Bacterial indole-3-lactic acid affects epithelium-macrophage crosstalk to regulate intestinal homeostasis.

Tryptophan and its derivatives perform a variety of biological functions; however, the role and specific mechanism of many tryptophan derivatives in intestinal inflammation remain largely unclear. Here, we identified that an Escherichia coli strain (Ec-TMU) isolated from the feces of tinidazole-treated individuals, and indole-3-lactic acid (ILA) in its supernatant, decreased the susceptibility of mice to dextran sulfate sodium-induced colitis. Ec-TMU and ILA contribute to the relief of colitis by inhibiting the production of epithelial CCL2/7, thereby reducing the accumulation of inflammatory macrophages in vitro and in vivo. Mechanistically, ILA downregulates glycolysis, NF-κB, and HIF signaling pathways via the aryl hydrocarbon receptor, resulting in decreased CCL2/7 production in epithelial cells. Clinical evidence suggests that the fecal ILA level is negatively correlated with the progression indicator of inflammatory bowel diseases. These results demonstrate that ILA has the potential to regulate intestinal homeostasis by modulating epithelium-macrophage interactions.

Prevalence and clinical profiles of primary sclerosing cholangitis in China: Data from electronic medical records and systematic literature retrieval.

BACKGROUND & AIMS: Epidemiology of primary sclerosing cholangitis (PSC) is lacking in China. We aimed to estimate the period prevalence and depict the clinical features of PSC in China. METHODS: We identified and included PSC cases between 2000 and 2023 from two sources: electronic medical records (EMR) and systematical literature retrieval (SLR). The period prevalence of PSC was estimated by the multiplier method. Rate ratios (RRs) for PSC prevalence in relation to macroeconomic indicators were calculated by the negative binomial regression model. RESULTS: A total of 1358 PSC cases were retrieved from 299 hospitals (162 from EMR and 1196 from SLR). Males accounted for 55.7 % of the PSC cases and 25.7 % had concomitant inflammatory bowel disease (IBD). The estimated period prevalence of PSC from 2000 to 2023 was 2.36 (95 % CI: 1.82, 3.34) per 100,000. Males had a numerically higher PSC prevalence than females (2.56, 95 % CI: 1.97, 3.63 vs. 2.14, 95 % CI: 1.65, 3.04 per 100,000). The highest prevalence of PSC was in East China at 4.87 (95 % CI: 3.44, 7.18) per 100,000, followed by North China at 2.94 (95 % CI: 2.33, 3.74) per 100,000, and the lowest in South China at 0.92 (95 % CI: 0.66, 1.30) per 100,000. Regional per capita GDP (RR 1.65, 95 % CI: 1.03, 2.65) and healthcare expenditure (RR 1.94, 95 % CI: 1.13, 3.38) were identified to be associated with PSC prevalence. CONCLUSION: Our study showed the estimated PSC prevalence varied within China, but was generally lower than that in Western countries.

The efficacy and safety of fexuprazan in treating erosive esophagitis: a phase III, randomized, double-blind, multicenter study.

BACKGROUND AND AIM: Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). This study aimed to explore the noninferior efficacy and safety of fexuprazan to esomeprazole in treating erosive esophagitis (EE). METHODS: This was a phase III, randomized, double-blind multicenter study. Patients with endoscopically confirmed EE were randomized to receive fexuprazan 40 mg or esomeprazole 40 mg once a daily for 4-8 weeks. The healing rates of EE, symptom response, GERD-health-related quality life (GERD-HRQL), and treatment-emergent adverse events (TEAEs) were compared between fexuprazan group and esomeprazole group. RESULTS: A total of 332 subjects were included in full analysis set (FAS) and 311 in per-protocol set (PPS). The healing rates of fexuprazan and esomeprazole groups at 8 weeks were 88.5% (146/165) and 89.0% (145/163), respectively, in FAS and 97.3% (145/149) and 97.9% (143/146), respectively, in PPS. Noninferiority of fexuprazan compared with esomeprazole according to EE healing rates at 8 weeks was demonstrated in both FAS and PPS analysis. No significant difference was found between groups in EE healing rates at 4 weeks, symptom responses, and changes of GERD-HRQL. The incidence of drug-related AEs was 19.4% (32/165) in fexuprazan arm and 19.6% (32/163) in esomeprazole arm. CONCLUSION: This study demonstrated noninferior efficacy of fexuprazan to esomeprazole in treating EE. The incidence of TEAEs was similar between fexuprazan and esomeprazole. Trial registration number NCT05813561.

