High Soluble Fiber Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites in Mice.

BACKGROUND & AIMS: Dietary fibers are mainly fermented by the gut microbiota, but their roles in colorectal cancer (CRC) are largely unclear. Here, we investigated the associations of different fibers with colorectal tumorigenesis in mice. METHODS: Apcmin/+ mice and C57BL/6 mice with azoxymethane (AOM) injection were used as CRC mouse models. Mice were fed with mixed high-fiber diet (20% soluble fiber and 20% insoluble fiber), high-inulin diet, high-guar gum diet, high-cellulose diet, or diets with different inulin dose. Germ-free mice were used for validation. Fecal microbiota and metabolites were profiled by shotgun metagenomic sequencing and liquid chromatography-mass spectrometry, respectively. RESULTS: Mixed high-fiber diet promoted colorectal tumorigenesis with increased tumor number and tumor load in AOM-treated and Apcmin/+ mice. Antibiotics use abolished the pro-tumorigenic effect of mixed high-fiber diet, while transplanting stools from mice fed with mixed high-fiber diet accelerated tumor growth in AOM-treated germ-free mice. We therefore characterized the contribution of soluble and insoluble fiber in CRC separately. Our results revealed that soluble fiber inulin or guar gum, but not insoluble fiber cellulose, promoted colorectal tumorigenesis in AOM-treated and Apcmin/+ mice. Soluble fiber induced gut dysbiosis with Bacteroides uniformis enrichment and Bifidobacterium pseudolongum depletion, accompanied by increased fecal butyrate and serum bile acids and decreased inosine. We also identified a positive correlation between inulin dosage and colorectal tumorigenesis. Moreover, transplanting stools from mice fed with high-inulin diet increased colonic cell proliferation and oncogene expressions in germ-free mice. CONCLUSION: High-dose soluble but not insoluble fiber potentiates colorectal tumorigenesis in a dose-dependent manner by dysregulating gut microbiota and metabolites in mice.

Spatial proteomics of immune microenvironment in nonalcoholic steatohepatitis-associated hepatocellular carcinoma.

BACKGROUND AND AIMS: NASH-HCC is inherently resistant to immune checkpoint blockade, but its tumor immune microenvironment is largely unknown. APPROACH AND RESULTS: We applied the imaging mass cytometry to construct a spatially resolved single-cell atlas from the formalin-fixed and paraffin-embedded tissue sections from patients with NASH-HCC, virus-HCC (HBV-HCC and HCV-HCC), and healthy donors. Based on 35 biomarkers, over 750,000 individual cells were categorized into 13 distinct cell types, together with the expression of key immune functional markers. Higher infiltration of T cells, myeloid-derived suppressor cell (MDSCs), and tumor-associated macrophages (TAMs) in HCC compared to controls. The distribution of immune cells in NASH-HCC is spatially heterogeneous, enriched at adjacent normal tissues and declined toward tumors. Cell-cell connections analysis revealed the interplay of MDSCs and TAMs with CD8 + T cells in NASH-HCC. In particular, exhausted programmed cell death 1 (PD-1 + )CD8 + T cells connected with programmed cell death-ligand 1 (PD-L1 + )/inducible T cell costimulator (ICOS + ) MDSCs and TAMs in NASH-HCC, but not in viral HCC. In contrast, CD4 + /CD8 + T cells with granzyme B positivity were reduced in NASH-HCC. Tumor cells expressed low PD-L1 and showed few connections with immune cells. CONCLUSIONS: Our work provides the first detailed spatial map of single-cell phenotypes and multicellular connections in NASH-HCC. We demonstrate that interactions between MDSCs and TAMs with effector T cells underlie immunosuppression in NASH-HCC and are an actionable target.

Microbial Dysregulation of the Gut-Lung Axis in Bronchiectasis.

