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Background Epidemiological evidence supports a relationship between adiposity and elevated risk of colorectal cancer (CRC). Nevertheless, the role of gut microbiota in mediating the carcinogenic effect of adiposity is unknown. In this study, we transplanted stool from obese patients to mice to evaluate its effects and mechanisms on intestinal carcinogenesis. Methods Azoxymethane (AOM)-treated mice, ApcMin/+ and germ-free mice were gavaged with feces from obese patients and control subjects respectively. The colonic tumor load and number were recorded at endpoint. The gut microbiota composition was assessed by metagenomic sequencing and colonic transcriptome was assessed by total RNA sequencing. Results The colonic tumor load and number were significantly higher in mice receiving feces from obese patients (OB), compared with those from control subjects (NB, normal BMI), in both AOM-induced and ApcMin/+ mice (IDDF2021-ABS-0166 Figure 1A-C). Histological assessments showed increased dysplasia proportions and Ki-67 positive cells (IDDF2021-ABS-0166 Figure 1D) in mice receiving feces from obese patients in both murine cancer models. Metagenomic analysis showed an altered microbiota composition (IDDF2021-ABS-0166 Figure 2A), with a lower alpha diversity (IDDF2021-ABS-0166 Figure 2B), decreased abundance of Faecalibaculum, Bifidobacterium and Lactobacillus, as well as increased abundance of Akkermansia in recipients of feces from obese patients (IDDF2021-ABS-0166 Figure 2C). Transcriptomic analysis on colon tissue showed upregulation of oncogenic (Wnt signaling pathway, MAPK signaling pathway and Rap1 signaling pathway) and pro-inflammatory pathways (TNF signaling pathway and chemokine signaling pathway). Mice received feces from obese patients showed impaired murine barrier function evidenced by decreased mucus layer thickness, loosened tight junction and over-expression of epithelial leaky protein Claudin-2 in the colonic crypt. Conclusions Feces from obese patients promoted colorectal carcinogenesis in mice. Such action was associated with the modulation of the gut microbiota composition, induction of oncogenic and pro-inflammatory factors and impairment of epithelial barrier. This study provides new insight into obesity-promoting colorectal carcinogenesis, at least in part by causing gut microbiome dysbiosis.

Background Gut microbiota contributes to colorectal cancer (CRC) pathogenesis through specific pathogens and their metabolites. We aim to determine gut microbiota-associated metabolites and their linkage to CRC. Methods We performed metabolomics by gas chromatography coupled to time-of-flight mass spectrometry, and shotgun metagenomics analysis on fecal samples from 386 subjects [118 CRC patients, 140 colorectal adenomas (CRA) patients and 128 normal controls (NC)]. Stepwise logistic regression models were used to identify metabolites and bacterial markers discriminating CRC stages. Associations among CRC-associated metabolites and bacteria were estimated with zero-inflated negative binomial regressions analysis. Results Principal component analysis and partial least squares-discriminant analysis showed differences in the gut metabolite profiles among CRC, CRA and NC groups. Norvaline and myristic acid showed increasing trends from NC, through CRA, to CRC. CRC-associated metabolites were enriched in branched-chain amino acids and aminoacyl-tRNA biosynthesis pathways. Twenty metabolites classified CRC from NC subjects with an area under the curve (AUC) of 0.80, and CRC from CRA with AUC of 0.79. Combinations of metabolites and bacterial markers improved the diagnostic performances (CRC vs NC, AUC: 0.94; CRC vs CRA, AUC 0.92; CRA vs NC, AUC: 0.86), indicating a potential for early diagnosis of colorectal neoplasia. Moreover, relationships among CRC-associated metabolites and bacteria were altered across CRC stages; certain associations exhibited increasing or decreasing strengths while some were reversed from negative to positive or vice versa. Conclusions Gut metabolites are altered in colorectal carcinogenesis. The combination of metabolites and bacterial species can increase the chance of a non-invasive diagnosis of colorectal neoplasia.