Clostridium butyricum inhibits epithelial-mesenchymal transition of intestinal carcinogenesis through downregulating METTL3.

Colorectal cancer (CRC) is related to gut microbiota dysbiosis, especially butyrate-producing bacteria reduction. Our previous study suggested that administration of Clostridium butyricum, a butyrate-producing bacterium, exerts a crucial effect against CRC, however the potential mechanism is not clear. We first found that methyltransferase-like 3 (METTL3) showed a positive correlation with proliferation, epithelial-mesenchymal transition (EMT), DNA repair, metastasis, and invasion in a database analysis. The expression of METTL3 gradually increased from human normal colon tissue, to adenoma, and carcinoma, and was positively correlated with E-cadherin and CD34 levels. Overexpression of METTL3 promoted the proliferation, migration, and invasion of CRC cells and induced vasculogenic mimicry (VM) formation. Clostridium butyricum could downregulate METTL3 expression in CRC cells and decrease the expression of vimentin and vascular endothelial growth factor receptor 2 to reduce EMT and VM formation. Clostridium butyricum alleviated the pro-oncogenic effect of METTL3 overexpressing plasmid in CRC cells. The anti-EMT effect on METTL3 reduction of C. butyricum could be blunted by knocking down G-protein coupled receptor 43. Moreover, C. butyricum prevented EMT and VM and inhibited tumor metastasis in nude mice. Accordingly, C. butyricum could inhibit EMT and VM formation of intestinal carcinogenesis through downregulating METTL3. These findings broaden our understanding of probiotics supplement in CRC prevention and treatment.

Asia-Pacific Colorectal Screening Score Combined With Stool DNA Test Improves the Detection Rate for Colorectal Advanced Neoplasms.

BACKGROUND & AIMS: The Asia-Pacific Colorectal Screening (APCS) scoring system was developed to stratify the risk of colorectal advanced neoplasm (AN). We aimed to evaluate the performance of the APCS score combined with a stool DNA test used for colorectal cancer screening. METHODS: A total of 2842 subjects who visited outpatient clinics or cancer screening centers were enrolled. Age, sex, smoking status, and family history were recorded and APCS scores were calculated in 2439 participants. A stool DNA test (SDC2 and SFRP2 tests) and fecal immunochemical test (FIT) were performed and colonoscopy was used as the gold standard among 2240 subjects who completed all study procedures. We used a threshold of 4.4 µg/g for the FIT, in addition to the manufacturer's recommended threshold of 20 µg/g to match the specificity of a stool DNA test. RESULTS: Based on the APCS score, 38.8% (946 of 2439) of the subjects were categorized as high risk, and they had a 1.8-fold increase in risk for AN (95% CI, 1.4-2.3) compared with low and moderate risk. The APCS combined with the stool DNA test detected 95.2% of invasive cancers (40 of 42) and 73.5% of ANs (253 of 344), while the colonoscopy workload was only 47.1% (1056 of 2240). The sensitivity for AN of APCS combined with stool DNA test was significantly higher than that of APCS combined with FIT (73.5% vs 62.8% with FIT cut-off value of 20 µg/g, and 73.5% vs 68.0% with FIT cut-off value of 4.4 µg/g; both P < .01). CONCLUSIONS: The APCS score combined with a stool DNA test significantly improved the detection of colorectal ANs, while limiting colonoscopy resource utilization (Chictr.org.cn, ChiCTR-DDD-17011169).

Fecal Signatures of Streptococcus anginosus and Streptococcus constellatus for Noninvasive Screening and Early Warning of Gastric Cancer.

