New Zealand's rising rates of early-onset colorectal cancer (EOCRC), particularly among Māori, underscore the growing concern about the role of metabolic dysregulation in disease development. There is increasing evidence suggesting that metabolic dysregulation associated with excessive dietary sugar intake may play a central role in colorectal carcinogenesis. Childhood obesity, impaired glucose metabolism and high consumption of sugar-sweetened beverages (SSBs) are prevalent among New Zealand youth, suggesting early metabolic dysfunction may precede and contribute to EOCRC risk. Given this, routinely measured metabolic biomarkers, including glucose and glycated haemoglobin (HbA1c), may offer early risk stratification within primary care settings. This viewpoint also considers whether reductions in SSB consumption could represent a simple and potentially impactful strategy to reduce long-term metabolic disease burden and, consequently, the incidence of EOCRC.

OBJECTIVES:Enterotoxigenic Bacteroides fragilis (ETBF) is a subspecies of B. fragilis that is considered to contribute to colorectal carcinogenesis through the activity of the B. fragilis toxin (BFT). However, colonic carriage of ETBF is also evident in a subset of asymptomatic individuals. In vitro studies using the HT29 cell line have linked BFT to the disruption of cell-cell adhesion and inflammation. This cell line, however, fails to consider the role of the mucus barrier in protecting the colonic epithelium in healthy individuals. This study aimed to investigate the role of a cell-associated mucus layer in modulating host responses to ETBF. METHODS:Mucus-producing HT29 MTX-E12 cells and non-mucus-producing HT29 cells were co-cultured with ETBF to evaluate the impact of the mucus layer on bacterial-host interactions. This was assessed by quantifying changes in mucus depth, mucin protein levels, E-cadherin expression, IL-8 secretion, and bft transcription. RESULTS:Both ETBF and nontoxigenic B. fragilis (NTBF) demonstrated the ability to infiltrate the mucus layer and were associated with decreased levels of the MUC2 mucin protein. The presence of a mucus layer, however, prevented the loss of E-cadherin and reduced IL-8 secretion, markers of cell-cell adhesion and inflammation, respectively. Downregulation of bft transcription following co-culture with mucus-producing cells directly linked the mucus layer to attenuated toxin production. CONCLUSIONS:These findings demonstrate that the colonic mucus layer functions not only as a physical barrier but also as an active regulator of bacterial virulence, potentially contributing to the asymptomatic carriage of ETBF in healthy individuals.

Background and aims: Disorders of gut-brain interactions (DGBIs), including irritable bowel syndrome (IBS), functional constipation (FC) and functional diarrhoea (FD), have a multifactorial aetiology, with colonic microbiota alterations likely contributing. To investigate how these changes relate to DGBIs, the faecal microbial taxonomic composition and gene abundance in DGBI subjects was characterised and integrated with gastrointestinal and non-gastrointestinal symptoms. Methods: Microbial DNA was extracted and analysed by shotgun sequencing. 239 faecal samples (IBS-constipation/FC, n = 60; IBS-diarrhoea/FD, n = 66; controls, n = 113) were used for integrative analysis with Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO). Results: High-level compositional patterns were similar between FD and IBS-diarrhoea but differed between FC and IBS-constipation, compared to controls. All DGBI subtypes showed altered relative abundance of hydrogen-metabolising taxa (Enterobacteriaceae, Lachnospiraceae, Bilophila, Desulphovibrio, Methanobrevibacter), compared to controls. Relative gene abundance associated to micronutrient homeostasis discriminated IBS-diarrhoea, IBS-constipation and FC, but not FD, from controls. Increased tyrosine metabolism relative gene abundance discriminated FC and IBS-diarrhoea from controls. FC was further distinguished from controls and other DGBIs by increased abundance of facultative anaerobes (Salmonella, Shigella, Escherichia) and genes related to aromatic amine catabolism, secretion systems, and virulence. In constipation- and diarrhoea-predominant DGBIs, Firmicutes negatively correlated with microbial “secondary metabolism” and “phages, prophages, transposable elements, plasmids”, while “aromatic compound metabolism” positively correlated with constipation severity and diarrhoea symptoms (abdominal pain). Conclusion: Distinctive microbial changes suggested FC as a distinct condition from IBS-constipation. Despite taxonomic similarities between FD and IBS-diarrhoea, microbial gene abundance discriminated IBS-diarrhoea but not FD from controls. Integrative analysis revealed potential microbial-symptom relationships in DGBIs.