Rationale: Emerging data support the existence of a microbial "gut-lung" axis that remains unexplored in bronchiectasis. Methods: Prospective and concurrent sampling of gut (stool) and lung (sputum) was performed in a cohort of n = 57 individuals with bronchiectasis and subjected to bacteriome (16S rRNA) and mycobiome (18S Internal Transcribed Spacer) sequencing (total, 228 microbiomes). Shotgun metagenomics was performed in a subset (n = 15; 30 microbiomes). Data from gut and lung compartments were integrated by weighted similarity network fusion, clustered, and subjected to co-occurrence analysis to evaluate gut-lung networks. Murine experiments were undertaken to validate specific Pseudomonas-driven gut-lung interactions. Results: Microbial communities in stable bronchiectasis demonstrate a significant gut-lung interaction. Multibiome integration followed by unsupervised clustering reveals two patient clusters, differing by gut-lung interactions and with contrasting clinical phenotypes. A high gut-lung interaction cluster, characterized by lung Pseudomonas, gut Bacteroides, and gut Saccharomyces, is associated with increased exacerbations and greater radiological and overall bronchiectasis severity, whereas the low gut-lung interaction cluster demonstrates an overrepresentation of lung commensals, including Prevotella, Fusobacterium, and Porphyromonas with gut Candida. The lung Pseudomonas-gut Bacteroides relationship, observed in the high gut-lung interaction bronchiectasis cluster, was validated in a murine model of lung Pseudomonas aeruginosa infection. This interaction was abrogated after antibiotic (imipenem) pretreatment in mice confirming the relevance and therapeutic potential of targeting the gut microbiome to influence the gut-lung axis. Metagenomics in a subset of individuals with bronchiectasis corroborated our findings from targeted analyses. Conclusions: A dysregulated gut-lung axis, driven by lung Pseudomonas, associates with poorer clinical outcomes in bronchiectasis.

An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

Timing of Endoscopy for Acute Upper Gastrointestinal Bleeding.

BACKGROUND: It is recommended that patients with acute upper gastrointestinal bleeding undergo endoscopy within 24 hours after gastroenterologic consultation. The role of endoscopy performed within time frames shorter than 24 hours has not been adequately defined. METHODS: To evaluate whether urgent endoscopy improves outcomes in patients predicted to be at high risk for further bleeding or death, we randomly assigned patients with overt signs of acute upper gastrointestinal bleeding and a Glasgow-Blatchford score of 12 or higher (scores range from 0 to 23, with higher scores indicating a higher risk of further bleeding or death) to undergo endoscopy within 6 hours (urgent-endoscopy group) or between 6 and 24 hours (early-endoscopy group) after gastroenterologic consultation. The primary end point was death from any cause within 30 days after randomization. RESULTS: A total of 516 patients were enrolled. The 30-day mortality was 8.9% (23 of 258 patients) in the urgent-endoscopy group and 6.6% (17 of 258) in the early-endoscopy group (difference, 2.3 percentage points; 95% confidence interval [CI], -2.3 to 6.9). Further bleeding within 30 days occurred in 28 patients (10.9%) in the urgent-endoscopy group and in 20 (7.8%) in the early-endoscopy group (difference, 3.1 percentage points; 95% CI, -1.9 to 8.1). Ulcers with active bleeding or visible vessels were found on initial endoscopy in 105 of the 158 patients (66.4%) with peptic ulcers in the urgent-endoscopy group and in 76 of 159 (47.8%) in the early-endoscopy group. Endoscopic hemostatic treatment was administered at initial endoscopy for 155 patients (60.1%) in the urgent-endoscopy group and for 125 (48.4%) in the early-endoscopy group. CONCLUSIONS: In patients with acute upper gastrointestinal bleeding who were at high risk for further bleeding or death, endoscopy performed within 6 hours after gastroenterologic consultation was not associated with lower 30-day mortality than endoscopy performed between 6 and 24 hours after consultation. (Funded by the Health and Medical Fund of the Food and Health Bureau, Government of Hong Kong Special Administrative Region; ClinicalTrials.gov number, NCT01675856.).

High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites.

BACKGROUND AND AIMS: Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites. METHODS: HFD or control diet was fed to mice littermates in CRC mouse models of an azoxymethane (AOM) model and Apcmin/+ model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were used for validation. Gut microbiota and metabolites were detected using metagenomic sequencing and high-performance liquid chromatography-mass spectrometry, respectively. Gut barrier function was determined using lipopolysaccharides level and transmission electron microscopy. RESULTS: HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apcmin/+ mice compared with control diet-fed mice. Gut microbiota depletion using antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipessp.Marseille-P5997 and Alistipessp.5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration, including elevated lysophosphatidic acid, which was confirmed to promote CRC cell proliferation and impair cell junction, was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function, and induced oncogenic genes expression. CONCLUSIONS: HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated lysophosphatidic acid, and gut barrier dysfunction in mice.