BACKGROUND & AIMS: Most patients with gastric cancer (GCa) are diagnosed at an advanced stage. We aimed to investigate novel fecal signatures for clinical application in early diagnosis of GCa. METHODS: This was an observational study that included 1043 patients from 10 hospitals in China. In the discovery cohort, 16S ribosomal RNA gene analysis was performed in paired samples (tissues and feces) from patients with GCa and chronic gastritis (ChG) to determine differential abundant microbes. Their relative abundances were detected using quantitative real-time polymerase chain reaction to test them as bacterial candidates in the training cohort. Their diagnostic efficacy was validated in the validation cohort. RESULTS: Significant enrichments of Streptococcus anginosus (Sa) and Streptococcus constellatus (Sc) in GCa tumor tissues (P < .05) and feces (P < .0001) were observed in patients with intraepithelial neoplasia, early and advanced GCa. Either the signature parallel test Sa∪Sc or single signature Sa/Sc demonstrated superior sensitivity (Sa: 75.6% vs 72.1%, P < .05; Sc: 84.4% vs 64.0%, P < .001; and Sa∪Sc: 91.1% vs 81.4%, P < .01) in detecting early GCa compared with advanced GCa (specificity: Sa: 84.0% vs 83.9%, Sc: 70.4% vs 82.3%, and Sa∪Sc: 64.0% vs 73.4%). Fecal signature Sa∪Sc outperformed Sa∪CEA/Sc∪CEA in the discrimination of advanced GCa (sensitivity: 81.4% vs 74.2% and 81.4% vs 72.3%, P < .01; specificity: 73.4% vs 81.0 % and 73.4% vs 81.0%). The performance of Sa∪Sc in the diagnosis of both early and advanced GCa was verified in the validation cohort. CONCLUSION: Fecal Sa and Sc are noninvasive, accurate, and sensitive signatures for early warning in GCa. (ClinicalTrials.gov, Number: NCT04638959).

Bile acid-gut microbiota crosstalk in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with an increasing prevalence, and its precise aetiology remains unclear. Gut microbiota dysbiosis has been found to be associated with IBS pathogenesis. In addition, a high incidence of bile acid diarrhoea and disturbed bile acid metabolism has been observed in IBS patients. The abundant microorganisms inhabited in human gut have essential functions in bile acid biotransformation, and can immensely affect the size and constitution of bile acid pool. Meanwhile, the alterations of bile acid profile can inversely interfere with the gut microbiota. This review discussed the role of intricate correlations between bile acids and gut microbiota in IBS pathogenesis and delineated the possible molecular mechanisms, mainly the signalling induced by farnesoid X receptor and transmembrane G protein-coupled receptor 5. Besides, some biomarkers for identifying bile acid diarrhoea in IBS population were listed, assisting the diagnosis and classification of IBS. Moreover, it also assessed some therapeutic strategies for IBS that regulate the bile acid-gut microbiota axis, such as dietary modulation, probiotics/prebiotics, faecal microbiota transplantation, and antibiotics. Collectively, this article illustrated the relationship between bile acids and gut microbiota in IBS pathophysiology and might offer some novel therapeutic options for IBS.

Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease. APPROACH AND RESULTS: We conducted a case-control association study of 1,622 Chinese patients with AIH type 1 and 10,466 population controls from two independent cohorts. A meta-analysis was performed to ascertain variants associated with AIH type 1. A single-nucleotide polymorphism within the human leukocyte antigen (HLA) region showed the strongest association with AIH (rs6932730: OR = 2.32; p = 9.21 × 10-73 ). The meta-analysis also identified two non-HLA loci significantly associated with AIH: CD28/CTLA4/ICOS on 2q33.3 (rs72929257: OR = 1.31; p = 2.92 × 10-9 ) and SYNPR on 3p14.2 (rs6809477: OR = 1.25; p = 5.48 × 10-9 ). In silico annotation, reporter gene assays, and CRISPR activation experiments identified a distal enhancer at 2q33.3 that regulated expression of CTLA4. In addition, variants near STAT1/STAT4 (rs11889341: OR = 1.24; p = 1.34 × 10-7 ), LINC00392 (rs9564997: OR = 0.81; p = 2.53 × 10-7 ), IRF8 (rs11117432: OR = 0.72; p = 6.10 × 10-6 ), and LILRA4/LILRA5 (rs11084330: OR = 0.65; p = 5.19 × 10-6 ) had suggestive association signals with AIH. CONCLUSIONS: Our study identifies two novel loci (CD28/CTLA4/ICOS and SYNPR) exceeding genome-wide significance and suggests four loci as potential risk factors. These findings highlight the importance of costimulatory signaling and neuro-immune interaction in the pathogenesis of AIH.

