Evaluation of 13,466 Fecal Immunochemical Tests in Patients Attending Primary Care for High- and Low-Risk Gastrointestinal Symptoms of Colorectal Cancer.

AIM/OBJECTIVE: Quantitative fecal immunochemical tests (FIT) were recommended by NICE for patients in primary care presenting with low-risk symptoms of colorectal cancer (CRC). FIT is more accurate in the detection of CRC than symptom criteria. Despite this, CRC still occurs with a negative FIT and the importance of safety netting for patients with severe or persistent symptoms is paramount. We aimed to evaluate the utilization and accuracy of FIT for CRC in low and high-risk symptom groups presenting to primary care, the effectiveness of safety netting in primary care, referral practices with FIT utilization for symptomatic patients and the clinical features of FIT negative patients with CRC. MATERIALS AND METHODS: Medical records and databases of all patients undertaking a FIT sample in the Herts Valleys CCG between June 2019 and November 2021 were reviewed. 13,466 consecutive FIT samples were requested for 12,231 patients between June 2019 and November 2021. RESULTS: Analysis of diagnostic accuracy was undertaken for the first 5341 patients with a minimum of 12 months follow up. Sensitivity for CRC, in FIT ≥ 4 µg Hb/g, ≥ 10 µg Hb/g and ≥ 100 µg Hb/g was 93% (95% CI 85-98%), 91% (95% CI 82-96%) and 72% (95% CI 60-81%) with a number needed to investigate of 36, 19 and 6, respectively. CONCLUSION: A FIT ≥ 10 µg Hb/g in conjunction with ongoing GP clinical concern within 8 weeks had a sensitivity for CRC of 97% (95% CI 90-100%), a PPV of 3.6% (95% CI 3.4-3.7%) and a number needed to investigate to detect one CRC of 28.

Clostridium difficile and cystic fibrosis: management strategies and the role of faecal transplantation.

Clostridium difficile is a bacterial infection that colonises the gut in susceptible hosts. It is associated with exposure to healthcare settings and antibiotic use. It could be assumed that cystic fibrosis (CF) patients are a high-risk group for C.difficile. However, despite high carriage rates, CF patients have low rates of active disease. There are guidelines for the treatment of C.difficile, however little is published specific to treating C.difficile in CF. This article provides an overview of the current management strategies for C.difficile in CF, including a description of the first faecal transplantation in this patient population.

Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.

Inflammatory bowel diseases are characterised by inflammation that compromises the integrity of the epithelial barrier. The intestinal epithelium is not only a static barrier but has evolved complex mechanisms to control and regulate bacterial interactions with the mucosal surface. Apical tight junction proteins are critical in the maintenance of epithelial barrier function and control of paracellular permeability. The characterisation of alterations in tight junction proteins as key players in epithelial barrier function in inflammatory bowel diseases is rapidly enhancing our understanding of critical mechanisms in disease pathogenesis as well as novel therapeutic opportunities. Here we give an overview of recent literature focusing on the role of tight junction proteins, in particular claudins, in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.

Innate immune factors in the development and maintenance of pouchitis.

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 ß7, 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 ß7 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.

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

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.

The microbiome in inflammatory bowel disease and beyond.

The diverse and complex community of microorganisms that has co-evolved with the human gut is vital to intestinal functioning, and disturbances in the microbiota and its relationship with the host immune system have been linked to inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. This has suggested several treatment options, including antibiotics, probiotics and faecal transplantation. The human microbiome project has been established to enable comprehensive characterisation of the human microbiota and in the coming years, knowledge in this area is expected to continue to expand.