ABSTRACT
OBJECTIVE: During the last decade, the management of gastric intestinal metaplasia (GIM) has been addressed by several distinct international evidence-based guidelines. In this review, we aimed to synthesise these guidelines and provide clinicians with a global perspective of the current recommendations for managing patients with GIM, as well as highlight evidence gaps that need to be addressed with future research. DESIGN: We conducted a systematic review of the literature for guidelines and consensus statements published between January 2010 and February 2023 that address the diagnosis and management of GIM. RESULTS: From 426 manuscripts identified, 15 guidelines were assessed. There was consistency across guidelines regarding the purpose of endoscopic surveillance of GIM, which is to identify prevalent neoplastic lesions and stage gastric preneoplastic conditions. The guidelines also agreed that only patients with high-risk GIM phenotypes (eg, corpus-extended GIM, OLGIM stages III/IV, incomplete GIM subtype), persistent refractory Helicobacter pylori infection or first-degree family history of gastric cancer should undergo regular-interval endoscopic surveillance. In contrast, low-risk phenotypes, which comprise most patients with GIM, do not require surveillance. Not all guidelines are aligned on histological staging systems. If surveillance is indicated, most guidelines recommend a 3-year interval, but there is some variability. All guidelines recommend H. pylori eradication as the only non-endoscopic intervention for gastric cancer prevention, while some offer additional recommendations regarding lifestyle modifications. While most guidelines allude to the importance of high-quality endoscopy for endoscopic surveillance, few detail important metrics apart from stating that a systematic gastric biopsy protocol should be followed. Notably, most guidelines comment on the role of endoscopy for gastric cancer screening and detection of gastric precancerous conditions, but with high heterogeneity, limited guidance regarding implementation, and lack of robust evidence. CONCLUSION: Despite heterogeneous populations and practices, international guidelines are generally aligned on the importance of GIM as a precancerous condition and the need for a risk-stratified approach to endoscopic surveillance, as well as H. pylori eradication when present. There is room for harmonisation of guidelines regarding (1) which populations merit index endoscopic screening for gastric cancer and GIM detection/staging; (2) objective metrics for high-quality endoscopy; (3) consensus on the need for histological staging and (4) non-endoscopic interventions for gastric cancer prevention apart from H. pylori eradication alone. Robust studies, ideally in the form of randomised trials, are needed to bridge the ample evidence gaps that exist.
ABSTRACT
Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.
ABSTRACT
Chemotherapy resistance is one of the main reasons for the poor prognosis of colorectal cancer (CRC). Moreover, dysbiosis of gut bacteria was found to be a specific environmental risk factor. In this study, enrichment of F. nucleatum was elucidated to be significantly associated with CRC recurrence after chemotherapy. Functional experiments showed that F. nucleatum could inhibit pyroptosis induced by chemotherapy drugs, thereby inducing chemoresistance. Furthermore, mechanistic investigation demonstrated that F. nucleatum could regulate the Hippo pathway and promote the expression of BCL2, thereby inhibiting the Caspase-3/GSDME pyroptosis-related pathway induced by chemotherapy drugs and mediating CRC cell chemoresistance. Taken together, these results validated the significant roles of F. nucleatum in CRC chemoresistance, which provided an innovative theoretical basis for the clinical diagnosis and therapy of CRC.
Subject(s)
Colorectal Neoplasms , Gastrointestinal Microbiome , Humans , Fusobacterium nucleatum/physiology , Colorectal Neoplasms/microbiology , Hippo Signaling Pathway , Drug Resistance, Neoplasm , Pyroptosis , Neoplasm Recurrence, LocalABSTRACT
Immunotherapy has revolutionized cancer treatment, but inconsistent responses persist. Our study delves into the intriguing phenomenon of enhanced immunotherapy sensitivity in older individuals with cancers. Through a meta-analysis encompassing 25 small-to-mid-sized trials of immune checkpoint blockade (ICB), we demonstrate that older individuals exhibit heightened responsiveness to ICB therapy. To understand the underlying mechanism, we reanalyze single-cell RNA sequencing (scRNA-seq) data from multiple studies and unveil distinct upregulation of exhausted and cytotoxic T cell markers within the tumor microenvironment (TME) of older patients. Recognizing the potential role of gut microbiota in modulating the efficacy of immunotherapy, we identify an aging-enriched enterotype linked to improved immunotherapy outcomes in older patients. Fecal microbiota transplantation experiments in mice confirm the therapeutic potential of the aging-enriched enterotype, enhancing treatment sensitivity and reshaping the TME. Our discoveries confront the prevailing paradox and provide encouraging paths for tailoring cancer immunotherapy strategies according to an individual's gut microbiome profile.
