Diet and physical activity advice for colorectal cancer survivors: critical synthesis of public-facing guidance.

PURPOSE: Colorectal cancer (CRC) survivors report that diet and physical activity guidance from healthcare professionals following discharge from care is limited. Survivors seek advice from alternative sources. This study critically synthesised the English language diet and physical activity guidance available online for CRC survivors. METHODS: We conducted an internet search to identify national cancer organisations (NCO) in countries with high CRC incidence rates. We searched NCO website content for guidance related to diet and physical activity. Recommendations were categorised by cancer phase (prevention/survivorship), cancer type, and the intended outcome (health or cancer-control-CRC recurrence/CRC-specific mortality). A synthesised guideline was derived from recommendations consistently made by at least half of the sources. RESULTS: We identified 12 NCOs from six countries, by whom 27 diet and physical activity recommendations were made. For CRC prevention, over 80% of recommendations were aimed at improving cancer-control outcomes. For CRC survivorship, less than 40% of recommendations were aimed at improving cancer-control outcomes. Physical activity was the only recommendation present on more than 50% of NCO websites aimed at improving cancer-control outcomes for CRC survivorship. CONCLUSION: Diet and physical activity guidance for CRC survivors on NCO websites is limited and primarily based on recommendations for improving general health, not improving cancer-control outcomes. NCO websites frequently refer survivors to primary prevention guidance, potentially reflecting the lack of evidence specific to CRC survivorship. There is a need for diet and physical activity advice for survivors that is evidence-based, comprehensive, and consistent across organisations and tailored to specific cancer sites.

Still too little evidence: the role of diet in colorectal cancer survivorship - a systematic review.

Colorectal cancer incidence (CRC) is influenced by dietary factors, yet the impact of diet on CRC-specific mortality and recurrence-free survival (RFS) remains unclear. This review provides a narrative summary of existing research on dietary factors affecting CRC-specific mortality, RFS, and disease-free survival (DFS). This study searched electronic databases to identify cross-sectional/prospective research investigating dietary intake on CRC-specific mortality, RFS, or DFS. Twenty-eight studies were included in the corpus. Because of high study heterogeneity, we performed a narrative synthesis of studies. Limited, but suggestive evidence indicates beneficial effects of adhering to the American Cancer Society (ACS) guidelines and a plant rich low-carbohydrate diet on risk of CRC-specific mortality, potentially driven by fiber from cereals, vegetables, and wholegrains, but not fruit. For RFS and DFS, a Western dietary pattern, high intake of refined grains, and sugar sweetened beverages correlated with increased risk of CRC recurrence and development of disease/death. Conversely, greater adherence to the ACS dietary and alcohol guidelines, higher ω-3 polyunsaturated fatty acids, and dark fish consumption reduced risk. Our findings underscore the need for (i) standardized investigations into diet's role in CRC survivorship, including endpoints, and (ii) comprehensive analyses to isolate specific effects within correlated lifestyle components.

Can an educational video improve the adequacy of bowel preparation for patients undergoing their first colonoscopy? Results of the EBOPS RCT.

Background and study aims The aim of this study was to assess the effect of an educational video on the quality of bowel preparation of patients from a UK population attending for their first colonoscopy. Patients and methods A prospective, endoscopist-blinded trial with 1:1 allocation was performed. Patients referred for their first colonoscopy were recruited between February 2019 and December 2019. All participants were prescribed Moviprep and received the trial site's standard written bowel preparation instructions, with the intervention group also receiving a bespoke educational video. Adequacy of bowel preparation (defined as a Boston Bowel Preparation Scale of ≥2 in each segment of the bowel) and polyp detection rates (PDRs) were compared. Fisher's chi squared test was utilized with P <0.05 as the threshold for significance. Results A total of 509 participants completed the trial from six centers; 251 were randomized to the intervention group. The mean age was 57 years and 52.3% were female. The primary endpoint was met with an adequacy rate of 216 of 251 (86.1%) in the intervention group, compared with 205 of 259 (79.1%) in the control group ( P <0.05, odds ratio [OR] 1.626, 95% CI 1.017-2.614). The PDR was significantly higher in the intervention group (39% vs 30%, OR 1.51, 95% CI 1.04-2.19, P <0.05). Conclusions An educational video leads to improved bowel preparation for patients attending for their first colonoscopy, and is also associated with greater detection of polyps. Widespread adoption of an educational video incurs minimal investment, but would reduce the number of inadequate procedures, missed pathology, and the cost that both these incur.