Rome IV disorders of gut-brain interaction (DGBI) subtypes are known to be unstable and demonstrate high rates of non-treatment response, likely indicating patient heterogeneity. Cluster analysis, a type of unsupervised machine learning, can identify homogeneous sub-populations. Independent cluster analyses of symptom and biological data have highlighted its value in predicting patient outcomes. Integrated clustering of symptom and biological data may provide a unique multimodal perspective that better captures the complexity of DGBI. Here, integrated symptom and multi-omic cluster analysis was performed on a cohort of healthy controls and patients with lower-gastrointestinal tract DGBI. Cluster stability was assessed by considering how frequently pairs of participants appeared in the same cluster between different bootstrapped datasets. Functional enrichment analysis was performed on the biological signatures of stable DGBI-predominant clusters, implicating disrupted ammonia handling and metabolism as possible pathophysiologies present in a subset of patients with DGBI. Integrated clustering revealed subtypes that were not apparent using a singular modality, suggesting a symptom-only classification is prone to capturing heterogeneous sub-populations.

BACKGROUND:Colorectal cancer (CRC) is the third most diagnosed cancer in the world, with an estimated 1.93 million cases diagnosed in 2020. While the overall CRC incidence in many countries is falling there has been a dramatic increase in CRC in those aged under 50 (early onset colorectal cancer, EOCRC). The reason for this increase in EOCRC is unknown. As the best predictor of survival is stage at diagnosis, early diagnosis is likely to be beneficial and population screening may facilitate this. METHODS:A narrative review of the literature was undertaken. RESULTS:Improving time to diagnosis in symptomatic patients is beneficial. However, by the time symptoms develop, over a third of patients already have metastatic disease. Screening asymptomatic patients (with Faecal Immunochemical test (FIT) and colonoscopy) has been proved to be effective in older patients (>60 years). In younger populations, the decreasing incidence rates of CRC previously made cost effectiveness, compliance and therefore benefit questionable. Now, with the increasing incidence of CRC in those under 50 years of age, modelling suggests screening with FIT and colonoscopy is cost effective from 40 years of age. There is evidence that some countries screening below 50 have prevented the rise in EOCRC incidence. Additionally the use of new and novel non-invasive biomarkers may also be able to improve the accuracy of screening asymptomatic patients. CONCLUSION:Diagnosis of EOCRC once symptoms develop is often too late, and screening patients from age 40 is the best way to improve outcomes in this group.

BACKGROUND:Helicobacter pylori is a gram-negative gut bacterium most often acquired during childhood. International guidelines state that children with suspected H. pylori infection should be referred to a gastroenterologist for investigation via gastroscopy and biopsy. Eradication therapy should be prescribed for children with peptic ulcer disease or following a treatment risk/benefit discussion for those with an incidental gastroscopy finding. Guidelines state that for children a "test-and-treat" approach is not warranted, contrasting recommendations for adults. The aim of this study was to profile pediatric H. pylori infections in the South Island of New Zealand (NZ) to determine diagnostic and management strategies, and adherence to international guidelines.MATERIALS AND METHODS:Retrospective data for positive H. pylori tests between 2010 and 2021 were retrieved from hospitals and regional testing laboratories throughout the South Island (NZ) for children ≤18 years. Outcome data were retrieved from tertiary care hospital records; sociodemographic, testing methods, eradication therapy, and symptoms.RESULTS:Two-hundred and forty children were identified: 105 (44%) male, mean age 13.2 years (SD 4.3). Participants of Pasifika, Asian, and Middle Eastern/Latin American/African heritage were overrepresented compared to the NZ census data. Overall, 138 (58%) children were diagnosed via stool antigen tests, 78 (32%) serum, and only 24 (10%) adhered to international guidelines in being confirmed via gastroscopy. Only 59 (25%) had a record of eradication therapy, and 39/59 (66%) were retested to determine eradication success, with 32 (82%) negative tests and seven (18%) remaining positive. Of the 181 (75%) that had eradication status unknown, 66 (28%) had a retest result available with 48 (73%) testing negative and 18 (27%) positive, suggesting a substantial proportion had received eradication therapy without adhering to international guidelines.CONCLUSIONS:International guidelines were not adhered to for most children in the study cohort. Implications of this include cost, unnecessary venipuncture, and unjustified antibiotic exposure.