Artificial Intelligence-Assisted Colonoscopy for Colorectal Cancer Screening: A Multicenter Randomized Controlled Trial.

BACKGROUND AND AIMS: Artificial intelligence (AI)-assisted colonoscopy improves polyp detection and characterization in colonoscopy. However, data from large-scale multicenter randomized controlled trials (RCT) in an asymptomatic population are lacking. METHODS: This multicenter RCT aimed to compare AI-assisted colonoscopy with conventional colonoscopy for adenoma detection in an asymptomatic population. Asymptomatic subjects 45-75 years of age undergoing colorectal cancer screening by direct colonoscopy or fecal immunochemical test were recruited in 6 referral centers in Hong Kong, Jilin, Inner Mongolia, Xiamen, and Beijing. In the AI-assisted colonoscopy, an AI polyp detection system (Eagle-Eye) with real-time notification on the same monitor of the endoscopy system was used. The primary outcome was overall adenoma detection rate (ADR). Secondary outcomes were mean number of adenomas per colonoscopy, ADR according to endoscopist's experience, and colonoscopy withdrawal time. This study received Institutional Review Board approval (CRE-2019.393). RESULTS: From November 2019 to August 2021, 3059 subjects were randomized to AI-assisted colonoscopy (n = 1519) and conventional colonoscopy (n = 1540). Baseline characteristics and bowel preparation quality between the 2 groups were similar. The overall ADR (39.9% vs 32.4%; P < .001), advanced ADR (6.6% vs 4.9%; P = .041), ADR of expert (42.3% vs 32.8%; P < .001) and nonexpert endoscopists (37.5% vs 32.1%; P = .023), and adenomas per colonoscopy (0.59 ± 0.97 vs 0.45 ± 0.81; P < .001) were all significantly higher in the AI-assisted colonoscopy. The median withdrawal time (8.3 minutes vs 7.8 minutes; P = .004) was slightly longer in the AI-assisted colonoscopy group. CONCLUSIONS: In this multicenter RCT in asymptomatic patients, AI-assisted colonoscopy improved overall ADR, advanced ADR, and ADR of both expert and nonexpert attending endoscopists. (ClinicalTrials.gov, Number: NCT04422548).

Use of probiotics, prebiotics, and synbiotics in non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Patients with non-alcoholic fatty liver disease (NAFLD) exhibit compositional changes in their gut microbiome, which represents a potential therapeutic target. Probiotics, prebiotics, and synbiotics are microbiome-targeted therapies that have been proposed as treatment for NAFLD. We aim to systematically review the effects of these therapies in liver-related outcomes of NAFLD patients. METHODS: We conducted a systematic search in Embase (Ovid), Medline (Ovid), Scopus, Cochrane, and EBSCOhost from inception to August 19, 2022. We included randomized controlled trials (RCTs) that treated NAFLD patients with prebiotics and/or probiotics. We meta-analyzed the outcomes using standardized mean difference (SMD) and assessed study heterogeneity using Cochran's Q test and I2 statistics. Risk of bias was assessed using the Cochrane Risk-of-Bias 2 tool. RESULTS: A total of 41 (18 probiotics, 17 synbiotics, and 6 prebiotics) RCTs were included. Pooled data demonstrated that the intervention had significantly improved liver steatosis (measured by ultrasound grading) (SMD: 4.87; 95% confidence interval [CI]: 3.27, 7.25), fibrosis (SMD: -0.61 kPa; 95% CI: -1.12, -0.09 kPa), and liver enzymes including alanine transaminase (SMD: -0.86 U/L; 95% CI: -1.16, -0.56 U/L), aspartate transaminase (SMD: -0.87 U/L; 95% CI: -1.22, -0.52 U/L), and gamma-glutamyl transferase (SMD: -0.77 U/L; 95% CI: -1.26, -0.29 U/L). CONCLUSIONS: Microbiome-targeted therapies were associated with significant improvements in liver-related outcomes in NAFLD patients. Nevertheless, limitations in existing literature like heterogeneity in probiotic strains, dosage, and formulation undermine our findings. This study was registered with PROSPERO (CRD42022354562) and supported by the Nanyang Technological University Start-up Grant and Wang Lee Wah Memorial Fund.

Artificial intelligence for gastroenterology: Singapore artificial intelligence for Gastroenterology Working Group Position Statement.