Background Gastrointestinal manifestations of the COVID-19 pandemic may mimic Irritable Bowel Syndrome (IBS), and social distancing measures may affect IBS patients negatively. We aimed to study the impact of COVID-19 on respondents with IBS. Methods We conducted an anonymised survey using MySurvey platform from May to June 2020 in 35 countries. The general public’s knowledge, attitudes and practices regarding personal hygiene and social distancing during this COVID-19 pandemic and the psychological impact of COVID-19 were assessed. Statistical analysis was performed to determine the differences in well-being and compliance to social distancing measures between IBS and non-IBS respondents. Factors associated with worsening of IBS symptoms were evaluated. For newly developed IBS-like symptoms, subjects must fulfill ROME IV criteria. Results Out of 2704 respondents, 2024 (74.9%) did not have IBS, 305 (11.3%) had IBS and 374 (13.8%) did not know what IBS was. Respondents with IBS reported significantly worse emotional, social and psychological well-being compared to non-IBS respondents and were less compliant to social distancing (28.2% vs 35.3%, p=0.029, table 1). Of the non-IBS respondents, 96 (4.7%) developed new IBS-like symptoms. Among IBS respondents, the majority reported no change in symptom severity (61.6%), while 26.6% reported improvement and 11.8% reported worsening in IBS symptoms. A higher proportion of respondents with no change in the severity of IBS symptoms was willing to practice social distancing indefinitely compared to those who deteriorated (74.9% vs 51.4%, p=0.016, table 2). In multivariate analysis (table 3), willingness to continue social distancing for only another 2–3 weeks was significantly associated with higher odds of worsening IBS while better emotional well-being was associated with lower odds. Flourishing was excluded from analysis due to overlap with emotional well-being. *Excluded from multivariable analysis due to 0 respondents in reference categories for respondents with no change in control IBS Conclusions Our study showed differences in well-being and compliance to social distancing between IBS and non-IBS respondents, and these factors influence the worsening in severity of IBS. Further research will focus on how occupational stress and dietary changes may influence IBS symptoms

Background High-risk esophagogastric varices (EGV) are prone to bleeding and are recommended to be eradicated through endoscopic therapy by practice guideline. However, a considerable number of patients may fail the endoscopic variceal eradication (VE) when second-line non-endoscopic treatments, including radio-interventional and surgical therapy are required. To date, predictive factors for the multidisciplinary therapy switch are unclear. We aimed to investigate factors that determine the therapy switch and the length of endoscopic therapy to VE. Methods We carried out this retrospective study based on an established cohort of cirrhosis recruiting patients from 2011 to 2018. Relevant medical and endoscopic data were collected and comprehensively assessed. Multivariate analyses were performed to identify factors associated with the therapy switch in all included patients, and the length of time to VE in endoscopic VE-achieved patients. Results A total of 330 patients were included for analysis, of which 289 cases (87.6%) achieved VE through sequential endoscopic therapies. The median (Interquartile range, IQR) time to VE was 5 (2–10.5) months and the median (IQR) number of endoscopic sessions required was 3 (2–5). Meanwhile, thirty-two cases (9.7%) failed endoscopic VE and transferred to multidisciplinary therapy during endoscopic intervals (25 cases for surgical therapy and 7 cases for radio-interventional therapy). Multivariate analysis showed that splenomegaly (hazard ratio, HR 1.21, 95%CI 1.09–1.34), portal vein thrombosis (HR 2.88, 95%CI 1.20–6.88) and thrombocytopenia (HR 0.99, 95%CI 0.97–1.00) were associated with the therapy switch. Among endoscopic VE-achieved patients, male sex (HR 1.49, 95%CI 1.12–1.99), large varices (HR 4.01, 95%CI 2.22–7.23), long-segment varices (HR 1.70, 95%CI 1.04–2.78), and intercurrent bleeding (HR 2.24, 95%CI 1.53–3.30) were associated with prolonged time required for VE. Conclusions Patients with an enlarged spleen, portal vein thrombosis and low platelet count are at high risk of undergoing multidisciplinary therapy to eradicate EGV. Severe varices, male sex and interval bleeding event impair endoscopic efficacy significantly. Our findings may help improve patient risk stratification and medical resources allocation.