Abstract Background The incidence of early-onset colorectal cancer (EOCRC), diagnosed before age 50, has been rising in many countries in the past few decades. This study aims to evaluate this trend in Aotearoa New Zealand and assess its impact on Māori. Methods Crude incidence and age-standardized incidence of colorectal cancer (CRC) was analyzed from all new cases from the Aotearoa New Zealand national cancer registry for the period 2000–2020. Trends were estimated by sex, ethnicity, age group and location of cancer and projections made to 2040. Results Between 2000 and 2020, there were a total of 56,761 cases of CRC diagnosed in Aotearoa New Zealand, 3,702 of these being EOCRC, with age-standardized incidence decreasing significantly (P = 8.2 × 10− 80) from 61.0 to 47.3 cases per 100,000. EOCRC incidence increased on average by 26% per decade (incidence rate ratio (IRR) 1.26, p = < 0.0001) at all sites (proximal colon, distal colon and rectum), while the incidence in those aged 50–79 years decreased on average by 18% per decade (IRR 0.82, p = < 0.0005), again across all sites. There was no significant average change in CRC incidence in those over 80 years. In Māori, there was no significant change in age-standardized incidence. There was however a significant increase in crude incidence rates (IRR 1.28, p = < 0.0005) driven by significant increases in EOCRC (IRR1.36, p = < 0.0005). By 2040, we predict the incidence of EOCRC will have risen from 8.00 to 14.9 per 100,000 (6.33 to 10.00 per 100,000 in Māori). However, due to the aging population an estimated 43.0% of all CRC cases will be diagnosed in those over 80 years of age (45.9% over 70 years of age in Māori). Conclusion The age-standardized incidence of CRC from 2000 to 2020 decreased in Aotearoa New Zealand, but not for Māori. The incidence of EOCRC over the same period continues to rise, and at a faster rate in Māori. However, with the ageing of the population in Aotearoa New Zealand, and for Māori, CRC in the elderly will continue to dominate case numbers.

There is evidence of perturbed microbial and host processes in the gastrointestinal tract of individuals with functional gastrointestinal disorders (FGID) compared to healthy controls. The faecal metabolome provides insight into the metabolic processes localised to the intestinal tract, while the plasma metabolome highlights the overall perturbances of host and/or microbial responses. This study profiled the faecal (n = 221) and plasma (n = 206) metabolomes of individuals with functional constipation (FC), constipation-predominant irritable bowel syndrome (IBS-C), functional diarrhoea (FD), diarrhoea-predominant IBS (IBS-D) and healthy controls (identified using the Rome Criteria IV) using multimodal LC-MS technologies. Discriminant analysis separated patients with the ‘all constipation’ group (FC and IBS-C) from the healthy control group and ‘all diarrhoea’ group (FD and IBS-D) from the healthy control group in both sample types. In plasma, almost all multimodal metabolite analyses separated the ‘all constipation’ or ‘all diarrhoea’ group from the healthy controls, and the IBS-C or IBS-D group from the healthy control group. Plasma phospholipids and metabolites linked to several amino acid and nucleoside pathways differed (p < 0.05) between healthy controls and IBS-C. In contrast, metabolites involved in bile acid and amino acid metabolism were the key differentiating classes in the plasma of subjects with IBS-D from healthy controls. Faecal lipids, particularly ceramides, diglycerides, and triglycerides, varied (p < 0.05) between healthy controls and the ‘all constipation’ group and between healthy controls and ‘all diarrhoea’ group. The faecal and plasma metabolomes showed perturbations between constipation, diarrhoea and healthy control groups that may reflect processes and mechanisms linked to FGIDs.