Metachronous Colorectal Adenomas Occur Close to the Index Lesion.

GOALS: The aim of this study is to assess the spatial relationship between index and metachronous colorectal adenoma location. BACKGROUND: After the complete excision of a human sporadic colorectal adenoma, patients are at elevated risk of developing a further metachronous adenoma. Data regarding the occurrence site of a metachronous colorectal adenoma relative to the index adenoma are scarce. STUDY: Prospectively maintained databases were interrogated to identify all colonoscopies and adenoma excisions performed over a 10-year period at a single university teaching hospital. Data for the colonic segments at which adenoma removal were reported at index and all subsequent colonoscopies were extracted and 2 allied data sets merged. RESULTS: A total of 15,121 colonoscopies and 4759 polyp events were recorded. Four hundred fifty-two patients [296 male, 156 female, median (range) age 75 (32 to 100) y] developed at least 1 metachronous adenoma at follow-up colonoscopy. When single index events only are considered (ie, synchronous adenoma cases excluded), over 61% of metachronous adenomas were recorded in the same or an adjacent colonic segment. When the full span of the colon is considered, metachronous adenomas were more likely to occur in a section of the colon proximal to that of the index adenoma (41%±5%) than the same (39%±5%) or distal segment (20%±5%; P =0.006; 1-way χ 2 test). CONCLUSIONS: A metachronous human sporadic colorectal adenoma is more likely to be found in the same colonic segment to that of the index adenoma or 1 immediately adjacent. These data suggest a shared origin of metachronous adenoma with preceding lesions, supporting the existence of precancerous fields.

The Second Nutrition and Cancer Networking Meeting Nutrition and Breast Cancer: Translating Evidence into Practice.

The 2nd Nutrition and Cancer Networking Meeting 'Nutrition and Breast Cancer: Translating Evidence into Practice' was held at Newcastle University in May 2022, with support from the Nutrition Society and British Association for Cancer Research. The first meeting in this series was held in Sheffield in 2019. The aim of this joint meeting was to bring together researchers with an interest in nutrition and breast cancer, with the programme spanning topics from risk and prevention to nutrition during treatment and beyond. Several key themes emerged, including the importance of engaging patients in the development of interventions and trials, making trials more accessible to diverse communities; training of clinical staff in nutrition and latest evidence; wider range of compounds should be considered in food composition tables; and alternative trial designs can be considered for prevention research to reduce financial burden and increase power.

Metastasising Fibroblasts Show an HDAC6-Dependent Increase in Migration Speed and Loss of Directionality Linked to Major Changes in the Vimentin Interactome.

Metastasising cells express the intermediate filament protein vimentin, which is used to diagnose invasive tumours in the clinic. We aimed to clarify how vimentin regulates the motility of metastasising fibroblasts. STED super-resolution microscopy, live-cell imaging and quantitative proteomics revealed that oncogene-expressing and metastasising fibroblasts show a less-elongated cell shape, reduced cell spreading, increased cell migration speed, reduced directionality, and stronger coupling between these migration parameters compared to normal control cells. In total, we identified and compared 555 proteins in the vimentin interactome. In metastasising cells, the levels of keratin 18 and Rab5C were increased, while those of actin and collagen were decreased. Inhibition of HDAC6 reversed the shape, spreading and migration phenotypes of metastasising cells back to normal. Inhibition of HDAC6 also decreased the levels of talin 1, tropomyosin, Rab GDI ß, collagen and emilin 1 in the vimentin interactome, and partially reversed the nanoscale vimentin organisation in oncogene-expressing cells. These findings describe the changes in the vimentin interactome and nanoscale distribution that accompany the defective cell shape, spreading and migration of metastasising cells. These results support the hypothesis that oncogenes can act through HDAC6 to regulate the vimentin binding of the cytoskeletal and cell-extracellular matrix adhesion components that contribute to the defective motility of metastasising cells.

