RESUMO
OBJECTIVE: To develop and externally validate an updated artificial intelligence (AI) prediction system for stratifying the risk of lymph node metastasis (LNM) in T2 colorectal cancer (CRC). SUMMARY BACKGROUND DATA: Recent technical advances allow complete local excision of T2 CRC, traditionally treated with surgical resection. Yet, the widespread adoption of this approach is hampered by the inability to stratify the risk of LNM. METHODS: Data from pT2 CRC patients undergoing surgical resection between April 2000 and May 2022 at one Japanese and one Italian center were analyzed. Primary goal was AI system development for accurate LNM prediction. Predictors encompassed seven variables: age, sex, tumor size and location, lympho-vascular invasion, histological differentiation, and carcinoembryonic antigen level. The tool's discriminating power was assessed via Area Under the Curve (AUC), sensitivity, and specificity. RESULTS: Out of 735 initial patients, 692 were eligible. Training and validation cohorts comprised of 492 and 200 patients, respectively. The AI model displayed an AUC of 0.75 in the combined validation dataset. Sensitivity for LNM prediction was 97.8% and specificity was 15.6%. The Positive and the Negative Predictive Value were 25.7% and 96% respectively. The False Negative (FN) rate was 2.2%, the False Positive was 84.4%. CONCLUSIONS: Our AI model, based on easily accessible clinical and pathological variables, moderately predicts LNM in T2 CRC. However, the risk of FN needs to be considered. The training of the model including more patients across Western and Eastern centers -differentiating between colon and rectal cancers- may improve its performance and accuracy.
RESUMO
Bile acids (BA) are synthesized in the human liver and undergo metabolism by host gut bacteria. In diseased states, gut microbial dysbiosis may lead to high primary unconjugated BA concentrations and significant perturbations to secondary BA. Hence, it is important to understand the microbial-mediated formation kinetics of secondary bile acids using physiologically relevant ex vivo human faecal microbiota models. Here, we optimized an ex vivo human faecal microbiota model to recapitulate the metabolic kinetics of primary unconjugated BA and applied it to investigate the formation kinetics of novel secondary BA metabolites and their sequential pathways. We demonstrated (1) first-order depletion of primary BA, cholic acid (CA) and chenodeoxycholic acid (CDCA), under non-saturable conditions and (2) saturable Michaelis-Menten kinetics for secondary BA metabolite formation with increasing substrate concentration. Notably, relatively lower Michaelis constants (Km) were associated with the formation of deoxycholic acid (DCA, 14.3 µM) and lithocholic acid (LCA, 140 µM) versus 3-oxo CA (>1000 µM), 7-keto DCA (443 µM) and 7-keto LCA (>1000 µM), thereby recapitulating clinically observed saturation of 7α-dehydroxylation relative to oxidation of primary BA. Congruently, metagenomics revealed higher relative abundance of functional genes related to the oxidation pathway as compared to the 7α-dehydroxylation pathway. In addition, we demonstrated gut microbial-mediated hyocholic acid (HCA) and hyodeoxycholic acid (HDCA) formation from CDCA. In conclusion, we optimized a physiologically relevant ex vivo human faecal microbiota model to investigate gut microbial-mediated metabolism of primary BA and present a novel gut microbial-catalysed two-step pathway from CDCA to HCA and, subsequently, HDCA.
Assuntos
Ácidos e Sais Biliares , Fezes , Humanos , Fezes/microbiologia , Cinética , Ácidos e Sais Biliares/metabolismo , Microbioma Gastrointestinal , Ácido Quenodesoxicólico/metabolismo , Modelos Biológicos , MicrobiotaRESUMO
The current standard treatment for muscularis propria-invasive (T2) colorectal cancer is surgical colectomy with lymph node dissection. With the advent of new endoscopic resection techniques, such as endoscopic full-thickness resection or endoscopic intermuscular dissection, T2 colorectal cancer, with metastasis to 20%-25% of the dissected lymph nodes, may be the next candidate for endoscopic resection following submucosal-invasive (T1) colorectal cancer. We present a novel endoscopic treatment strategy for T2 colorectal cancer and suggest further study to establish evidence on oncologic and endoscopic technical safety for its clinical implementation.
Assuntos
Neoplasias Colorretais , Humanos , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Endoscopia , Linfonodos/patologia , Linfonodos/cirurgia , Dissecação , Metástase LinfáticaRESUMO
Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception.