The mechanisms of nerve injury caused by viral infection in the occurrence of gastrointestinal motility disorder-related diseases.

Gastrointestinal motility refers to the peristalsis and contractility of gastrointestinal muscles, including the force and frequency of gastrointestinal muscle contraction. Gastrointestinal motility maintains the normal digestive function of the human body and is a critical component of the physiological function of the digestive tract. At present, gastrointestinal motility disorder-related diseases are gradually affecting human production and life. In recent years, it has been consistently reported that the enteric nervous system has a coordinating and controlling role in gastrointestinal motility. Motility disorders are closely related to functional or anatomical changes in the gastrointestinal nervous system. At the same time, some viral infections, such as herpes simplex virus and varicella-zoster virus infections, can cause damage to the gastrointestinal nervous system. Therefore, this paper describes the mechanisms of viral infection in the gastrointestinal nervous system and the associated clinical manifestations. Studies have indicated that the means by which viruses can cause the infection of the enteric nervous system are various, including retrograde transport, hematogenous transmission and centrifugal transmission from the central nervous system. When viruses infect the enteric nervous system, they can cause clinical symptoms, such as abdominal pain, abdominal distension, early satiation, belching, diarrhea, and constipation, by recruiting macrophages, lymphocytes and neutrophils and regulating intestinal microbes. The findings of several case‒control studies suggest that viruses are the cause of some gastrointestinal motility disorders. It is concluded that one of the causes of gastrointestinal motility disorders is viral infection of the enteric nervous system. In such disorders, the relationships between viruses and nerves remain to be studied more deeply. Further studies are necessary to evaluate whether prophylactic antiviral therapy is feasible in gastrointestinal motility disorders.

Efficacy of endoscopic ultrasound and endoscopic resection for esophageal schwannoma.

BACKGROUND: Esophageal schwannoma (ES) is a rare submucosal tumor, and its complete and safe resection is a topic that deserves special attention. AIM: This study aimed to investigate the clinical value of endoscopic ultrasound (EUS) in the diagnosis of ES and the clinical efficacy of endoscopic resection for ES. METHODS: The clinical data, endoscopic characteristics, endoscopic treatment, postoperative complications, immunohistochemical results, and follow-up records of patients with ES admitted to the Tianjin Medical University General Hospital from January 2012 to January 2022 were retrospectively analyzed. RESULTS: Under white-light endoscopy, 81.8% (9/11) of lesions were submucosal elevations, covering the normal esophageal epithelium. Two of the lesions with redness and erosive surface. Eight lesions (72.7%) appear on EUS originating from the muscularis propria were homogeneous or inhomogeneous hypoechoic signals. Two lesions were inhomogeneous hyperechoic originating from the submucosa or muscularis propria, respectively. One lesion was homogeneous hypoechoic originating from the submucosa. All lesions had no blood flow signals, cystic changes, or calcification, and were completely removed by submucosal tunnel endoscopic resection (STER) or endoscopic submucosal dissection (ESD). All patients did not experience serious adverse events as well as recurrence, metastasis, or cicatricial esophageal stenosis during the follow-up period. CONCLUSION: ES is a rare submucosal lesion, which endoscopic characteristics are difficult to distinguish from other esophageal submucosal tumors. Endoscopic resection can provide a minimally invasive and alternative treatment for ES.

Influence of Anxiety and Depression on the Symptoms of Achalasia Patients: A Retrospective Cohort Study in China during COVID-19.