BACKGROUND:The current gold standard non-invasive test for detecting pre-cancerous changes is the faecal immunochemical test (FIT). However, this test can lack sensitivity and specificity and testing for another biomarker may address these limitations. Chitinase 3-like 1 (CHI3L1) is emerging as a potential biomarker of inflammation-associated carcinogenic changes in epithelial cells.  In this study CHI3L1 levels were analysed in patients and controls to determine their ability to improve detection of early CRC either alone or in combination with a FIT.METHODS:CHI3L1 levels were measured by ELISA in serum and stool samples from cohorts of CRC and healthy donors as well as stool samples from a cohort of symptomatic primary care patients. Faecal haemoglobin was also analysed in the same primary care samples using FIT.RESULTS:CHI3L1 levels were a good discriminatory marker of CRC, with no significant difference between levels detected in the stool and serum samples.  ROC curves that determined the optimal cut-point however identified that stool samples gave higher sensitivity (83% versus 69%) and specificity (89% versus 74%) than matched serum samples. Faecal CHI3L1 levels in the primary care patients were not significantly different (p=0.193) from those detected in the healthy controls. ROC curve analysis confirmed that faecal CHI3L1 levels had limited ability to discriminate between patients who did or didn't have evidence of lesions (AUC=0.52, p=0.74). Similarly, CHI3L1 levels did not reliably identify those symptomatic primary care patients who subsequently presented with early-stage disease (polyps and adenomas) or CRC. The discriminatory power of FIT was not increased by incorporating the CHI3L1 results in this setting.CONCLUSION:There was no evidence that measurement of faecal CHI3L1 has the potential to increase diagnostic accuracy, either alone or in combination with a FIT, in symptomatic primary care patients.

Introduction: The incidence of colorectal cancer in those under 50 years of age (early onset colorectal cancer (EOCRC)) is increasing throughout the world. This has predominantly been an increase in distal colonic and rectal cancers, which are biologically similar to late onset colorectal cancer (LOCRC) but with higher rates of mucinous or signet ring histology, or poorly differentiated cancers. The epidemiology of this change suggests that it is a cohort effect since 1960, and is most likely driven by an environmental cause. We explore the possible role of microplastics as a driver for this change. Review: The development of sporadic colorectal cancer is likely facilitated by the interaction of gut bacteria and the intestinal wall. Normally, a complex layer of luminal mucus provides colonocytes with a level of protection from the effects of these bacteria and their toxins. Plastics were first developed in the early 1900s. After 1945 they became more widely used, with a resultant dramatic increase in plastic pollution and their breakdown to microplastics. Microplastics (MPs) are consumed by humans from an early age and in increasingly large quantities. As MPs pass through the gastrointestinal tract they interact with the normal physiological mechanism of the body, particularly in the colon and rectum, where they may interact with the protective colonic mucus layer. We describe several possible mechanisms of how microplastics may disrupt this mucus layer, thus reducing its protective effect and increasing the likelihood of colorectal cancer. Conclusions: The epidemiology of increase in EOCRC suggests an environmental driver. This increase in EOCRC matches the time sequence in which we could expect to see an effect of rapid increase of MPs in the environment and, as such, we have explored possible mechanisms for this effect. We suggest that it is possible that the MPs damage the barrier integrity of the colonic mucus layer, thus reducing its protective effect. MPs in CRC pathogenesis warrants further investigation. Future directions: Further clarification needs to be sought regarding the interaction between MPs, gut microbiota and the mucus layer. This will need to be modelled in long-term animal studies to better understand how chronic consumption of environmentally-acquired MPs may contribute to an increased risk of colorectal carcinogenesis.