Colorectal keratins: Integrating nutrition, metabolism and colorectal health.

The colon mucosa is lined with crypts of circa 300 cells, forming a continuous barrier whose roles include absorption of water, recovery of metabolic energy sources (notably short chain fatty acids), secretion of a protective mucus barrier, and physiological signalling. There is high turnover and replenishment of cells in the mucosa, disruption of this may lead to bowel pathologies including cancer and inflammatory bowel disease. Keratins have been implicated in the processes of cell death, epithelial integrity, response to inflammation and as a result are often described as guardians of the colonic epithelium. Keratin proteins carry extensive post-translational modifications, the cofactors for kinases, acetyl transferases and other modification-regulating enzymes are themselves products of metabolism. A cluster of studies has begun to reveal a bidirectional relationship between keratin form and function and metabolism. In this paper we hypothesise a mechanistic interaction between keratins and metabolism is governed through regulation of post-translational modifications and may contribute significantly to the normal functioning of the colon, placing keratins at the centre of a nutrition-metabolism-health triangle.

Is it time we split bowel preparation for all colonoscopies? Outcomes from a national survey of bowel preparation practice in the UK.

INTRODUCTION: Adequate bowel preparation is a prerequisite for effective colonoscopy. Split bowel preparation results in optimal cleansing. This study assessed the bowel preparation regimes advised by endoscopy units across the UK, and correlated the differences with outcomes. METHODS: Trusts in the UK were surveyed, with data requested between January 2018 and January 2019, including: the type and timing of preparation, pre-endoscopy diet, adequacy rates and polyp detection. Trusts were grouped according to the timing of bowel preparation. χ2 test was used to assess for differences in bowel preparation adequacy. RESULTS: Moviprep was the first line bowel preparation in 79% of trusts. Only 7% of trusts advised splitting bowel preparation for all procedures, however, 91% used split bowel preparation for afternoon procedures. Trusts that split preparation for all procedures had an inadequacy rate of 6.7%, compared with 8.5% (p<0.001) for those that split preparation for PM procedures alone and 9.5% (p<0.001) for those that provided day before preparation for all procedures. Morning procedures with day-before preparation had a higher rate of inadequate cleansing than afternoon procedures that received split preparation (7.7% vs 6.5 %, p<0.001). The polyp detection rate for procedures with adequate preparation was 37.1%, compared with 26.4% for those that were inadequate. CONCLUSION: Most trusts in the UK do not provide instructions optimising the timing of bowel preparation prior to colonoscopy. This correlated with an increased rate of inadequate cleansing. Splitting bowel preparation is likely to reduce the impacts of poor cleansing: missed lesions, repeat colonoscopies and significant costs.

Nutrition and cancer: evidence gaps and opportunities for improving knowledge.

The Nutrition Society's 1st Annual Nutrition and Cancer Networking Conference brought together scientists from the fields of Nutrition, Epidemiology, Public Health, Medical Oncology and Surgery with representatives of the public, cancer survivors and cancer charities. Speakers representing these different groups presented the challenges to collaboration, how the needs of patients and the public can be met, and the most promising routes for future research. The conference programme promoted debate on these issues to highlight current gaps in understanding and barriers to generating and implementing evidence-based nutrition advice. The main conclusions were that the fundamental biology of how nutrition influences the complex cancer risk profiles of diverse populations needs to be better understood. Individual and population level genetics interact with the environment over a lifespan to dictate cancer risk. Large charities and government have a role to play in diminishing our current potently obesogenic environment and exploiting nutrition to reduce cancer deaths. Understanding how best to communicate, advise and support individuals wishing to make dietary and lifestyle changes, can reduce cancer risk, enhance recovery and improve the lives of those living with and beyond cancer.