BACKGROUND: Idiopathic achalasia (AC) may be affected by anxiety and/or depression; however, reliable evidence is still lacking. The present retrospective cohort study aimed to explore the influence of psycho-mental factors on the severity of AC. METHODS: All patients in the AC database of the Tianjin Medical University General Hospital from 2012 to 2020 were divided into two subgroups, intervention (n = 202) and medication (n = 84), according to previous treatments. Healthy people (n = 300) who underwent gastrointestinal endoscopy comprised the control group. The severity of symptoms and the anxiety and depression score of AC patients and controls were monitored by telephone and compared before and during COVID-19. In addition, the factors of AC symptoms during the COVID-19 were discussed by multiple linear regression. RESULTS: During COVID-19, the anxiety and depression levels of AC patients and healthy individuals were deteriorated. For AC patients, before and after COVID-19, symptoms, anxiety, and depression scores in the medication group were more serious than those in the intervention group. Furthermore, previous therapy, depression, and gender were found to be significantly related to the severity of AC symptoms during COVID-19. CONCLUSIONS: The outbreak of COVID-19 made AC patients and healthy people anxious and depressed. Depression rather than anxiety might worsen the AC symptoms. Interventional therapy might protect AC patients against psychological abnormalities during COVID-19.

Cardiometabolic Index (CMI), Lipid Accumulation Products (LAP), Waist Triglyceride Index (WTI) and the risk of acute pancreatitis: a prospective study in adults of North China.

OBJECTIVE: To investigate the correlation between anthropometric indexes [cardiometabolic index (CMI), lipid accumulation products (LAP), waist triglyceride index (WTI), and body mass index (BMI)] and acute pancreatitis (AP) in a Chinese adult population. METHODOLOGY: The present investigation consisted of a prospective group including 117,326 subjects who were enrolled in the Kailuan investigation. The individuals were categorized into quartiles based on their baseline levels of CMI, LAP, and WIT. BMI was categorized into three distinctive groups: normal weight group (BMI < 24 kg/m2), overweight group (BMI 24-28 kg /m2), and obesity group (BMI ≥ 28 kg/m2). The data were subjected to analysis in order to investigate the correlation between these anthropometric indexes and the incidence of AP. Cox regression models were employed to assess the relative risk of AP while accounting for known risk factors through appropriate adjustments. OUTCOMES: Over the course of a median follow-up duration of 12.59 ± 0.98 years, we documented 401 incident AP cases. Incidence density and cumulative incidence rates of AP increased with the increase of CMI, LAP, and WTI. After multivariate adjustment, the fourth quartile of CMI, LAP, and WTI exhibited the greatest risk of AP [CMI: hazard ratio (HR) 1.93, 95% confidential interval (CI) (1.45-2.57); LAP: HR 2.00, 95% CI(1.49-2.68); WTI: HR 2.13,95% CI (1.59-2.83)]. In comparison to the normal weight group, the obesity group (BMI ≥ 28 kg/m2) had an elevated risk of AP (HR = 1.58, 95% CI: 1.21-2.05). Furthermore, the incremental effect of BMI combined with CMI on the prognostic value of AP was greater than that of BMI alone (the C statistics demonstrated a result of 0.607 versus 0.546; the integrated discrimination improvement revealed a result of 0.321%; net reclassification improvement was 1.975%). CONCLUSION: We found that CMI, LAP, and WTI were positively and independently connected to the risk of AP. Additionally, CMI demonstrates a superior prognostic capacity than other indexes in anticipating AP.

Anti-gp210-positive primary biliary cholangitis: The dilemma of clinical treatment and emerging mechanisms.

Anti-gp210 is the disease-specific anti-nuclear antibody (ANA) of primary biliary cholangitis (PBC). Anti-gp210-positive PBC patients have worse responses to ursodeoxycholic acid (UDCA) as compared with anti-gp210-negative patients. Moreover, anti-gp210-positive patients always present with more severe histopathologic features including lobular inflammation, interfacial hepatitis, and bile duct injury, and have a worse prognosis than their anti-gp210-negative counterparts. Previous studies have identified two antigenic epitopes recognized by anti-gp210. Although the pathogenetic mechanism of anti-gp210 production remains unclear, evidence suggests that the autoimmune response to anti-gp210 production might be due to molecular mimicry induced by bacteria or endogenous peptides. T cells and related cytokines play a critical role in the pathogenesis of PBC, however, the mechanism hasn't been fully understood. Thus, this review focuses on the clinicopathological characteristics of anti-gp210-positive PBC patients, the fundamental research of gp210 antigen, and the possible mechanism of anti-gp210 production to clarify the mechanism of anti-gp210-positive PBC and provide potential molecular targets for disease prevention and treatment in the future.

