Butyrate Produced by Commensal Bacteria Down-Regulates Indolamine 2,3-Dioxygenase 1 (IDO-1) Expression via a Dual Mechanism in Human Intestinal Epithelial Cells

Commensal bacteria are crucial for the development and maintenance of a healthy immune system therefore contributing to the global well-being of their host. A wide variety of metabolites produced by commensal bacteria are influencing host health but the characterization of the multiple molecular mechanisms involved in host-microbiota interactions is still only partially unraveled. The intestinal epithelial cells (IECs) take a central part in the host-microbiota dialogue by inducing the first microbial-derived immune signals. Amongst the numerous effector molecules modulating the immune responses produced by IECs, indoleamine 2,3-dioxygenase-1 (IDO-1) is essential for gut homeostasis. IDO-1 expression is dependent on the microbiota and despites its central role, how the commensal bacteria impacts its expression is still unclear. Therefore, we investigated the impact of individual cultivable commensal bacteria on IDO-1 transcriptional expression and found that the short chain fatty acid (SCFA) butyrate was the main metabolite controlling IDO-1 expression in human primary IECs and IEC cell-lines. This butyrate-driven effect was independent of the G-protein coupled receptors GPR41, GPR43, and GPR109a and of the transcription factors SP1, AP1, and PPARγ for which binding sites were reported in the IDO-1 promoter. We demonstrated for the first time that butyrate represses IDO-1 expression by two distinct mechanisms. Firstly, butyrate decreases STAT1 expression leading to the inhibition of the IFNγ-dependent and phosphoSTAT1-driven transcription of IDO-1. In addition, we described a second mechanism by which butyrate impairs IDO-1 transcription in a STAT1-independent manner that could be attributed to its histone deacetylase (HDAC) inhibitor property. In conclusion, our results showed that IDO-1 expression is down-regulated by butyrate via a dual mechanism: the reduction of STAT1 level and the HDAC inhibitor property of SCFAs

Elastodontic Therapy of Hyperdivergent Class II Patients Using AMCOP® Devices: A Retrospective Study

Background: The management of a hyperdivergent growth pattern is one of the most challenging in orthodontics and different treatments are advocated. The present study analyses the effectiveness of elastodontic therapy with AMCOP® devices in treating children with hyperdivergent class II malocclusion and the effect on the upper airway patency. Methods: The study group included 21 patients (10 males and 11 females, mean age 8.22 ± 1.17 years) with a hyperdivergent growth and a class II malocclusion treated with AMCOP® devices. Cephalometric analysis was performed before treatment (T0) and after treatment (T1). Results: After treatment, the cephalometric analysis revealed a correction of the class II malocclusion and a modification of the growth pattern with a divergence reduction. The improvement of the upper airway space was also observed. Conclusion: The elastodontic therapy effectively corrected hyperdivergent class II malocclusion in growing patients over a short period

New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer

We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Mécanisme d'activation de la voie AhR dans les cellules intestinales épithéliales intestinales par les bactéries commensales