BACKGROUND: Successful implementation of artificial intelligence in gastroenterology and hepatology practice requires more than technology. There are ethical, legal, and social issues that need to be settled. AIM: A group consisting of AI developers (engineer), AI users (gastroenterologist, hepatologist, and surgeon) and AI regulators (ethicist and administrator) formed a Working Group to draft these Positions Statements with the objective of arousing public and professional interest and dialogue, to promote ethical considerations when implementing AI technology, to suggest to policy makers and health authorities relevant factors to take into account when approving and regulating the use of AI tools, and to engage the profession in preparing for change in clinical practice. STATEMENTS: These series of Position Statements point out the salient issues to maintain the trust between care provider and care receivers, and to legitimize the use of a non-human tool in healthcare delivery. It is based on fundamental principles such as respect, autonomy, privacy, responsibility, and justice. Enforcing the use of AI without considering these factor risk damaging the doctor-patient relationship.

Impact of COVID-19 infection and vaccination in pancreatobiliary IgG4-related disease patients: An international multicenter study.

BACKGROUND AND AIM: Dedicated studies evaluating the impact of COVID-19 on outcomes of pancreatobiliary IgG4 related disease (IgG4-RD) patients are scarce. Whether COVID-19 infection or vaccination would trigger IgG4-RD exacerbation remains unknown. METHODS: Pancreatobiliary IgG4-RD patients ≥ 18 years old with active follow-up since January 2020 from nine referral centers in Asia, Europe, and North America were included in this multicenter retrospective study. Outcome measures include incidence and severity of COVID-19 infection, IgG4-RD disease activity and treatment status, interruption of indicated IgG4-RD treatment. Prospective data on COVID-19 vaccination status and new COVID-19 infection during the Omicron outbreak were also retrieved in the Hong Kong cohort. RESULTS: Of the 124 pancreatobiliary IgG4-RD patients, 25.0% had active IgG4-RD, 71.0% were on immunosuppressive therapies and 80.6% had ≥ 1 risk factor for severe COVID. In 2020 (pre-vaccination period), two patients (1.6%) had COVID-19 infection (one requiring ICU admission), and 7.2% of patients had interruptions in indicated immunosuppressive treatment for IgG4-RD. Despite a high vaccination rate (85.0%), COVID-19 infection rate has increased to 20.0% during Omicron outbreak in the Hong Kong cohort. A trend towards higher COVID-19 infection rate was noted in the non-fully vaccinated/unvaccinated group (17.6% vs 33.3%, P = 0.376). No IgG4-RD exacerbation following COVID-19 vaccination or infection was observed. CONCLUSION: While a low COVID-19 infection rate with no mortality was observed in pancreatobiliary IgG4-RD patients in the pre-vaccination period of COVID-19, infection rate has increased during the Omicron outbreak despite a high vaccination rate. No IgG4-RD exacerbation after COVID-19 infection or vaccination was observed.

Comparison of a Hemostatic Powder and Standard Treatment in the Control of Active Bleeding From Upper Nonvariceal Lesions : A Multicenter, Noninferiority, Randomized Trial.

BACKGROUND: The effectiveness of the hemostatic powder TC-325 as a single endoscopic treatment for acute nonvariceal upper gastrointestinal bleeding is uncertain. OBJECTIVE: To compare TC-325 with standard endoscopic hemostatic treatments in the control of active bleeding from nonvariceal upper gastrointestinal causes. DESIGN: One-sided, noninferiority, randomized, controlled trial. (ClinicalTrials.gov: NCT02534571). SETTING: University teaching hospitals in the Asia-Pacific region. PATIENTS: 224 adult patients with acute bleeding from a nonvariceal cause on upper gastrointestinal endoscopy. INTERVENTION: TC-325 (n = 111) or standard hemostatic treatment (n = 113). MEASUREMENTS: The primary outcome was control of bleeding within 30 days. Other outcomes included failure to control bleeding during index endoscopy, recurrent bleeding after initial hemostasis, further interventions, blood transfusion, hospitalization, and death. RESULTS: 224 patients were enrolled (136 with gastroduodenal ulcers [60.7%], 33 with tumors [14.7%], and 55 with other causes of bleeding [24.6%]). Bleeding was controlled within 30 days in 100 of 111 patients (90.1%) in the TC-325 group and 92 of 113 (81.4%) in the standard treatment group (risk difference, 8.7 percentage points [1-sided 95% CI, 0.95 percentage point]). There were fewer failures of hemostasis during index endoscopy with TC-325 (3 [2.7%] vs. 11 [9.7%]; odds ratio, 0.26 [CI, 0.07 to 0.95]). Recurrent bleeding within 30 days did not differ between groups (9 [8.1%] vs. 10 [8.8%]). The need for further interventions also did not differ between groups (further endoscopic treatment: 8 [7.2%] vs. 10 [8.8%]; angiography: 2 [1.8%] vs. 4 [3.5%]; surgery: 1 [0.9%] vs. 0). There were 14 deaths in each group (12.6% vs. 12.4%). LIMITATION: Clinicians were not blinded to treatment. CONCLUSION: TC-325 is not inferior to standard treatment in the endoscopic control of bleeding from nonvariceal upper gastrointestinal causes. PRIMARY FUNDING SOURCE: General Research Fund to the University Grants Committee, Hong Kong SAR Government.