Lafutidine Ameliorates Indomethacin-Induced Small Intestinal Damage in Rats by Modifying the Intestinal Mucosal Barrier, Inflammation, and Microbiota.

INTRODUCTION: Nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage is a serious and escalating clinical problem without effective treatment. Lafutidine (LAF) is a novel histamine H2 receptor antagonist with a mucosal protective action. This study aimed to investigate the protective effect of LAF on indomethacin (IND)-induced enteropathy in rats. METHODS: Rats were treated with LAF for 10 days with concomitant IND treatment on the final 5 days. Changes in metabolism and hematological and biochemical parameters were measured, and intestinal damage was blindly scored. Intestinal mucosal tissue and luminal contents were collected for transcriptome and microbiota sequencing. Intestinal inflammation and barrier function were also evaluated. RESULTS: LAF treatment prevented anorexia and weight loss in rats and ameliorated reductions in hemoglobin, hematocrit, total protein, and albumin levels. LAF reduced the severity of IND-induced intestinal damage including macroscopic and histopathological damage score. Transcriptome sequencing results indicated that LAF might have positive effects on intestinal inflammation and the intestinal mucosal barrier. Further research revealed that LAF decreased neutrophil infiltration, and IL-1ß and TNF-α expression in intestinal tissue. Besides, the treatment increased mucus secretion, MUC2, Occludin, and ZO-1 expression, and decreased serum D-lactate levels. LAF treatment also ameliorates microbial dysbiosis in small intestine induced by IND and increased the abundance of Lactobacillus acidophilus. CONCLUSION: LAF may protect against NSAID enteropathy via enhancing the intestinal mucosal barrier, inhibiting inflammation, and regulating microbiota.

Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis: A Randomized Clinical Trial.

Importance: Olamkicept, a soluble gp130-Fc-fusion-protein, selectively inhibits interleukin 6 (IL-6) trans-signaling by binding the soluble IL-6 receptor/IL-6 complex. It has anti-inflammatory activities in inflammatory murine models without immune suppression. Objective: To assess the effect of olamkicept as induction therapy in patients with active ulcerative colitis. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled phase 2 trial of olamkicept in 91 adults with active ulcerative colitis (full Mayo score ≥5, rectal bleeding score ≥1, endoscopy score ≥2) and an inadequate response to conventional therapy. The study was conducted at 22 clinical study sites in East Asia. Patients were recruited beginning in February 2018. Final follow-up occurred in December 2020. Interventions: Eligible patients were randomized 1:1:1 to receive a biweekly intravenous infusion of olamkicept 600 mg (n = 30) or 300 mg (n = 31) or placebo (n = 30) for 12 weeks. Main Outcomes and Measures: The primary end point was clinical response at week 12 (defined as ≥3 and ≥30% decrease from baseline total Mayo score; range, 0-12 [worst] with ≥1 decrease and ≤1 in rectal bleeding [range, 0-3 {worst}]). There were 25 secondary efficacy outcomes, including clinical remission and mucosal healing at week 12. Results: Ninety-one patients (mean age, 41 years; 25 women [27.5%]) were randomized; 79 (86.8%) completed the trial. At week 12, more patients receiving olamkicept 600 mg (17/29 [58.6%]) or 300 mg (13/30 [43.3%]) achieved clinical response than placebo (10/29 [34.5%]), with adjusted difference vs placebo of 26.6% (90% CI, 6.2% to 47.1%; P = .03) for 600 mg and 8.3% (90% CI, -12.6% to 29.1%; P = .52) for 300 mg. Among patients randomized to receive 600 mg olamkicept, 16 of 25 secondary outcomes were statistically significant compared with placebo. Among patients randomized to receive 300 mg, 6 of 25 secondary outcomes were statistically significant compared with placebo. Treatment-related adverse events occurred in 53.3% (16/30) of patients receiving 600 mg olamkicept, 58.1% (18/31) receiving 300 mg olamkicept, and 50% (15/30) receiving placebo. The most common drug-related adverse events were bilirubin presence in the urine, hyperuricemia, and increased aspartate aminotransferase levels, and all were more common in the olamkicept groups compared with placebo. Conclusions and Relevance: Among patients with active ulcerative colitis, biweekly infusion of olamkicept 600 mg, but not 300 mg, resulted in a greater likelihood of clinical response at 12 weeks compared with placebo. Further research is needed for replication and to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT03235752.