Assuntos
Lesões Pré-Cancerosas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Estudos Prospectivos , Mucosa Gástrica/patologia , Genômica , Metaplasia/genética , Lesões Pré-Cancerosas/genéticaRESUMO
Anaerostipes hadrus strains BA1 and GIF7 were isolated from a healthy man. The complete genomes' sizes are 2,946,270 bp (BA1) and 2,907,308 bp (GIF7), with high average nucleotide identity (ANIb = 100%) and alignments ≥96.86% between strains. Conversely, both strains share 97.47% (ANIb) identity and ≤77.36% alignments to A. hadrus ATCC 29173T.
RESUMO
The field of onco-microbiome is rapidly expanding. Multiple studies have shown the crucial role of gut microbiota in the regulation of nutrient metabolism, immunomodulation and protection against pathogens. Tools for manipulating the gut microbiota include dietary modification and faecal microbiota transfer. Accumulating evidence has also documented the application of specific intestinal microbiome in cancer immunotherapy, notably in enhancing the efficacy of immune checkpoint inhibitors. The aim of this review is to focus on the East Asian microbiome and to provide a current overview of microbiome science and its clinical application in cancer biology and immunotherapy.
RESUMO
Environmental exposures are a major risk factor for developing colorectal cancer, and the gut microbiome may serve as an integrator of such environmental risk. To study the microbiome associated with premalignant colon lesions, such as tubular adenomas (TAs) and sessile serrated adenomas (SSAs), we profiled stool samples from 971 participants undergoing colonoscopy and paired these data with dietary and medication history. The microbial signatures associated with either SSA or TA are distinct. SSA associates with multiple microbial antioxidant defense systems, whereas TA associates with a depletion of microbial methanogenesis and mevalonate metabolism. Environmental factors, such as diet and medications, link with the majority of identified microbial species. Mediation analyses found that Flavonifractor plautii and Bacteroides stercoris transmit the protective or carcinogenic effects of these factors to early carcinogenesis. Our findings suggest that the unique dependencies of each premalignant lesion may be exploited therapeutically or through dietary intervention.
Assuntos
Adenoma , Pólipos do Colo , Neoplasias Colorretais , Humanos , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , ColonoscopiaRESUMO
INTRODUCTION: Computer-aided diagnosis (CADx) of polyp histology could support endoscopists in clinical decision-making. However, this has not been validated in a real-world setting. METHODS: We performed a prospective, multicenter study comparing CADx and endoscopist predictions of polyp histology in real-time colonoscopy. Optical diagnosis based on visual inspection of polyps was made by experienced endoscopists. After this, the automated output from the CADx support tool was recorded. All imaged polyps were resected for histological assessment. Primary outcome was difference in diagnostic performance between CADx and endoscopist prediction of polyp histology. Subgroup analysis was performed for polyp size, bowel preparation, difficulty of location of the polyps, and endoscopist experience. RESULTS: A total of 661 eligible polyps were resected in 320 patients aged ≥40 years between March 2021 and July 2022. CADx had an overall accuracy of 71.6% (95% confidence interval [CI] 68.0-75.0), compared with 75.2% (95% CI 71.7-78.4) for endoscopists ( P = 0.023). The sensitivity of CADx for neoplastic polyps was 61.8% (95% CI 56.9-66.5), compared with 70.3% (95% CI 65.7-74.7) for endoscopists ( P < 0.001). The interobserver agreement between CADx and endoscopist predictions of polyp histology was moderate (83.1% agreement, κ 0.661). When there was concordance between CADx and endoscopist predictions, the accuracy increased to 78.1%. DISCUSSION: The overall diagnostic accuracy and sensitivity for neoplastic polyps was higher in experienced endoscopists compared with CADx predictions, with moderate interobserver agreement. Concordance in predictions increased this diagnostic accuracy. Further research is required to improve the performance of CADx and to establish its role in clinical practice.