Timing of endoscopy for acute upper gastrointestinal bleeding: a territory-wide cohort study.

OBJECTIVE: While it is recommended that patients presenting with acute upper gastrointestinal bleeding (AUGIB) should receive endoscopic intervention within 24 hours, the optimal timing is still uncertain. We aimed to assess whether endoscopy timing postadmission would affect outcomes. DESIGN: We conducted a retrospective, territory-wide, cohort study with healthcare data from all public hospitals in Hong Kong. Adult patients (age ≥18) that presented with AUGIB between 2013 and 2019 and received therapeutic endoscopy within 48 hours (n=6474) were recruited. Patients were classified based on endoscopic timing postadmission: urgent (t≤6), early (6

Third Asia-Pacific consensus recommendations on colorectal cancer screening and postpolypectomy surveillance.

The Asia-Pacific region has the largest number of cases of colorectal cancer (CRC) and one of the highest levels of mortality due to this condition in the world. Since the publishing of two consensus recommendations in 2008 and 2015, significant advancements have been made in our knowledge of epidemiology, pathology and the natural history of the adenoma-carcinoma progression. Based on the most updated epidemiological and clinical studies in this region, considering literature from international studies, and adopting the modified Delphi process, the Asia-Pacific Working Group on Colorectal Cancer Screening has updated and revised their recommendations on (1) screening methods and preferred strategies; (2) age for starting and terminating screening for CRC; (3) screening for individuals with a family history of CRC or advanced adenoma; (4) surveillance for those with adenomas; (5) screening and surveillance for sessile serrated lesions and (6) quality assurance of screening programmes. Thirteen countries/regions in the Asia-Pacific region were represented in this exercise. International advisors from North America and Europe were invited to participate.

The Role of Angiotensin Converting Enzyme 2 in Modulating Gut Microbiota, Intestinal Inflammation, and Coronavirus Infection.

The role of angiotensin converting enzyme 2 has expanded from regulating the renin angiotensin system to regulating intestinal amino acid homeostasis and the gut microbiome. Recently, angiotensin converting enzyme 2 was identified as a primary receptor for severe acute respiratory syndrome coronaviruses 1 and 2 being expressed in multiple tissues including the luminal surface of the gut. In this brief perspective, we examine the role of angiotensin converting enzyme 2 as the receptor for severe acute respiratory syndrome coronavirus 2 and the impact of coronavirus disease 19 infection on the gut microbiome and on the gut epithelium.

Two vs One Forward View Examination of Right Colon on Adenoma Detection: An International Multicenter Randomized Trial.

