Project description:The human intestinal microbiota plays an essential role in host health. Modifications in its composition and diversity could induce pathologies such as inflammatory bowel diseases (IBD). These diseases are characterized by an unbalanced intestinal microbiota (a process known as dysbiosis) and an altered immune response. Faecalibacterium prausnitzii, the most abundant commensal bacterium in the human intestinal microbiota of healthy individuals (representing more than 5% of the total bacterial population), has been reported to be lower in feces and mucosa-associated microbiota of IBD patients. In addition, we have shown that both F. prausnitzii and its culture supernatant (SN) have anti-inflammatory and protective effects in both acute and chronic colitis models. However, the host molecular mechanisms involved in these anti-inflammatory effects remain unknown. In order to address this issue, we performed DNA chip-based transcriptomic analyses in HT-29 human intestinal epithelial cells stimulated with TNF-a and exposed to F. prausnitzii SN or to BHI (growth medium for F prausnitzii).
Project description:To elucidate whether Faecalibacterium prausnitzii has effects on intestinal toxicity induced by immune checkpoint inhibitors, we performed RNA-seq analysis of colon tissues of mice receiving DSS, DSS+ICB and DSS+ICB+F. prausnitzii gavage to compare the gene expression profiles.
Project description:Immunotherapy has improved the prognosis of patients with advanced non-small cell lung
cancer (NSCLC), but only a small subset of patients achieved clinical benefit. The purpose of our study was to integrate multidimensional data using a machine learning method to predict the therapeutic efficacy of immune checkpoint inhibitors (ICIs) monotherapy in patients with advanced NSCLC.The authors retrospectively enrolled 112 patients with stage IIIB-IV NSCLC receiving ICIs monotherapy. The random forest (RF) algorithm was used to establish efficacy prediction models based on five different input datasets, including precontrast computed tomography (CT) radiomic data, postcontrast CT radiomic data, combination of the two CT radiomic data, clinical data, and a combination of radiomic and clinical data. The 5-fold cross-validation was used to train and test the random forest classifier. The performance of the models was assessed according to the area under the curve (AUC) in the receiver operating characteristic (ROC) curve. Among these models(RF MLP LR XGBoost), our reproduced onnx models have better performance, especially for random forest. The response variable with a value (1/0) indicates the (efficacy/inefficacy) of PD-1/PD-L1 monotherapy in patients with advanced NSCLC
Project description:Gut microbiota impacts responses to immune checkpoint inhibitors (ICI). High level of Faecalibacterium prausnitzii has been associated with a positive response to ICI in multiple cancer types. Here, we show in two independent cohorts of patients with non-small cell lung cancer and advanced melanoma that high level of F. prausnitzii at baseline is positively associated with a better clinical response to ICI. In a mouse preclinical model, we show that the F. prausnitzii strain EXL01, already in clinical development for Inflammatory Bowel Disease, restores the anti-tumor response to ICI in the context of antibiotic-induced microbiota perturbation at clinical and tumor transcriptomics level. In vitro, EXL01 strain enhances T cell activation in the presence of ICI. Interestingly, oral administration of EXL01 strain is not associated with a change in fecal microbiota diversity or composition suggesting a direct effect on immune cells in the small intestine.
Project description:Faecalibacterium prausnitzii is a dominant member of healthy human colon microbiota, regarded as a beneficial gut bacterium due to its ability to produce anti-inflammatory substances. However, little is known about how F. prausnitzii utilizes the nutrients present in the human gut, influencing its prevalence in the host intestinal environment. The phosphoenolpyruvate (PEP):carbohydrate phosphotransferase system (PTS) is a widely distributed and highly efficient carbohydrate transport system found in most bacterial species that catalyses the simultaneous phosphorylation and import of cognate carbohydrates; its components play physiological roles through interaction with other regulatory proteins. Here, we performed a systematic analysis of the 16 genes encoding putative PTS components (2 enzyme I, 2 HPr, and 12 enzyme II components) in F. prausnitzii A2-165. We identified the general PTS components responsible for the PEP-dependent phosphotransfer reaction and the sugar-specific PTS components involved in the transport of two carbohydrates, N-acetylglucosamine and fructose, among five enzyme II complexes. We suggest that the dissection of the functional PTS in F. prausnitzii may help to understand how this species outcompetes other bacterial species in the human intestine.
Project description:Parkinson's disease (PD) is a common neurodegenerative disease in middle-aged and elderly people. The disorder of gut microbiota is involved in the pathophysiological process of various neurological diseases, and many studies have confirmed that gut microbiota is involved in the progression of PD. As one of the most effective methods to reconstruct gut microbiota, fecal microbiota transplantation (FMT) has been considered as an important treatment for PD. However, the mechanism of FMT treatment for PD is still lacking, which requires further exploration and can facilitate the application of FMT. As a model organism, Drosophila is highly conserved with mammalian system in maintaining intestinal homeostasis. In this study, there were significant differences in the gut microbiota of conventional Drosophila colonized from PD patients compared to those transplanted from normal controls. And we constructed rotenone-induced PD model in Drosophila followed by FMT in different groups, and investigated the impact of gut microbiome on transcriptome of the PD host. Microbial analysis by 16S rDNA sequencing showed that gut microbiota could affect bacterial structure of PD, which was confirmed by bacterial colonization results. In addition, transcriptome data suggested that gut microbiota can influence gene expression pattern of PD. Further experimental validations confirmed that lysosome and neuroactive ligand-receptor interaction are the most significantly influenced functional pathways by PD-derived gut microbiota. In summary, our data reveals the influence of PD-derived gut microbiota on host transcriptome and helps better understanding the interaction between gut microbiota and PD through gut-brain axis. The present study will facilitate the understanding of the mechanism underlying PD treatment with FMT in clinical practice.
Project description:Patients with advanced melanoma have shown an improved outlook after receiving anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapy efficacy remains a major challenge. Here, our findings show significantly higher abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanomas via STAT1/3. We also found that supplementation with α-KG significantly increased methylcytosine dioxygenase TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 had been recognized and stabilized in PD-L1 promoter to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that the TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, we provide a novel insight into α-KG's function in melanoma anti-PD1 treatment and supplement of α-KG is a novel promising strategy to improve the efficacy of anti-PD1 therapy.
Project description:The gut microbiota and tumor-associated macrophages (TAM) impact anti-PD-1 checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor TREM2 attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 combined with TREM2 deficiency induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus (R. gnavus) in the gut microbiota. Gavage of wild-type mice with R. gnavus recapitulated enhancement of anti-PD-1-mediated tumor elimination occurring in the absence of TREM2. The intestinal proinflammatory environment coincided with expansion, increased circulation and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.