Subject(s)
Gastrointestinal Microbiome , Humans , Animals , Mice , Aged , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy , Aging , CD3 ComplexABSTRACT
OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions. METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia. RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed. CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.
Subject(s)
Drugs, Chinese Herbal , Gastritis, Atrophic , Helicobacter Infections , Helicobacter pylori , Precancerous Conditions , Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Gastritis, Atrophic/drug therapy , Gastritis, Atrophic/pathology , Helicobacter Infections/complications , Helicobacter Infections/drug therapy , Precancerous Conditions/drug therapy , Precancerous Conditions/pathology , Metaplasia , Folic Acid/therapeutic use , Gastric Mucosa/pathologyABSTRACT
BACKGROUND AND AIM: Cohort studies have linked metabolic syndrome (MetS) to gastrointestinal (GI) cancer risk. We aimed to evaluate the associations between MetS, its components, and combinations of MetS components with eight GI cancers risk. METHODS: We conducted a systematic search of prospective cohort studies and performed a meta-analysis. Subgroup analyses regarding diagnostic criteria, sex, cancer sites, histological subtypes, ethnic groups, and studies adjusted for alcohol consumption were carried out. Mendelian randomization (MR) was employed to evaluate the causality between 17 MetS-related traits and eight GI cancers among Europeans and Asians separately. RESULTS: Meta-analyses of 31 prospective studies indicated that MetS was significantly associated with an increased risk of colorectal cancer (CRC) (RR [95% CI] = 1.13 [1.12-1.15]), esophageal cancer (EC) (RR [95% CI] = 1.17 [1.03-1.32]), gallbladder cancer (GBC) (RR [95% CI] = 1.37[1.10-1.71]), liver cancer (LC) (RR [95% CI] = 1.46 [1.29-1.64]), and pancreatic cancer (PaC) (RR [95% CI] = 1.25 [1.20-1.30]), but not gastric cancer (GC) (RR [95% CI] = 1.11 [0.96-1.28]). Regarding the associations between MetS components and GI cancers risk, the following associations showed statistical significance: obesity-CRC/LC/EC/, hypertriglyceridemia-LC/PaC, reduced high-density lipoprotein (HDL)-CRC/LC/GC/PaC, hyperglycemia-CRC/LC/PaC, and hypertension-CRC/LC/EC/PaC. Sex-specific associations were observed between individual MetS components on GI cancers risk. Among the top three common combinations in both sexes, obesity + HTN + hyperglycemia had the strongest association with CRC risk (RR [95% CI] = 1.54 [1.49-1.61] for males and 1.27 [1.21-1.33] for females). MR analyses revealed causality in 16 exposure-outcome pairs: waist-to-hip ratio/BMI/HbA1c-CRC; BMI/childhood obesity/waist circumference/T2DM/glucose-EC; BMI/waist circumference/cholesterol-LC; cholesterol/childhood obesity/waist circumference/HbA1c-PaC; and HbA1c-GBC. These results were robust against sensitivity analyses. CONCLUSIONS: Since MetS is reversible, lifestyle changes or medical interventions targeting MetS patients might be potential prevention strategies for GI cancers.