BACKGROUND & AIMS: Second forward view (SFV) examination of the right colon (RC) in colonoscopy was suggested to improve the adenoma detection rate (ADR), but multicenter data to inform its routine use remain limited. We performed an international multicenter randomized trial comparing SFV vs a standard single forward view examination of the RC on adenoma detection. METHODS: Asymptomatic individuals undergoing screening or surveillance colonoscopies from 6 Asia Pacific regions were invited for study. A forward view examination of the RC was first performed in all patients, followed by randomization at the hepatic flexure to either SFV examination of the RC and standard withdrawal examination from the hepatic flexure to rectum, or a standard withdrawal colonoscopy (SWC) examination from the hepatic flexure to rectum. The primary outcome was RC ADR. RESULTS: Between 2016 and 2019, there were 1011 patients randomized (SFV group, 502 patients; SWC group, 509 patients). Forty-five endoscopists performed the colonoscopies. The RC ADR was significantly higher in the SFV group than in the SWC group (27.1% vs 21.6%; P = .042). The whole-colon ADR was high in both groups (49.0% vs 45.0%; P =.201). The SFV examination identified 58 additional adenomas in 49 patients (9.8%), leading to a change in surveillance recommendations in 15 patients (3.0%). The median overall withdrawal time was 1.5 minutes longer in the SFV group (12.0 vs 10.5 min; P < .001). Older age, male sex, ever smoking, and longer RC withdrawal time were independent predictors of right-sided adenoma detection. CONCLUSIONS: In this multicenter trial, SFV examination significantly increased the RC ADR in screening and surveillance colonoscopies. Routine RC SFV examination should be considered. ClinicalTrials.gov ID: NCT03121495.

Population-Level Configurations of Gut Mycobiome Across 6 Ethnicities in Urban and Rural China.

BACKGROUND & AIMS: Beyond bacteria, the human gastrointestinal tract is host to a vast diversity of fungi, collectively known as the gut mycobiome. Little is known of the impact of geography, ethnicity, and urbanization on the gut mycobiome at a large population level. We aim to delineate the variation of human gut mycobiome and its association with host factors, environmental factors, and diets. METHODS: Using shotgun metagenomic sequencing, we profiled and compared the fecal mycobiome of 942 healthy individuals across different geographic regions in China (Hong Kong and Yunnan), spanning 6 ethnicities: Han, Zang, Bai, Hani, Dai, and Miao (including both urban and rural residents of each ethnicity). In parallel to fecal sampling, we collected participant metadata (environmental exposure, bowel habits, anthropometrics, and medication), diet, and clinical blood measurement results (a total of 118 variables) and investigated their impact on the gut mycobiome variation in humans. RESULTS: The human gut mycobiome was highly variable across populations. Urbanization-related factors had the strongest impact on gut mycobiome variation, followed by geography, dietary habit, and ethnicity. The Hong Kong population (highly urbanized) had a significantly lower fungal richness compared with Yunnan population. Saccharomyces cerevisiae was highly enriched in urban compared with rural populations and showed significant inverse correlations with liver pathology-associated blood parameters, including aspartate transaminase, alanine transaminase, gamma-glutamyltransferase, and direct bilirubin. Candida dubliniensis, which was decreased in urban relative to rural populations, showed correlations with host metabolism-related parameters in blood, including a positive correlation with fasting high-density lipoprotein cholesterol levels and a negative correlation with fasting glucose levels. The fungal-blood parameter correlations were highly geography- and ethnicity-specific. Food choices had differential influences on gut mycobiome and bacterial microbiome, where taxa from the same genus tended to be coregulated by food and thereby cobloom. Ethnicity-specific fungal signatures were associated with distinct habitual foods in each ethnic group. CONCLUSIONS: Our data highlight, for the first time to our knowledge, that geography, urbanization, ethnicity, and habitual diet play an important role in shaping the gut mycobiome composition. Gut fungal configurations in combination with population characteristics (such as residing region, ethnicity, diet, lifestyle) influence host metabolism and health.

Elucidation of Proteus mirabilis as a Key Bacterium in Crohn's Disease Inflammation.

BACKGROUND & AIMS: Proteus spp, Gram-negative facultative anaerobic bacilli, have recently been associated with Crohn's disease (CD) recurrence after intestinal resection. We investigated the genomic and functional role of Proteus as a gut pathogen in CD. METHODS: Proteus spp abundance was assessed by ure gene-specific polymerase chain in 54 pairs of fecal samples and 101 intestinal biopsies from patients with CD and healthy controls. The adherence, invasion, and intracellular presence of 2 distinct isolates of Proteus mirabilis in epithelial cells were evaluated using immunofluorescence and electron microscopy. Intracellular gene expression profiles and regulated pathways were analyzed by RNA sequencing and KEGG pathway analysis. Biologic functions of 2 isolates of P mirabilis were determined by in vitro cell culture, and in vivo using conventional mice and germ-free mice. RESULTS: Proteus spp were significantly more prevalent and abundant in fecal samples and colonic tissue of patients with CD than controls. A greater abundance of the genus Fusobacterium and a lesser abundance of the genus Faecalibacterium were seen in patients with CD with a high Proteus spp abundance. All 24 Proteus monoclones isolated from patients with CD belonged to members of P mirabilis lineages and 2 isolates, recovered from stool or mucosa, were used in further studies. Mice gavaged with either P mirabilis strain had more severe colonic inflammation. Co-culture of the isolates with epithelial cell lines showed bacterial adherence, invasion, increased production of pro-inflammatory cytokines IL-18 and IL-1α, and cell necrosis. Both isolates induced key pro-inflammatory pathways, including NOD-like receptor signaling, Jak-STAT signaling, and MAPK signaling, and induced pro-inflammatory genes and activated inflammation-related pathways in gnotobiotic mice. CONCLUSIONS: P mirabilis in the gut is associated with CD and can induce inflammation in cells and animal models of colitis. P mirabilis can act as a pathobiont and play a crucial role in the pathogenesis of CD.