Construction and Validation of a Reliable Disulfidptosis-Related LncRNAs Signature of the Subtype, Prognostic, and Immune Landscape in Colon Cancer.

Disulfidptosis, a novel form of regulated cell death (RCD) associated with metabolism, represents a promising intervention target in cancer therapy. While abnormal lncRNA expression is associated with colon cancer development, the prognostic potential and biological characteristics of disulfidptosis-related lncRNAs (DRLs) remain unclear. Consequently, the research aimed to discover a novel indication of DRLs with significant prognostic implications, and to investigate their possible molecular role in the advancement of colon cancer. Here, we acquired RNA-seq data, pertinent clinical data, and genomic mutations of colon adenocarcinoma (COAD) from the TCGA database, and then DRLs were determined through Pearson correlation analysis. A total of 434 COAD patients were divided in to three subgroups through clustering analysis based on DRLs. By utilizing univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) algorithm, and multivariate Cox regression analysis, we ultimately created a prognostic model consisting of four DRLs (AC007728.3, AP003555.1, ATP2B1.AS1, and NSMCE1.DT), and an external database was used to validate the prognostic features of the risk model. According to the Kaplan-Meier curve analysis, patients in the low-risk group exhibited a considerably superior survival time in comparison to those in the high-risk group. Enrichment analysis revealed a significant association between metabolic processes and the genes that were differentially expressed in the high- and low-risk groups. Additionally, significant differences in the tumor immune microenvironment landscape were observed, specifically pertaining to immune cells, function, and checkpoints. High-risk patients exhibited a low likelihood of immune evasion, as indicated by the Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Patients who exhibit both a high risk and high Tumor Mutational Burden (TMB) experience the least amount of time for survival, whereas those belonging to the low-risk and low-TMB category demonstrate the most favorable prognosis. In addition, the risk groups determined by the 4-DRLs signature displayed distinct drug sensitivities. Finally, we confirmed the levels of expression for four DRLs through rt-qPCR in both tissue samples from colon cancer patients and cell lines. Taken together, the first 4-DRLs-based signature we proposed may serve for a hopeful instrument for forecasting the prognosis, immune landscape, and therapeutic responses in colon cancer patients, thereby facilitating optimal clinical decision-making.

Microbial metabolite deoxycholic acid promotes vasculogenic mimicry formation in intestinal carcinogenesis.

A high-fat diet (HFD) leads to long-term exposure to gut microbial metabolite secondary bile acids, such as deoxycholic acid (DCA), in the intestine, which is closely linked to colorectal cancer (CRC). Evidence reveals that vasculogenic mimicry (VM) is a critical event for the malignant transformation of cancer. Therefore, this study investigated the crucial roles of DCA in the regulation of VM and the progression of intestinal carcinogenesis. The effects of an HFD on VM formation and epithelial-mesenchymal transition (EMT) in human CRC tissues were investigated. The fecal DCA level was detected in HFD-treated Apcmin/+ mice. Then the effects of DCA on VM formation, EMT, and vascular endothelial growth factor receptor 2 (VEGFR2) signaling were evaluated in vitro and in vivo. Here we demonstrated that compared with a normal diet, an HFD exacerbated VM formation and EMT in CRC patients. An HFD could alter the composition of the gut microbiota and significantly increase the fecal DCA level in Apcmin/+ mice. More importantly, DCA promoted tumor cell proliferation, induced EMT, increased VM formation, and activated VEGFR2, which led to intestinal carcinogenesis. In addition, DCA enhanced the proliferation and migration of HCT-116 cells, and induced EMT process and vitro tube formation. Furthermore, the silence of VEGFR2 reduced DCA-induced EMT, VM formation, and migration. Collectively, our results indicated that microbial metabolite DCA promoted VM formation and EMT through VEGFR2 activation, which further exacerbated intestinal carcinogenesis.