Subject(s)
Gastrointestinal Neoplasms , Mendelian Randomization Analysis , Metabolic Syndrome , Humans , Metabolic Syndrome/genetics , Metabolic Syndrome/epidemiology , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/etiology , Gastrointestinal Neoplasms/epidemiology , Prospective Studies , Male , Risk Factors , Female , Risk , Cohort Studies , Obesity/complicationsABSTRACT
BACKGROUND AND AIM: Patients with cholelithiasis (CL) or cholecystectomy (CE) would have more chances of getting colorectal adenoma (CRA) or cancer (CRC). We aimed to figure out the effects of gut microbiota and bile acid on colorectal neoplasm in CL and CE patients. METHODS: This was a retrospective observational study that recruited 514 volunteers, including 199 people with normal gallbladders (normal), 152 CL, and 163 CE patients. Discovery cohort was established to explore the difference in gut microbiota through 16S rRNA and metagenomics sequencing. Validation cohort aimed to verify the results through quantitative polymerase chain reaction (qPCR). RESULTS: Significant enrichment of Escherichia coli was found in patients with cholelithiasis or cholecystectomy both in the discovery cohort (16S rRNA sequencing, PNormal-CL = 0.013, PNormal-CE = 0.042; metagenomics sequencing, PNormal-CE = 0.026) and validation cohort (PNormal-CL < 0.0001, PNormal-CE < 0.0001). Pks+ E. coli was found enriched in CL and CE patients through qPCR (in discovery cohort: PNormal-CE = 0.018; in validation cohort: PNormal-CL < 0.0001, PNormal-CE < 0.0001). The differences in bile acid metabolism were found both through Tax4Fun analysis of 16S rRNA sequencing (Ko00120, primary bile acid biosynthesis, PNormal-CE = 0.014; Ko00121, secondary bile acid biosynthesis, PNormal-CE = 0.010) and through metagenomics sequencing (map 00121, PNormal-CE = 0.026). The elevation of serum total bile acid of CE patients was also found in validation cohort (PNormal-CE < 0.0001). The level of serum total bile acid was associated with the relative abundance of pks+ E. coli (r = 0.1895, P = 0.0012). CONCLUSIONS: E. coli, especially pks+ species, was enriched in CL and CE patients. Pks+ E. coli and bile acid metabolism were found associated with CRA and CRC in people after cholecystectomy.
Subject(s)
Bile Acids and Salts , Cholecystectomy , Cholelithiasis , Colorectal Neoplasms , Escherichia coli , Humans , Bile Acids and Salts/metabolism , Bile Acids and Salts/blood , Colorectal Neoplasms/microbiology , Colorectal Neoplasms/etiology , Retrospective Studies , Male , Female , Middle Aged , Cholelithiasis/microbiology , Cholelithiasis/etiology , Cholelithiasis/surgery , Gastrointestinal Microbiome , Adult , Carcinogenesis , RNA, Ribosomal, 16S/genetics , AgedABSTRACT
OBJECTIVE: Branched-chain amino acid (BCAA) metabolism is involved in the development of colorectal cancer (CRC); however, the underlying mechanism remains unclear. Therefore, this study investigates the role of BCAA metabolism in CRC progression. METHODS: Dietary BCAA was administered to both azoxymethane-induced and azoxymethane/dextran sodium sulfate-induced CRC mouse models. The expression of genes related to BCAA metabolism was determined using RNA sequencing. Adjacent tissue samples, obtained from 58 patients with CRC, were subjected to quantitative real-time PCR and immunohistochemical analysis. Moreover, the suppressive role of branched-chain aminotransferase 2 (BCAT2) in cell proliferation, apoptosis, and xenograft mouse models was investigated. Alterations in BCAAs and activation of downstream pathways were also assessed using metabolic analysis and western blotting. RESULTS: High levels of dietary BCAA intake promoted CRC tumorigenesis in chemical-induced CRC and xenograft mouse models. Both the mRNA and protein levels of BCAT2 were decreased in tumor tissues of patients with CRC compared to those in normal tissues. Proliferation assays and xenograft models confirmed the suppressive role of BCAT2 in CRC progression. Furthermore, the accumulation of BCAAs caused by BCAT2 deficiency facilitated the chronic activation of mTORC1, thereby mediating the oncogenic effect of BCAAs. CONCLUSION: BCAT2 deficiency promotes CRC progression through inhibition of BCAAs metabolism and chronic activation of mTORC1.