Assuntos
Pólipos do Colo , Neoplasias Colorretais , Humanos , Pólipos do Colo/diagnóstico , Pólipos do Colo/patologia , Estudos Prospectivos , Valor Preditivo dos Testes , Colonoscopia/métodos , Computadores , Neoplasias Colorretais/patologia , Imagem de Banda Estreita/métodosRESUMO
BACKGROUND: Recent studies demonstrate the association of the gut microbiome in regulating interactions between the central nervous system and intestinal function. Individuals with attention-deficit hyperactivity disorder (ADHD) have been shown to have unique gut microbial signature, with depletion of beneficial commensal microbes. Fecal microbiota transplant (FMT) restores the imbalanced gut microbiome and may replete missing microbes to increase production of hormones and neurotransmitters regulating human behavior and cognition. RESEARCH DESIGN & METHODS: Here, we present an interesting case of a 22-year-old woman treated with FMT primarily to treat recurrent Clostridioides difficile infection, which coincidentally alleviated her ADHD symptoms. We also present the pre- and post-FMT gut microbiota profiles conducted using shotgun metagenomic sequencing on the patient's fecal samples to thereby highlight potential microbial-associated mechanisms associated with the relief of ADHD symptoms. RESULTS & CONCLUSIONS: Our case report provides preliminary evidence regarding the use of FMT in a patient with C. difficile and ADHD. We speculate that gut microbiome modulation, in particular the gain or loss of specific microbial species and pathways involving the metabolism of SCFAs, tryptophan and GABA, may merit further exploration as a potential therapeutic strategy for ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Clostridioides difficile , Infecções por Clostridium , Microbioma Gastrointestinal , Feminino , Humanos , Adulto Jovem , Adulto , Transplante de Microbiota Fecal/métodos , Transtorno do Deficit de Atenção com Hiperatividade/terapia , FezesRESUMO
Clostridioides difficile infection (CDI) results in significant morbidity and mortality in hospitalised patients. The pathogenesis of CDI is intrinsically related to the ability of C. difficile to shuffle between active vegetative cells and dormant endospores through the processes of germination and sporulation. Here, we hypothesise that dysregulation of microbiome-mediated bile salt metabolism contributes to CDI and that its alleviation can limit the pathogenesis of CDI. We engineer a genetic circuit harbouring a genetically encoded sensor, amplifier and actuator in probiotics to restore intestinal bile salt metabolism in response to antibiotic-induced microbiome dysbiosis. We demonstrate that the engineered probiotics limited the germination of endospores and the growth of vegetative cells of C. difficile in vitro and further significantly reduced CDI in model mice, as evidenced by a 100% survival rate and improved clinical outcomes. Our work presents an antimicrobial strategy that harnesses the host-pathogen microenvironment as the intervention target to limit the pathogenesis of infection.
Assuntos
Clostridioides difficile , Infecções por Clostridium , Probióticos , Animais , Antibacterianos/farmacologia , Ácidos e Sais Biliares/metabolismo , Clostridioides difficile/genética , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/prevenção & controle , Camundongos , Esporos Bacterianos/metabolismoRESUMO
BACKGROUND AND AIMS: Microbiome dysbiosis is associated with inflammatory destruction in Crohn's disease [CD]. Although gut microbiome dysbiosis is well established in CD, the oral microbiome is comparatively under-studied. This study aims to characterize the oral microbiome of CD patients with/without oral manifestations. METHODS: Patients with CD were recruited with age-, gender- and race-matched controls. Potential confounders such as dental caries and periodontal condition were recorded. The oral microbiome was collected using saliva samples. Microbial DNA was extracted and sequenced using shotgun sequencing. Metagenomic taxonomic and functional profiles were generated and analysed. RESULTS: The study recruited 41 patients with CD and 24 healthy controls. Within the CD subjects, 39.0% had oral manifestations with the majority presenting with cobblestoning and/or oral ulcers. Principal coordinate analysis demonstrated distinct oral microbiome profiles between subjects with and without CD, with four key variables responsible for overall oral microbiome variance: [1] diagnosis of CD, [2] concomitant use of steroids, [3] concomitant use of azathioprine and 4] presence of oral ulcers. Thirty-two significant differentially abundant microbial species were identified, with the majority associated with the diagnosis of CD. A predictive model based on differences in the oral microbiome found that the oral microbiome has strong discriminatory function to distinguish subjects with and without CD [AUROC 0.84]. Functional analysis found that an increased representation of microbial enzymes [n = 5] in the butyrate pathway was positively associated with the presence of oral ulcers. CONCLUSIONS: The oral microbiome can aid in the diagnosis of CD and its composition was associated with oral manifestations.