Early life Lactobacillus rhamnosus GG colonisation inhibits intestinal tumour formation.

BACKGROUND: Gut microbiota dysbiosis is closely related to the progression of colorectal cancer. Our previous study revealed that early life colonisation with Lactobacillus rhamnosus GG (LGG) had long-term positive effects on health. We sought to investigate whether early life LGG colonisation could inhibit intestinal tumour formation in offspring. METHODS: Adult C57BL/6 female mice were mated with Apcmin/+ male mice. Pregnant mice with the same conception date received 108 cfu live or fixed LGG from day 18 of pregnancy until natural delivery. After genotyping, offspring mice received 107 cfu of live or fixed LGG for 0-5 days after birth. RESULTS: Early life LGG colonisation significantly promoted intestinal development, inhibited low-grade intestinal inflammation and altered the gut microbiota composition of offspring in the weaning period (3 week old). Notably, early life LGG colonisation reduced the multiplicity of intestinal tumours in adulthood (12 week old), possibly due to inhibition of Wnt signalling and promotion of tumour cell apoptosis. Importantly, at the genus level, Bifidobacterium and Anaeroplasma with potential anti-tumour effects were increased in adulthood, while Peptostreptococcus, which potentially contributes to tumour formation, was decreased. CONCLUSIONS: Early life LGG colonisation inhibited the intestinal tumour formation of offspring in adulthood.

Interplay between gut microbiota and bile acids in diarrhoea-predominant irritable bowel syndrome: a review.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease that disturbs the physiology and psychology of patients and increases the burden on families, the healthcare system, society, and economic development, affecting more and more people around the world. Despite the multiple factors that account for IBS remaining incompletely studied, emerging evidence demonstrated the abnormal changes in gut microbiota and bile acids (BAs) metabolism closely associated with IBS. Moreover, microbiota drives significant modifications for BAs, consisting of deconjugation, 7α-dehydroxylation, oxidation, epimerization, desulfation, esterification, and so on, while BAs, in turn, affect the microbiota directly or indirectly. In light of the complex connection among gut microbiota, BAs, and IBS, it is urgent to review the latest research progress in this field. In this review, we described the disorders of intestinal microecology and BAs profiles in IBS-D and also highlighted the cross-talk between gut microbiota and BAs in the context of IBS-D. Integrating these, we suggest that new therapeutic strategies targeting the microbiota-BAs axis for IBS-D, even for other related diseases caused by bacteria-bile acid dysbiosis should be expected.

Lactobacillus rhamnosus GG Promotes Intestinal Vitamin D Absorption by Upregulating Vitamin D Transporters in Senile Osteoporosis.

Intestinal absorption of vitamin D is an important way to improve the vitamin D level in senile osteoporosis (SOP). There is a link between oral probiotics and vitamin D, but the mechanism is still unclear. We aimed to evaluate whether Lactobacillus rhamnosus GG culture supernatant (LCS) can affect cholecalciferol absorption, transport, and hydroxylation in SOP, and explore underlying mechanisms. In the study, specific-pathogen-free SAMP6 mice were randomly divided into an experimental group administered undiluted LCS and a control group administered normal drinking water. Furthermore, levels of cholecalciferol absorption were compared between Caco-2 cells cultured with varying concentrations of cholecalciferol and stimulated with LCS or de Man, Rogosa, and Sharpe (MRS) broth (control). Similarly, LCS-stimulated HepG2 cells were compared with MRS-stimulated HepG2 cells. Finally, protein levels of VD transporters in small intestine tissues and Caco-2 cells, as well as vitamin D-binding protein and 25-hydroxylase in liver tissues and HepG2 cells, were detected by western blot. The results showed that plasma concentrations of cholecalciferol and 25OHD3 were higher in mice of the LCS group compared with the control group, and these values were positively correlated. With the addition of LCS, cholecalciferol uptake was increased with 0.5 µM or 10 µM cholecalciferol in the medium. Protein levels of CD36 and NPC1L1 were higher in the LCS group compared with the control group, while SR-BI protein was decreased, both in vitro and in vivo. In conclusion, LCS can promotes intestinal absorption cholecalciferol by affecting protein levels of VD transporters and improves 25OHD3 levels in SOP.