Subject(s)
Colorectal Neoplasms , Pregnancy Proteins , Humans , Mice , Animals , Amino Acids, Branched-Chain/metabolism , RNA, Messenger , Mechanistic Target of Rapamycin Complex 1 , Azoxymethane , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/genetics , Transaminases/genetics , Transaminases/metabolism , Pregnancy Proteins/metabolism , Minor Histocompatibility Antigens/genetics , Minor Histocompatibility Antigens/metabolismABSTRACT
BACKGROUND AND AIMS: Deregulation of RNA N6-methyladenosine (m6A) modification in intestinal epithelial cells (IECs) influences intestinal immune cells and leads to intestinal inflammation. We studied the function of fat mass-and obesity-associated protein (FTO), one of the m6A demethylases, in patients with ulcerative colitis (UC). METHODS: We analysed colon tissues of Ftoflox/flox; Villin-cre mice and their Ftoflox/flox littermates with dextran sulfate sodium (DSS) using real-time PCR and 16s rRNA sequencing. RNA and methylated RNA immunoprecipitation sequencing were used to analyse immunocytes and IECs. Macrophages were treated with conditioned medium of FTO-knockdown MODE-K cells or sphingosine-1-phosphate (S1P) and analysed for gene expression. Liquid chromatograph mass spectrometry identified C16-ceramide. RESULTS: FTO downregulation was identified in our in-house cohort and external cohorts of UC patients. Dysbiosis of gut microbiota, increased infiltration of proinflammatory macrophages, and enhanced differentiation of Th17 cells were observed in Ftoflox/flox;Villin-cre mice under DSS treatment. FTO deficiency resulted in an increase in m6A modification and a decrease in mRNA stability of CerS6, the gene encoding ceramide synthetase, leading to the downregulation of CerS6 and the accumulation of S1P in IECs. Subsequentially, the secretion of S1P by IECs triggered proinflammatory macrophages to secrete serum amyloid A protein 1/3, ultimately inducing Th17 cell differentiation. In addition, through bioinformatic analysis and experimental validation, we identified UC patients with lower FTO expression might respond better to vedolizumab treatment. CONCLUSIONS: FTO downregulation promoted UC by decreasing CerS6 expression, leading to increased S1P accumulation in IECs and aggravating colitis via m6A-dependent mechanisms. Lower FTO expression in UC patients may enhance their response to vedolizumab treatment.
Subject(s)
Colitis, Ulcerative , Colitis , Humans , Animals , Mice , Colitis, Ulcerative/metabolism , RNA, Ribosomal, 16S/metabolism , Intestinal Mucosa/metabolism , Colitis/chemically induced , Colitis/genetics , Colon/metabolism , Sphingolipids/metabolism , Dextran Sulfate , Disease Models, Animal , Mice, Inbred C57BL , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolismABSTRACT
Immune checkpoint blockade (ICB) therapy has improved treatment effects in multiple cancers. Gene mutations in the DNA damage repair pathway (DDR) may cause genomic instability and may relate to the efficacy of ICB. Checkpoint kinase 2 (CHEK2) and polymerase epsilon (POLE) are important genes in the DDR. In this study, we aimed to study the impact of CHEK2 deficiency mutations on the response to ICB. We found that tumors with CHEK2 mutations had a significantly higher tumor mutational burden (TMB) compared to those with CHEK2-WT in a pancancer database. We noted that CHEK2 deficiency mutations potentiated the anti-tumor effect of anti-PD-1 therapy in MC38 and B16 tumor-bearing mice with the decrease of tumor volume and tumor weight after anti-PD-1 treatment. Mechanistically, CHEK2 deficiency tumors were with the increased cytotoxic CD8+ T-cell infiltration, especially cytotoxic CD8+ T cells, and modulated the tumor-immune microenvironment with an upregulated immune inflammatory pathway and antigen presentation pathway after anti-PD-1 treatment. Furthermore, murine models with POLE mutations confirmed that CHEK2 deficiency shaped similar mutational and immune landscapes as POLE mutations after anti-PD-1 treatment. Taken together, our results demonstrated that CHEK2 deficiency mutations may increase the response to ICB (eg. anti-PD-1) by influencing the tumor immune microenvironment. This indicated that CHEK2 deficiency mutations were a potentially predictive biomarker and CHEK2 deficiency may potentiate response to immunotherapy.