Amino acids are important in several biochemical pathways as precursors to neurotransmitters which impact biological processes previously linked to functional gastrointestinal disorders (FGIDs). Dietary protein consumption, metabolic host processes, and the gut microbiome can influence the plasma concentration of amino acids and neurotransmitters, and their uptake by tissues. The aim of this analysis was to quantify 19 proteogenic and 4 non-proteogenic amino acids and 19 neurotransmitters (including precursors and catabolites, herein referred to as neurotransmitters) to ascertain if their circulating concentrations differed between healthy participants and those with FGIDs. Plasma proteogenic and non-proteogenic amino acids and neurotransmitters were measured using ultra-performance liquid chromatography and liquid chromatography–mass spectrometry, respectively, from 165 participants (Rome IV: irritable bowel syndrome (IBS-constipation, IBS-diarrhea), functional constipation, functional diarrhea, and healthy controls). There were significant differences (p < 0.05) in pairwise comparisons between healthy controls and specific FGID groups for branched-chain amino acids (BCAAs), ornithine, and alpha-aminobutyric acid. No other significant differences were observed for the neurotransmitters or any other amino acids analyzed. Multivariate and bivariate correlation analyses between proteogenic and non-proteogenic amino acids and neurotransmitters for constipation (constipation (IBS-C and functional constipation) and phenotypes diarrhea (IBS-D and functional diarrhea)) and healthy controls suggested that associations between BCAAs, 5-hydroxytryptophan, and kynurenine in combination with tyrosine, 3,4-dihydroxyphenylalanine, and 3,4-dihydroxyphenylacetic acid and associations with gamma-aminobutyric acid, glutamate, asparagine, and serine are likely disrupted in FGID phenotypes. In conclusion, although correlations were evident between some proteogenic and non-proteogenic amino acids and neurotransmitters, the results showed minor concentration differences in plasma proteogenic and non-proteogenic amino acids, amino acid-derived metabolites, and neurotransmitters between FGID phenotypes and healthy controls.

Colorectal cancer is the third most diagnosed cancer worldwide with an estimated 1.93 million cases diagnosed in 2020. Over the past few decades there has been a dramatic rise in the incidence of early onset colorectal cancer, defined as colorectal cancer diagnosed in those aged under 50 years. The largest predictor of survival is early stage at diagnosis, therefore ways to improve prompt diagnosis of early onset colorectal cancer at an early stage is an effective way of managing the impact of this rising disease. Diagnosing colorectal cancer in younger patients has unique challenges with patients falling outside the age of most screening programs and early symptoms of colorectal cancer being common, non-specific and initially intermittent. While colonoscopy remains the gold standard investigation, it is a limited and expensive resource, and current patterns of practice result in large numbers of patients being scoped unnecessarily. The development and use of new and novel non-invasive biomarkers may help (either alone or in combination) identify either symptomatic patients in primary care, or aid with screening asymptomatic patients to focus resources where they are needed most. This review discusses challenges around diagnosing early onset colorectal cancer, with an overview of both current and future methods that might help overcome these challenges. These include increased assessment of familial risk, and the measurement of different biomarkers including faecal haemoglobin, markers of inflammation, gut microbiota, and selected metabolites.

Although chitinase-3-like-1 (CHI3L1), predominately produced by epithelial cells and macrophages, is relevant to pulmonary disease in cystic fibrosis (CF), fecal levels have not yet been assessed in children with CF. Fecal CHI3L1 was measured with a commercial immunoassay using fecal samples provided by children with CF and healthy control (HC) children. Higher median (interquartile range) fecal CHI3L1 levels were seen in the 52 children with CF than in the 35 controls: 15.97 (3.34-50.53) ng/g versus 2.93 (2.13-9.27) ng/g ( P = 0.001). Fecal CHI3LI did not differ according to sex. In the children with CF, fecal CHI3L1 levels did not correlate with growth parameters nor were the levels affected by pancreatic insufficiency. Children with CF had higher fecal CHI3L1 levels, suggesting underlying gut inflammation. Further work is required to confirm the current findings and to ascertain the longer-term significance of elevated CHI3L1.

consent and assent were obtained from parents and children, respectively.Participants were categorized into 5 groups: active IBD, inactive IBD, non-IBD, healthy sibling (HS), and celiac disease (CeD).Patients with IBD were diagnosed based on the revised Porto criteria. 1The active IBD group included those with newly diagnosed untreated IBD or those with relapsed disease requiring treatment to reinduce remission.The inactive IBD group included participants with known IBD who were in clinical remission based on clinical indexes (Pediatric Crohn' s Disease Activity Index [PCDAI] < 10 for CD or Pediatric Ulcerative Colitis Activity Index [PUCAI] < 10 for UC) and had no alteration to their IBD medications 3 months prior to enrolment.Children who underwent investigations for gastrointestinal symptoms and in whom IBD was excluded were categorized as the non-IBD group.Siblings of children with known IBD who were reported to be healthy were enrolled into the HS group.Children with newly diagnosed untreated CeD (based on any positive celiac serologies and histological modified Marsh-Oberhuber classification ≥ 2) were included as a disease control group.Baseline demographics including clinical (PCDAI and PU-CAI) and endoscopic disease activity (Simple Endoscopic Score for CD [SES-CD] and Mayo endoscopic score) were recorded.All disease groups provided baseline blood and urine samples, whilst HS group provided a urine sample only.Urine samples were collected and stored at 4°C within 24 hours of participant' s clinic appointment.Received samples were immediately aliquoted and stored at -80°C.

