytokine have revolutionized treatment of CD since their introduction in the late 1990s, thanks to their ability to induce and maintain remission, heal mucosa, reduce hospital admissions and surgical procedures, and restore quality of life. Despite widespread use of these therapies in CD, their precise mechanism of action remains unclear, although several different mechanisms have been proposed. This review summarizes the biology of the TNF-α cytokine and the development of biological therapies targeting TNF-α, and updates our current understanding of mechanisms of action of the commercially available anti-TNF-α therapies used in the treatment of CD.
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http://dx.doi.org/10.1097/MIB.0b013e318281333bDOI Listing
June 2013

Microbiota/host crosstalk biomarkers: regulatory response of human intestinal dendritic cells exposed to Lactobacillus extracellular encrypted peptide.

PLoS One 2012 14;7(5):e36262. Epub 2012 May 14.

Antigen Presentation Research Group, Imperial College London, Harrow, United Kingdom.

The human gastrointestinal tract is exposed to a huge variety of microorganisms, either commensal or pathogenic; at this site, a balance between immunity and immune tolerance is required. Intestinal dendritic cells (DCs) control the mechanisms of immune response/tolerance in the gut. In this paper we have identified a peptide (STp) secreted by Lactobacillus plantarum, characterized by the abundance of serine and threonine residues within its sequence. STp is encoded in one of the main extracellular proteins produced by such species, which includes some probiotic strains, and lacks cleavage sites for the major intestinal proteases. When studied in vitro, STp expanded the ongoing production of regulatory IL-10 in human intestinal DCs from healthy controls. STp-primed DC induced an immunoregulatory cytokine profile and skin-homing profile on stimulated T-cells. Our data suggest that some of the molecular dialogue between intestinal bacteria and DCs may be mediated by immunomodulatory peptides, encoded in larger extracellular proteins, secreted by commensal bacteria. These peptides may be used for the development of nutraceutical products for patients with IBD. In addition, this kind of peptides seem to be absent in the gut of inflammatory bowel disease patients, suggesting a potential role as biomarker of gut homeostasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036262PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351486PMC
October 2012

IL-6 promotes immune responses in human ulcerative colitis and induces a skin-homing phenotype in the dendritic cells and Tcells they stimulate.

Eur J Immunol 2012 May;42(5):1337-53

Antigen Presentation Research Group, Imperial College London, Northwick Park & St Mark's Campus, Watford Road, Harrow, United Kingdom.

Dendritic cells (DCs) control the type and location of immune responses. Ulcerative colitis (UC) is considered a Th2 disease mediated by IL-13 where up to one third of patients can develop extraintestinal manifestations. Colonic biopsies from inflamed and noninflamed areas of UC patients were cultured in vitro and their supernatants were used to condition human blood enriched DCs from healthy controls. Levels of IL-13 in the culture supernatants were below the detection limit in most cases and the cytokine profile suggested a mixed profile rather than a Th2 cytokine profile. IL-6 was the predominant cytokine found in inflamed areas from UC patients and its concentration correlated with the Mayo endoscopic score for severity of disease. DCs conditioned with noninflamed culture supernatants acquired a regulatory phenotype with decreased stimulatory capacity. However, DCs conditioned with inflamed culture supernatants acquired a proinflammatory phenotype with increased expression of the skin-homing chemokine CCR8. These DCs did not have decreased T-cell stimulatory capacity and primed T cells with the skin-homing CLA molecule in an IL-6-dependent mechanism. Our results highlight the role of IL-6 in UC and question the concept of UC as a Th2 disease and the relevance of IL-13 in its etiology.
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http://dx.doi.org/10.1002/eji.201142327DOI Listing
May 2012

T-cell proliferation and forkhead box P3 expression in human T cells are dependent on T-cell density: physics of a confined space?

Hum Immunol 2012 Mar 3;73(3):223-31. Epub 2012 Jan 3.

Antigen, Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, HA1 3UJ, UK.

T-cell proliferation rates in vitro depend on factors including initial T-cell number, dose of stimulus, culture time, and available physical space. The role of forkhead box P3 (FoxP3) in the identification of T cells with a regulatory phenotype remains controversial in humans. Through 5-carboxyfluorescein diacetate succinimidyl ester labeling of human T cells and subsequent culture of different numbers of T cells and antigen-presenting cells (APC), we studied proliferative T-cell responses and FoxP3 expression in divided T cells. T-cell proliferation rates depended on initial T-cell/APC numbers. Proliferation rates decreased when high initial T-cell numbers were increased. FoxP3 expression was expressed exclusively in virtually all divided T cells cultured at high T-cell densities, irrespective of their CD4 nature or cytokine content, and was coexpressed with T-bet. However, when T cells were cultured on larger surfaces or at lower initial numbers, FoxP3 expression was not induced in divided T cells, even when most of the cells had undergone cell division. FoxP3(+) T cells generated at high cell densities did not elicit a suppressive phenotype and FoxP3 expression was subsequently lost in time when the stimulus was removed. Therefore, caution should be observed in the use of FoxP3 expression to identify regulatory T cells in humans because its expression may be only a consequence of activation status in a restricted environment.
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http://dx.doi.org/10.1016/j.humimm.2011.12.017DOI Listing
March 2012

Prospective study of immunological factors in non-inflammatory bowel disease enterocutaneous fistulas.

BMC Surg 2011 May 27;11:12. Epub 2011 May 27.

Colorectal and Intestinal Failure Surgery, St, Mark's Hospital and Academic Institute Watford Road, Harrow, Middlesex, HA1 3UJ, UK.

Background: Enterocutaneous fistulas (ECF) are debilitating and usually result following complex abdominal surgery. While there is an association with inflammatory bowel disease (IBD), a large number of fistulas occur after surgery not related to IBD. The consequences of ECF include short bowel syndrome and the need for long term parenteral nutrition.ECF can heal spontaneously and in the case of IBD can be cured by medical therapy in some instances. Those that do not resolve spontaneously have to be cured by surgery which is complex and associated with a high morbidity. It is not considered traditional treatment to use the same medical therapy as in IBD to cure ECF caused by other conditions.A small case series has reported three patients with persistent ECF not related to IBD to have healed following use of Infliximab which is the treatment commonly used for ECF caused by IBD. Infliximab acts by inhibiting the activity of the inflammatory cytokine TNF- alpha. It is not known if this cytokine is present in ECF tissue in the absence of IBD.The aim of this study is to demonstrate the presence of inflammatory markers in tissue surrounding non-IBD ECF and in particular to quantify the presence of the cytokine TNF- alpha. We hypothesise that TNF - alpha levels are raised in non-IBD ECF.

Methods/design: Tissue and serum from ECF of IBD and non-IBD patients will be prospectively collected at St. Mark's Hospital Intestinal Failure Unit. The control group will consist of patients undergoing colonoscopy for bowel cancer screening, with normal findings. Biopsies of the terminal ileum will be obtained from this group during colonoscopy. The fistula tract and serum cytokine profiles of interleukins (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, TNF- alpha, IFN-y, MCP-1, EGF and VEGF will be assessed.

Discussion: This study aims to assess the presence or absence of TNF- alpha expression in the ECF tissue in non-IBD origin. If our hypothesis is correct we would then be able to study the use of the TNF- alpha inhibitor Infliximab as a therapeutic option in the treatment of non-IBD ECF. Secondary aims include assessing the spectrum of inflammatory cytokines and markers present in tissue and serum of non-IBD ECF when compared with IBD ECF and normal controls.

Trial Registration: ISRCTN44000447.
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http://dx.doi.org/10.1186/1471-2482-11-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116454PMC
May 2011
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