Assuntos
Doença de Crohn , Cárie Dentária , Microbioma Gastrointestinal , Úlceras Orais , Humanos , Doença de Crohn/diagnóstico , Disbiose , Fezes , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND: A significant proportion of the non-alcoholic fatty liver disease (NAFLD) population is non-obese. Prior studies reporting the severity of NAFLD amongst non-obese patients were heterogenous. Our study, using data from the largest biopsy-proven NAFLD international registry within Asia, aims to characterize the demographic, metabolic and histological differences between non-obese and obese NAFLD patients. METHODS: 1812 biopsy-proven NAFLD patients across nine countries in Asia assessed between 2006 and 2019 were pooled into a curated clinical registry. Demographic, metabolic and histological differences between non-obese and obese NAFLD patients were evaluated. The performance of Fibrosis-4 index for liver fibrosis (FIB-4) and NAFLD fibrosis score (NFS) to identify advanced liver disease across the varying obesity subgroups was compared. A random forest analysis was performed to identify novel predictors of fibrosis and steatohepatitis in non-obese patients. FINDINGS: One-fifth (21.6%) of NAFLD patients were non-obese. Non-obese NAFLD patients had lower proportions of NASH (50.5% vs 56.5%, pâ¯=â¯0.033) and advanced fibrosis (14.0% vs 18.7%, pâ¯=â¯0.033). Metabolic syndrome in non-obese individuals was associated with NASH (OR 1.59, 95% CI 1.01-2.54, pâ¯=â¯0.047) and advanced fibrosis (OR 1.88, 95% CI 0.99-3.54, pâ¯=â¯0.051). FIB-4 performed better than the NFS score (AUROC 81.5% vs 73.7%, pâ¯<â¯0.001) when classifying patients with F2-4 fibrosis amongst non-obese NAFLD patients. Haemoglobin, GGT, waist circumference and cholesterol are additional variables found on random forest analysis useful for identifying non-obese NAFLD patients with advanced liver disease. CONCLUSION: A substantial proportion of non-obese NAFLD patients has NASH or advanced fibrosis. FIB-4, compared to NFS better identifies non-obese NAFLD patients with advanced liver disease. Serum GGT, cholesterol, haemoglobin and waist circumference, which are neither components of NFS nor FIB-4, are important biomarkers for advanced liver disease in non-obese patients.
Assuntos
Cirrose Hepática/patologia , Fígado/patologia , Síndrome Metabólica/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/patologia , Adulto , Ásia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos RetrospectivosRESUMO
BACKGROUND: The human gut harbors trillions of microbes that play dynamic roles in health. While the microbiome contributes to many cardiometabolic traits by modulating host inflammation and metabolism, there is an incomplete understanding regarding the extent that and mechanisms by which individual microbes impact risk and development of cardiovascular disease (CVD). The Framingham Heart Study (FHS) is a multi-generational observational study following participants over decades to identify risk factors for CVD by correlating genetic and phenotypic factors with clinical outcomes. As a large-scale population-based cohort with extensive clinical phenotyping, FHS provides a rich landscape to explore the relationships between the gut microbiome and cardiometabolic traits. METHODS: We performed 16S rRNA gene sequencing on stool from 1423 participants of the FHS Generation 3, OMNI2, and New Offspring Spouse cohorts. Data processing and taxonomic assignment were performed with the 16S bioBakery workflow using the UPARSE pipeline. We conducted statistical analyses to investigate trends in overall microbiome composition and diversity in relation to disease states and systematically examined taxonomic associations with a variety of clinical traits, disease phenotypes, clinical blood markers, and medications. RESULTS: We demonstrate that overall microbial diversity decreases with increasing 10-year CVD risk and body mass index measures. We link lifestyle factors, especially diet and exercise, to microbial diversity. Our association analyses reveal both known and unreported microbial associations with CVD and diabetes, related prescription medications, as well as many anthropometric and blood test measurements. In particular, we observe a set of microbial species that demonstrate significant associations with CVD risk, metabolic syndrome, and type 2 diabetes as well as a number of shared associations between microbial species and cardiometabolic subphenotypes. CONCLUSIONS: The identification of significant microbial taxa associated with prevalent CVD and diabetes, as well as risk for developing CVD, adds to increasing evidence that the microbiome may contribute to CVD pathogenesis. Our findings support new hypothesis generation around shared microbe-mediated mechanisms that influence metabolic syndrome, diabetes, and CVD risk. Further investigation of the gut microbiomes of CVD patients in a targeted manner may elucidate microbial mechanisms with diagnostic and therapeutic implications.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Doenças Cardiovasculares/genética , Dieta , Microbioma Gastrointestinal/genética , Humanos , Estilo de Vida , RNA Ribossômico 16S/genéticaRESUMO
The intestinal microbiome is a key determinant of responses to biologic therapy in inflammatory bowel disease (IBD). However, diverse therapeutics and variable responses among IBD patients have posed challenges in predicting clinical therapeutic success. In this prospective study, we profiled baseline stool and blood in patients with moderate-to-severe Crohn's disease or ulcerative colitis initiating anti-cytokine therapy (anti-TNF or -IL12/23) or anti-integrin therapy. Patients were assessed at 14 weeks for clinical remission and 52 weeks for clinical and endoscopic remission. Baseline microbial richness indicated preferential responses to anti-cytokine therapy and correlated with the abundance of microbial species capable of 7α/ß-dehydroxylation of primary to secondary bile acids. Serum signatures of immune proteins reflecting microbial diversity identified patients more likely to achieve remission with anti-cytokine therapy. Remission-associated multi-omic profiles were unique to each therapeutic class. These profiles may facilitate a priori determination of optimal therapeutics for patients and serve as targets for newer therapies.