Aims: To assess the role of neural and remodelling pathways, alongside inflammatory mechanisms, in eosinophilic (EA) and non-eosinophilic asthma (NEA). Methods: 111 asthmatics and 62 non-asthmatics (14-21 years) underwent sputum induction testing. Twenty-four mediators were measured in supernatant. EA (n=52) and NEA (n=59) were defined using a sputum eosinophil cut-point of 2.5%. Results: Elevated levels of nociceptin (median: 39.1 vs 22.4 ng/mL, p=0.03), periostin (33.8 vs 9.4 pg/mL, p=0.01), and eosinophil cationic protein (ECP; 220.1 vs 83.7 ng/mL, p=0.03) were found in asthmatics compared to non-asthmatics. Nociceptin was elevated in EA (54.8 vs 22.4 ng/mL, p=0.02) but not NEA (27.8 vs 22.4 ng/mL, p=0.22). EA had higher levels of inflammatory (ECP: 496 vs 100.3 ng/mL, p=<0.01; interleukin-1β: 286 vs 209.3 pg/mL, p=0.03; histamine: 5805 vs 3173 pg/mL, p=<0.01) and remodelling (vascular endothelial growth factor: VEGF; 3.3 vs 2.5 ng/mL, p=0.03; periostin: 47.7 vs 22.1 pg/mL, p=0.04) mediators compared to NEA. Whilst macrophage counts were correlated with neural mediators such as neurokinin A (r=0.27, p=0.01), nociceptin (r=0.30, p=0.02), and nerve growth factor-β: NGF-β; r=0.19, p=0.04), granulocytes correlated with inflammatory and remodelling mediators; e.g., ECP and VEGF correlated with neutrophils (r=0.53 & r=0.33 respectively, p≤0.01) and eosinophils (r=0.53& r=0.29 respectively, p≤0.01). Conclusions: Inflammatory cells/mediators were often associated with neural and remodelling mediators, suggesting that these mechanisms coexist with inflammation. Neural and remodelling pathways may not play a role in NEA, but nociceptin may be important in EA.

Colorectal cancer is a leading cause of mortality worldwide. The high incidence and the acceleration of incidence in younger people reinforces the need for better techniques of early detection. The use of noninvasive biomarkers has potential to more accurately inform how patients are prioritised for clinical investigation, which, in turn, may ultimately translate into improved survival for those subsequently found to have curable-stage CRC. This review surveys a wide range of CRC biomarkers that may (alone or in combination) identify symptomatic patients presenting in primary care who should be progressed for clinical investigation.

BACKGROUND:Less invasive inflammatory bowel disease (IBD) tests are increasingly being incorporated into clinical practice as adjuncts to endoscopy to monitor disease activity and guide optimal care. Little is known about patient perspectives of these tests.AIMS:To assess patient perspectives of the current IBD tests and potential future tests, such as saliva, urine or breath.METHODS:New Zealand adults with IBD were invited to complete an anonymous online survey. Experiences relating to blood or faecal tests, medical imaging (abdominal ultrasound, abdominal computed tomography and magnetic resonance enterography) and colonoscopy were collected.RESULTS:Of the 117 completed surveys, 112 respondents provided background details. The majority (85%) of participants were female and 88% were aged <55 years with a mean disease duration of 8.98 years. General blood tests were reported as the most prescribed, completed, comfortable test and the least worrying test results. Imaging tests were reported as the least ordered and the most refused tests. Colonoscopy was rated as the least comfortable and generated the most worry. Test explanations by a referring clinician significantly impacted on respondents' levels of understanding across all tests, but did not affect the level of worry when receiving test results. Saliva, blood and breath tests were chosen as the most preferred disease monitoring tests.CONCLUSIONS:Patients with IBD preferred any tests less invasive than colonoscopy. An explanation by referring doctor enhanced patients' understanding, but did not necessarily influence their level of comfort or worry.