Volatile organic compounds emitted from faeces as a biomarker for colorectal cancer.

BACKGROUND: Colorectal cancer remains a leading cause of mortality and morbidity. The UK Bowel Cancer Screening Programme (BCSP) has demonstrated that detection of colorectal cancer at an earlier stage and identification of advanced pre-malignant adenomas reduces mortality and morbidity. AIM: To assess the utility of volatile organic compounds as a biomarker for colorectal neoplasia. METHODS: Faeces were collected from symptomatic patients and people participating in the UK BCSP, prior to colonoscopy. Headspace extraction followed by gas chromatography mass spectrometry was performed on faeces to identify volatile organic compounds. Logistic regression modelling and 10-fold cross-validation were used to test potential biomarkers. RESULTS: One hundred and thirty-seven participants were included (mean age 64 years [range 22-85], 54% were male): 60 had no neoplasia, 56 had adenomatous polyp(s) and 21 had adenocarcinoma. Propan-2-ol was significantly more abundant in the cancer samples (P < 0.0001, q = 0.004) with an area under ROC (AUROC) curve of 0.76. When combined with 3-methylbutanoic acid the AUROC curve was 0.82, sensitivity 87.9% (95% CI 0.87-0.99) and specificity 84.6% (95% CI 0.65-1.0). Logistic regression analysis using the presence/absence of specific volatile organic compounds, identified a three volatile organic compound panel (propan-2-ol, hexan-2-one and ethyl 3-methyl- butanoate) to have an AUROC of 0.73, with a person six times more likely to have cancer if all three volatile organic compounds were present (P < 0.0001). CONCLUSIONS: Volatile organic compound analysis may have a superior diagnostic ability for the identification of colorectal adenocarcinoma, when compared to other faecal biomarkers, including those currently employed in UK. Clinical trial details: National Research Ethics Service Committee South West - Central Bristol (REC reference 14/SW/1162) with R&D approval from University of Liverpool and Broadgreen University Hospital Trust (UoL 001098).

Prospective Study of Psychological Morbidity and Illness Perceptions in Young People With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Psychological morbidity is increased in young people with inflammatory bowel disease [IBD]. Illness perceptions may be an important factor. This study aimed to describe the prevalence and severity of psychological morbidity and to examine relationships between baseline illness perceptions and anxiety, depression, and health-related quality of life [HRQoL], at baseline and 12 months later, in 16-21 year olds with IBD. METHODS: IBD patients [n = 121] completed measures of anxiety, depression, HRQoL, and illness perceptions [IPQ-R] at baseline and follow-up [n = 100, 83%]. RESULTS: Among the 121 patients at baseline [median age 19.3 years, 40% female, 62% Crohn's disease, 73% in clinical remission], 55% reported elevated symptoms of anxiety/depression and 83% reported low HRQoL. Negative illness perceptions at baseline were significantly correlated with greater anxiety, depression, and lower HRQoL at baseline and follow-up. In regression analysis at baseline, the IPQ-R domain of greater perception of a cyclical nature of IBD was an independent predictor of anxiety, and a greater perceived emotional impact of IBD was an independent predictor of anxiety, depression, and HRQoL. Female gender and clinical relapse were also independent predictors of lower HRQoL. After controlling for baseline measures, clinical risk factors and illness perceptions did not explain additional variance in psychological morbidity at follow-up. CONCLUSIONS: A high prevalence of psychological morbidity, stable over 1 year, was demonstrated in young people with IBD. Having negative illness perceptions, being female, and having active disease predicted those at greatest risk of psychological morbidity. Illness perceptions may be an appropriate target for psychological interventions.