Subject(s)
Immune Checkpoint Inhibitors , Neoplasms , Mice , Animals , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , CD8-Positive T-Lymphocytes , Checkpoint Kinase 2/genetics , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Mutation , Immunotherapy/methods , Tumor MicroenvironmentABSTRACT
The perturbations of the gut microbiota and metabolites are closely associated with the progression of inflammatory bowel disease (IBD). However, inconsistent findings across studies impede a comprehensive understanding of their roles in IBD and their potential as reliable diagnostic biomarkers. To address this challenge, here we comprehensively analyze 9 metagenomic and 4 metabolomics cohorts of IBD from different populations. Through cross-cohort integrative analysis (CCIA), we identify a consistent characteristic of commensal gut microbiota. Especially, three bacteria, namely Asaccharobacter celatus, Gemmiger formicilis, and Erysipelatoclostridium ramosum, which are rarely reported in IBD. Metagenomic functional analysis reveals that essential gene of Two-component system pathway, linked to fecal calprotectin, are implicated in IBD. Metabolomics analysis shows 36 identified metabolites with significant differences, while the roles of these metabolites in IBD are still unknown. To further elucidate the relationship between gut microbiota and metabolites, we construct multi-omics biological correlation (MOBC) maps, which highlights gut microbial biotransformation deficiencies and significant alterations in aminoacyl-tRNA synthetases. Finally, we identify multi-omics biomarkers for IBD diagnosis, validated across multiple global cohorts (AUROC values ranging from 0.92 to 0.98). Our results offer valuable insights and a significant resource for developing mechanistic hypotheses on host-microbiome interactions in IBD.
Subject(s)
Inflammatory Bowel Diseases , Microbiota , Humans , Multiomics , Inflammatory Bowel Diseases/metabolism , Metabolome , Biomarkers/metabolismABSTRACT
Recent studies revealed that intestinal microbiota played important roles in colorectal cancer (CRC) carcinogenesis. Particularly, Fusobacterium nucleatum was confirmed to promote the proliferation and metastasis of CRC. Therefore, targeting F. nucleatum may be a potential preventive and therapeutic approach for CRC. Herein, 2,272 off-patent drugs were screened inhibitory activity against F. nucleatum. Among the hits, nitisinone was identified as a promising anti-F. nucleatum lead compound. Further optimization of nitisinone led to the discovery of more potent derivatives. Particularly, compounds 19q and 22c showed potent anti-F. nucleatum activity (MIC50 = 1 and 2 µg/mL, respectively) with low cytotoxicity. Among them, compound 19q effectively attenuated the migratory ability of MC-38 cells induced by F. nucleatum. Preliminary mechanism studies suggested that nitisinone and its derivatives might act by downregulating nitroreductase and tryptophanase. Thus, the development of small molecule F. nucleatum inhibitors represents an effective strategy to treat CRC.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Humans , Fusobacterium nucleatum/physiology , Colorectal Neoplasms/pathology , Tryptophanase , Drug Repositioning , Colonic Neoplasms/drug therapyABSTRACT
The effect of gut bacteria on the response to immune checkpoint inhibitors (ICIs) has been studied, but the relationship between fungi and ICI responses is not fully understood. Herein, 862 fecal metagenomes from 9 different cohorts were integrated for the identification of differentially abundant fungi and subsequent construction of random forest (RF) models to predict ICI responses. Fungal markers demonstrate excellent performance, with an average area under the curve (AUC) of 0.87. Their performance improves even further, reaching an average AUC of 0.89 when combined with bacterial markers. Higher enrichment of exhausted T cells is detected in responders, as predicted by fungal markers. Multi-kingdom network and functional analysis reveal that the fungus Schizosaccharomyces octosporus may ferment starch into short-chain fatty acids in responders. This study provides a fungal profile of the ICI response and the identification of multi-kingdom microbial markers with good performance that may improve the overall applicability of ICI therapy.