Background In the absence of properly designed studies, the clinical implication of genetic findings in Inflammatory Bowel Disease (IBD) is a matter of persistent debate especially in Asian population where the prevalence of IBD including Crohn’s Disease (CD) and Ulcerative Colitis (UC) is rising. We aimed to investigate the predictability of IBD, CD, and UC by the means of Genetic Risk Score (GRS), in yet unaffected high-risk individuals from East Asia (EA) and Central Asia (CA). Methods This present study included 9,698 subjects, consisting of 2,003 CD, 2,730 UC and 4,965 countries, age and gender-matched controls, genotyped on the Immunochip array of three EA (Japan, South-Korea and China) and two CA countries (India and Iran). We generated a multi-locus GRS for each population by combining information from up to 201 known genome-wide significant IBD associated variants to summarize a total load of genetic risk for each phenotype. We estimated explained variance and predictability of IBD, CD, and UC by GRS. We shuffled the EA data into: training set including two out of the three EA populations to build a model to calculate the odds ratio (OR) for each IBD variants, and a test set including the third population for the validation of predictive model built in the training set. For Indian and Iranian populations, we used the previously estimated ORs for the Caucasian population, to build GRS and test the predictive model in these two populations. Results GRS of IBD could significantly explain up to 4.40% and 4.14% of IBD variance in EA and CA populations but given a prevalence of 0.01% and 0.04% for IBD it yields to a negligible predictive probability up to 8.8x10-4 and 5.52x10-4. GRS of CD and UC could significantly explain CD and UC to a lesser extent compared to IBD given a lower prevalence of CD and UC (figure 1). Conclusions The present study shows that genetic findings based on Trans-ethnic analyses are applicable across Asian populations. GRS alone can explain a limited percentage of disease occurrence in general population (

Background Biological therapies are increasingly used to treat inflammatory bowel disease (IBD) and other immune-mediated diseases. However, real-world epidemiological data on the risk of tuberculosis (TB) in these patients are scarce. We investigated the incidence of TB in patients with immune-mediated diseases in a population-based setting and stratified the risk of TB among different biologics. Methods Data on patient demographics, disease diagnosis, types of biologics and TB infections were collected from a territory-wide computerised database of patient records managed by the Hong Kong Hospital Authority. We calculated the incidence rates (IRs) of TB infections in subjects treated with different biologics between 2006 and 2015, and reported standardised incidence ratio (SIR) by comparing with the general population. Subgroup analyses were performed based on the types of immune-mediated diseases and biologic drugs. Results A total of 2485 patients with immune-mediated diseases were identified (10.6% IBD, 77.7% rheumatology, and 11.8% dermatology). 54 subjects developed active TB during 6921 person-years of follow-up. The mean age was 43 years, and the median follow up duration was 748 days. The overall SIR for TB in patients with included immune-mediated disease was 10.91. Patients with IBD had an over 17-fold increased risk of TB compared to the general population (SIR, 17.53), and patients on infliximab had a nearly 26-fold increased risk of TB compared to the general population (SIR, 25.95). Risk of TB was highest in the age group 50–59 years (SIR, 15.72). The risk of TB with infliximab was higher than etanercept (hazard ratio [HR], 4.10) and adalimumab (HR 2.08). No significant difference in the risk of TB was observed among the subgroups of IBD, rheumatology and dermatology. Conclusions In the population-based study, biological therapy is associated with higher risk of TB in patients with immune-mediated diseases compared with the general population, and infliximab is associated with the highest risk of TB amongst all biologics. This study suggests patient and biologic selection may be important in balancing the benefit and risk of TB when treating patients with immune-mediated diseases.