Application of Proteomics to Inflammatory Bowel Disease Research: Current Status and Future Perspectives.

Inflammatory bowel disease (IBD) is a chronic relapsing/remitting inflammatory illness of the gastrointestinal tract of unknown aetiology. Despite recent advances in decoding the pathophysiology of IBD, many questions regarding disease pathogenesis remain. Genome-wide association studies (GWAS) and knockout mouse models have significantly advanced our understanding of genetic susceptibility loci and inflammatory pathways involved in IBD pathogenesis. Despite their important contribution to a better delineation of the disease process in IBD, these genetic findings have had little clinical impact to date. This is because the presence of a given gene mutation does not automatically correspond to changes in its expression or final metabolic or structural effect(s). Furthermore, the existence of these gene susceptibility loci in the normal population suggests other driving prerequisites for the disease manifestation. Proteins can be considered the main functional units as almost all intracellular physiological functions as well as intercellular interactions are dependent on them. Proteomics provides methods for the large-scale study of the proteins encoded by the genome of an organism or a cell, to directly investigate the proteins and pathways involved. Understanding the proteome composition and alterations yields insights into IBD pathogenesis as well as identifying potential biomarkers of disease activity, mucosal healing, and cancer progression. This review describes the state of the art in the field with respect to the study of IBD and the potential for translation from biomarker discovery to clinical application.

Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. However, its molecular pathogenesis is incompletely characterized and clinical biomarkers remain scarce. The aims of these experiments were to identify and characterize liver protein alterations in an animal model of early, diet-related, liver injury and to assess novel candidate biomarkers in NAFLD patients. Methods: Liver membrane and cytosolic protein fractions from high fat fed apolipoprotein E knockout (ApoE-/-) animals were analyzed by quantitative proteomics, utilizing isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). Differential protein expression was confirmed independently by immunoblotting and immunohistochemistry in both murine tissue and biopsies from paediatric NAFLD patients. Candidate biomarkers were analyzed by enzyme-linked immunosorbent assay in serum from adult NAFLD patients. Results: Through proteomic profiling, we identified decreased expression of hepatic glyoxalase 1 (GLO1) in a murine model. GLO1 protein expression was also found altered in tissue biopsies from paediatric NAFLD patients. In vitro experiments demonstrated that, in response to lipid loading in hepatocytes, GLO1 is first hyperacetylated then ubiquitinated and degraded, leading to an increase in reactive methylglyoxal. In a cohort of 59 biopsy-confirmed adult NAFLD patients, increased serum levels of the primary methylglyoxal-derived advanced glycation endproduct, hydroimidazolone (MG-H1) were significantly correlated with body mass index (r = 0.520, p < 0.0001). Conclusion: Collectively these results demonstrate the dysregulation of GLO1 in NAFLD and implicate the acetylation-ubquitination degradation pathway as the functional mechanism. Further investigation of the role of GLO1 in the molecular pathogenesis of NAFLD is warranted.

Vitamin D status in irritable bowel syndrome and the impact of supplementation on symptoms: what do we know and what do we need to know?

BACKGROUND: Low vitamin D status is associated with risk of colorectal cancer and has been implicated in inflammatory bowel disease. Irritable bowel syndrome (IBS) is a chronic, relapsing, functional bowel disorder. A nascent literature suggests a role for vitamin D in IBS, but this has not been collated or critiqued. To date, seven studies have been published: four observational studies and three randomised controlled trials (RCTs). All observational studies reported that a substantial proportion of the IBS population was vitamin D deficient. Two intervention studies reported improvement in IBS symptom severity scores and quality of life (QoL) with vitamin D supplementation. There are limited data around the role of vitamin D in IBS. CONCLUSIONS: The available evidence suggests that low vitamin D status is common among the IBS population and merits assessment and rectification for general health reasons alone. An inverse correlation between serum vitamin D and IBS symptom severity is suggested and vitamin D interventions may benefit symptoms. However, the available RCTs do not provide strong, generalisable evidence; larger and adequately powered interventions are needed to establish a case for therapeutic application of vitamin D in IBS.