Use of topical mineral powder as monotherapy for treatment of active peptic ulcer bleeding.

BACKGROUND AND AIMS: The aim of this study was to evaluate the safety and effectiveness of Hemospray (Cook Medical, Winston-Salem, NC, USA), a hemostatic powder, as monotherapy for active peptic ulcer bleeding. METHODS: In this prospective, multicenter, single-arm study, patients with Forrest Ia or Ib peptic ulcers underwent endoscopic application of Hemospray as treatment of first intent. Effectiveness endpoints were successful hemostasis at the end of the index endoscopy, recurrent bleeding within 72 hours and from 72 hours to 30 days, adverse events requiring reintervention or resulting in morbidity or mortality, and 30-day mortality. RESULTS: Hemospray was successfully administered in 98.5% of patients (66/67). Hemostasis was achieved at the index endoscopy in 90.9% of patients (60/66) with Hemospray alone and in an additional 4 patients treated with additional modalities, yielding an overall hemostasis rate of 97.0% (64/66). Rebleeding occurred in 13.3% of patients (8/60), 5 within 72 hours and 3 between 72 hours and 30 days. Two cases of perforation and 2 patient deaths occurred during the study, but none of these cases or any other adverse events were attributed to the use of Hemospray. The rate of early rebleeding was significantly higher in patients with Forrest Ia ulcers compared with patients with Forrest Ib ulcers. Higher rates of early bleeding in patients with Forrest Ia ulcers is consistent with results from studies where Hemospray was used as rescue after failure of conventional methods. CONCLUSIONS: Hemospray is an effective initial treatment for patients with active peptic ulcer bleeding, but care should be taken to monitor for recurrent bleeding. (Clinical trial registration number: NCT01306864.).

What is unknown in using microbiota as a therapeutic?

Fecal microbiota transplantation (FMT) has been used extensively in the treatment of various gastrointestinal and extraintestinal conditions, despite that there are still a lot of missing gaps in our knowledge in the gut microbiota and its behavior. This article describes the unknowns in microbiota biology (undetected microbes, uncertain colonization, unclear mechanisms of action, uncertain indications, unsure long-term efficacy, or side effects). We discuss how these unknowns may affect the therapeutic uses of FMT, and the potentials and caveats of other related microbiota-based therapies. When used as an experimental therapy or last resort in difficult conditions, caution should be taken against inadvertent complications. Clear documentations of post-treatment events should be made mandatory, classified, and graded as in clinical trials. Further robust scientific experiments and properly designed clinical studies are needed.

GdX/UBL4A specifically stabilizes the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis.

Impaired phosphatase activity contributes to the persistent activation of STAT3 in tumors. Given that STAT family members with various or even opposite functions are often phosphorylated or dephosphorylated by the same enzymes, the mechanism for STAT3-specific dephosphorylation in cells remains largely unknown. Here, we report that GdX (UBL4A) promotes STAT3 dephosphorylation via mediating the interaction between TC45 (the nuclear isoform of TC-PTP) and STAT3 specifically. GdX stabilizes the TC45-STAT3 complex to bestow upon STAT3 an efficient dephosphorylation by TC45. Inasmuch, GdX suppresses tumorigenesis and tumor development by reducing the level of phospho-STAT3 (p-STAT3), whereas deletion of GdX results in a high level of p-STAT3 and accelerated colorectal tumorigenesis induced by AOM/DSS. Thus, GdX converts TC45, a nonspecific phosphatase, into a STAT3-specific phosphatase by bridging an association between TC45 and STAT3.