Subject(s)
Gastrointestinal Microbiome , Neoplasms , Humans , Metagenome , Immunotherapy , Bacteria/genetics , Neoplasms/therapySubject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Stomach Neoplasms , Humans , Carcinoma, Renal Cell/surgery , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/secondary , Stomach Neoplasms/surgery , Stomach Neoplasms/pathology , Nephrectomy , Kidney Neoplasms/surgery , Kidney Neoplasms/pathologyABSTRACT
Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy; however, their application is limited by the occurrence of immune-related adverse events. The gut microbiota plays important roles in the response to and toxicity of immunotherapy and Faecalibacterium prausnitzii (F. prausnitzii) has been shown to possess immunomodulatory potential. Here, we found that patients receiving ICIs who developed colitis had a lower abundance of F. prausnitzii. In vivo, immunocompetent mice administered with dextran sodium sulfate and immunodeficient NSG mice with human peripheral blood mononuclear cell transfer were treated with ICIs to study ICI-induced colitis. Dual CTLA4 and PD-1 blockade exacerbated autoimmune colitis, activated an inflammatory response, and promoted myeloid cell infiltration, with higher percentages of macrophages, dendritic cells, monocytes, and neutrophils. F. prausnitzii administration mitigated the exacerbated colitis induced by ICIs. Concomitantly, F. prausnitzii enhanced the antitumor immunity elicited by ICIs in tumor-bearing mice while abrogating colitis. In addition, administration of F. prausnitzii increased gut microbial alpha diversity and modulated the microbial composition, increasing a subset of gut probiotics and decreasing potential gut pathogens. F. prausnitzii abundance was reduced in mice that developed ICI-associated colitis. Together, this study shows that F. prausnitzii administration ameliorates ICI-induced colitis, reshapes the gut microbial composition, and enhances the antitumor activity of immunotherapy. SIGNIFICANCE: F. prausnitzii alleviates colitis while enhancing the tumor-suppressive effects of immune checkpoint blockade, indicating that supplementation with F. prausnitzii could be a treatment strategy to mitigate immunotherapy toxicity in patients with cancer.
Subject(s)
Colitis , Neoplasms , Humans , Mice , Animals , Faecalibacterium prausnitzii , Programmed Cell Death 1 Receptor , Leukocytes, Mononuclear , CTLA-4 Antigen , Colitis/chemically inducedABSTRACT
Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.
Subject(s)
Colitis , Inflammatory Bowel Diseases , Animals , Mice , Mercaptopurine/therapeutic use , Azathioprine/therapeutic use , Immunosuppressive Agents/therapeutic use , Biological Availability , Inflammatory Bowel Diseases/drug therapy , Colitis/chemically induced , Colitis/drug therapy , BacteriaABSTRACT
BACKGROUND: Colorectal cancer (CRC) incidence has increased among patients aged <50 years. Exploring high-risk factors and screening high-risk populations may help lower early-onset CRC (EO-CRC) incidence. We developed noninvasive predictive models for EO-CRC and investigated its risk factors. METHODS: This retrospective multicenter study collected information on 1756 patients (811 patients with EO-CRC and 945 healthy controls) from two medical centers in China. Sociodemographic features, clinical symptoms, medical and family history, lifestyle, and dietary factors were measured. Patients from one cohort were randomly assigned (8:2) to two groups for model establishment and internal validation, and another independent cohort was used for external validation. Multivariable logistic regression, random forest, and eXtreme Gradient Boosting (XGBoost) were performed to establish noninvasive predictive models for EO-CRC. Some variables in the model influenced EO-CRC occurrence and were further analyzed. Multivariable logistic regression analysis yielded adjusted odd ratios (ORs) and 95% confidence intervals (CIs). RESULTS: All three models showed good performance, with areas under the receiver operator characteristic curves (AUCs) of 0.82, 0.84, and 0.82 in the internal and 0.78, 0.79, and 0.78 in the external validation cohorts, respectively. Consumption of sweet (OR 2.70, 95% CI 1.89-3.86, P < 0.001) and fried (OR 2.16, 95% CI 1.29-3.62, P < 0.001) foods ≥3 times per week was significantly associated with EO-CRC occurrence. CONCLUSION: We established noninvasive predictive models for EO-CRC and identified multiple nongenetic risk factors, especially sweet and fried foods. The model has good performance and can help predict the occurrence of EO-CRC in the Chinese population.