An agent-based model of anoikis in the colon crypt displays novel emergent behaviour consistent with biological observations.

Colorectal cancer (CRC) is a major cause of cancer mortality. Colon crypts are multi-cellular flask-shaped invaginations of the colonic epithelium, with stem cells at their base which support the continual turnover of the epithelium with loss of cells by anoikis from the flat mucosa. Mutations in these stem cells can become embedded in the crypts, a process that is strongly implicated in CRC initiation. We describe a computational model which includes novel features, including an accurate representation of the geometry of the crypt mouth. Model simulations yield previously unseen emergent phenomena, such as localization of cell death to a small region of the crypt mouth which corresponds with that observed in vivo. A mechanism emerges in the model for regulation of crypt cellularity in response to changes in either cell proliferation rates or membrane adhesion strengths. We show that cell shape assumptions influence this behaviour, with cylinders recapitulating biology better than spheres. Potential applications of the model include determination of roles of mutations in neoplasia and exploring factors for altered crypt morphodynamics.

Correlation between Faecal Tumour M2 Pyruvate Kinase and Colonoscopy for the Detection of Adenomatous Neoplasia in a Secondary Care Cohort.

BACKGROUND AND AIMS: Colorectal cancer screening programmes that target detection and excision of adenomatous colonic polyps have been shown to reduce colorectal cancer related mortality. Many screening programmes include an initial faecal occult blood test (FOBt) prior to colonoscopy. To refine the selection of patients for colonoscopy other faecal-based diagnostic tools have been proposed, including tumour M2-pyruvate kinase (tM2-PK). To determine whether tM2-PK quantification may have a role in diverse settings we have assessed the assay in a cohort of patients derived from both the England bowel cancer screening programme (BCSP) and symptomatic individuals presenting to secondary care. METHOD: Patients undergoing colonoscopy provided faecal samples prior to bowel preparation. Faecal tM2-PK concentrations were measured by ELISA. Sensitivity, specificity, positive predictive value, negative predictive value and ROC analyses were calculated. RESULTS: Ninety-six patients returned faecal samples: 50 of these with adenomas and 7 with cancer. Median age was 68. Median faecal tM2-PK concentration was 3.8 U/mL for individuals without neoplastic findings at colonoscopy, 7.7 U/mL in those with adenomas and 24.4 U/mL in subjects with colorectal cancer (both, p=0.01). ROC analysis demonstrated an AUROC of 0.66 (sensitivity 72.4%, specificity 48.7%, positive predictive value 67.7%, negative predictive value 36.7%). Amongst BCSP patients with a prior positive FOBt faecal tM2-PK was more abundant (median 6.4 U/mL, p=0.03) and its diagnostic accuracy was greater (AUROC 0.82). CONCLUSION: Our findings confirm that faecal tM2-PK ELISA may have utility as an adjunct to FOBt in a screening context, but do not support its use in symptomatic patients.

A deterministic oscillatory model of microtubule growth and shrinkage for differential actions of short chain fatty acids.

Short chain fatty acids (SCFA), principally acetate, propionate, butyrate and valerate, are produced in pharmacologically relevant concentrations by the gut microbiome. Investigations indicate that they exert beneficial effects on colon epithelia. There is increasing interest in whether different SCFAs have distinct functions which may be exploited for prevention or treatment of colonic diseases including colorectal cancer (CRC), inflammatory bowel disease and obesity. Based on experimental evidence, we hypothesised that odd-chain SCFAs may possess anti-mitotic capabilities in colon cancer cells by disrupting microtubule (MT) structural integrity via dysregulation of ß-tubulin isotypes. MT dynamic instability is an essential characteristic of MT cellular activity. We report a minimal deterministic model that takes a novel approach to explore the hypothesised pathway by triggering spontaneous oscillations to represent MT dynamic behaviour. The dynamicity parameters in silico were compared to those reported in vitro. Simulations of untreated and butyrate (even-chain length) treated cells reflected MT behaviour in interphase or untreated control cells. The propionate and valerate (odd-chain length) simulations displayed increased catastrophe frequencies and longer periods of MT-fibre shrinkage. Their enhanced dynamicity was dissimilar to that observed in mitotic cells, but parallel to that induced by MT-destabilisation treatments. Antimicrotubule drugs act through upward or downward modulation of MT dynamic instability. Our computational modelling suggests that metabolic engineering of the microbiome may facilitate managing CRC risk by predicting outcomes of SCFA treatments in combination with AMDs.

Reduced keratin expression in colorectal neoplasia and associated fields is reversible by diet and resection.

BACKGROUND: Patients with adenomatous colonic polyps are at increased risk of developing further polyps suggesting field-wide alterations in cancer predisposition. The current study aimed to identify molecular alterations in the normal mucosa in the proximity of adenomatous polyps and to assess the modulating effect of butyrate, a chemopreventive compound produced by fermentation of dietary residues. METHODS: A cross-sectional study was undertaken in patients with adenomatous polyps: biopsy samples were taken from the adenoma, and from macroscopically normal mucosa on the contralateral wall to the adenoma and from the mid-sigmoid colon. In normal subjects biopsies were taken from the mid-sigmoid colon. Biopsies were frozen for proteomic analysis or formalin-fixed for immunohistochemistry. Proteomic analysis was undertaken using iTRAQ workflows followed by bioinformatics analyses. A second dietary fibre intervention study arm used the same endpoints and sampling strategy at the beginning and end of a high-fibre intervention. RESULTS: Key findings were that keratins 8, 18 and 19 were reduced in expression level with progressive proximity to the lesion. Lesional tissue exhibited multiple K8 immunoreactive bands and overall reduced levels of keratin. Biopsies from normal subjects with low faecal butyrate also showed depressed keratin expression. Resection of the lesion and elevation of dietary fibre intake both appeared to restore keratin expression level. CONCLUSION: Changes in keratin expression associate with progression towards neoplasia, but remain modifiable risk factors. Dietary strategies may improve secondary chemoprevention. TRIAL REGISTRATION NUMBER: ISRCTN90852168.

Inflammation decreases keratin level in ulcerative colitis; inadequate restoration associates with increased risk of colitis-associated cancer.

BACKGROUND: Keratins are intermediate filament (IF) proteins, which form part of the epithelial cytoskeleton and which have been implicated pathology of inflammatory bowel diseases (IBD). METHODS: In this study biopsies were obtained from IBD patients grouped by disease duration and subtype into eight categories based on cancer risk and inflammatory status: quiescent recent onset (<5 years) UC (ROUC); UC with primary sclerosing cholangitis; quiescent long-standing pancolitis (20-40 years) (LSPC); active colitis and non-inflamed proximal colonic mucosa; pancolitis with dysplasia-both dysplastic lesions (DT) and distal rectal mucosa (DR); control group without pathology. Alterations in IF protein composition across the groups were determined by quantitative proteomics. Key protein changes were validated by western immunoblotting and immunohistochemical analysis. RESULT: Acute inflammation resulted in reduced K8, K18, K19 and VIM (all p<0.05) compared to controls and non inflamed mucosa; reduced levels of if- associated proteins were also seen in DT and DR. Increased levels of keratins in LSPC was noted relative to controls or ROUC (K8, K18, K19 and VIM, p<0.05). Multiple K8 forms were noted on immunoblotting, with K8 phosphorylation reduced in progressive disease along with an increase in VIM:K8 ratio. K8 levels and phosphorylation are reduced in acute inflammation but appear restored or elevated in subjects with clinical and endoscopic remission (LSPC) but not apparent in subjects with elevated risk of cancer. CONCLUSIONS: These data suggest that keratin regulation in remission may influence subsequent cancer risk.