The intestinal microbiota shapes the host physiology through the production of various metabolites. The transcription factor Aryl hydrocarbon Receptor (AhR) emerges as an actor of the host-microbiota crosstalk. Indeed, numerous bacterial molecules are described to activate AhR pathway and being involved in the intestinal homeostasis. Among them, indoles and other tryptophan-derived metabolites produced by commensal and probiotic strains were described for protecting mice from induced colitis and their abundance being inversely correlated with inflammatory bowel diseases (IBD) in humans. However, the current knowledge on bacterial molecules activating AhR pathway, is still limited, considering the complexity of the intestinal microbial community. By screening a collection of commensal bacteria on human intestinal epithelial cell lines, we identified microbial modulators of AhR pathway. The use of cells expressing an AhR reporter system allowed the identification of activating bacterial strains and discriminate different mechanisms of action. Firstly, bacteria producing short chain fatty acids (SCFA) emerged as strong activators of AhR pathway and we showed for the first time that butyrate acts as a novel AhR ligand. Additionally, some bacteria not predicted to produce butyrate nor indoles, were identified as AhR activators in our screen. Among them, some species belonging to the Actinobacteria phylum seem a promising group of AhR activators, through the production of a microbial metabolite not yet identified. In conclusion, this work sheds light on a novel role of butyrate as AhR ligand and introduces a newly potential family of AhR activator produced by Actinobacteria.Le microbiote intestinal joue un rôle fondamental dans la modulation du métabolisme et du système immunitaire de l’hôte à travers la production de métabolites. Le récepteur aux hydrocarbures aromatiques (AhR) est un acteur important dans l’interaction entre le microbiote et l’hôte. En effet, plusieurs métabolites microbiens ont été décrits comme activateurs de la voie AhR et impliqués dans l’homéostasie intestinale. Parmi eux, les indoles et autres métabolites dérivés du tryptophane, produits par des bactéries commensales ou probiotiques, ont été décrites pour protéger les souris lors de colites induites alors que leur présence est peu détectée chez les patients atteints de maladies inflammatoires chroniques de l’intestin (MICI). Le criblage d’une collection de bactéries commensales sur des lignées de cellules épithéliales intestinales a permis d’identifier des souches bactériennes modulatrices de la voie AhR. L’utilisation des cellules exprimant un système rapporteur AhR, a révélé des activateurs bactériens et mis en évidence différents mécanismes d’action. Nous avons montré que des bactéries productrices d’acides gras à chaine courte (AGCC) sont de forts activateurs de la voie AhR et que le butyrate semblait être un nouveau ligand d’AhR. De plus, nous avons identifié des Actinobacteries, non décrites pour produire du butyrate ou des indoles, comme activateurs de la voie AhR via la production d'un métabolite microbien non identifié à ce jour. En conclusion, ce travail illustre un nouveau rôle fonctionnel du butyrate comme ligand d’AhR et montre l’existence d’une nouvelle famille de métabolites microbiens produits par des Actinobacteries et activatrice de la voie AhR

Sviluppo ed applicazione di modelli di stima del danno alluvionale al settore agricolo

Alla luce delle richieste delle politiche di gestione e mitigazione del rischio alluvionale, definite a livello comunitario dalla Direttiva Alluvioni (Direttiva 2007/60/CE), risulta necessario lo sviluppo di modelli in grado di quantificare le conseguenze economiche che gli eventi alluvionali provocano, tra gli altri, anche al settore agricolo. Per rispondere a questa esigenza è stato recente proposto il modello concettuale AGRIDE (AGRIculture Damage Estimation; Molinari et al., 2019), il cui primo sviluppo si è focalizzato sulle coltivazioni più diffuse, in particolare su quelle annuali (es. cereali; AGRIDE-c). In questo studio si è implementato il modello AGRIDE-c per l’area emiliano-modenese, sviluppando un nuovo modulo di stima del danno alle colture pluriennali, in questo caso esemplificate con i vigneti. Si è inoltre proceduto ad una validazione del modello mettendo a confronto le stime fornite da AGRIDE-c con i dati di danno raccolti a seguito dell’evento alluvionale del fiume Secchia nel 2014. La validazione ha evidenziato una buona affidabilità della metodologia predisposta, dimostrandosi un valido strumento a disposizione delle autorità competenti per la stima dei danni attesi al settore agricolo nel caso di eventi alluvionali. In aggiunta, AGRIDE-C può essere adottato anche come strumento di supporto decisionale per le attività di tipo Cost-Benefit Analysis (CBA) nell’ambito della definizione dei piani di gestione e mitigazione del rischio alluvionale

Flood mapping using ERS tandem coherence image: a case study in Southern France

Flood mapping proved to be feasible using multitemporal ERS SAR amplitude images. However, it allows to map the flood extent only at given acquisition dates, rarely corresponding to the maximal flood extent. In this paper, we report first results of a study on the use of coherence images, in order to improve the flood detection which can be difficult in some flood conditions. We focused our study on a major flood that occured in 1996 in southern France. In this area was available a large data set including water height measurements, DEM's, different thematic vector layers in a GIS and Tandem INSAR ESR images. Then, we compared the results of flood detection, obtained with using respectively amplitude and coherence images, to flood simulations derived from a simple hydraulic model. We showed that coherence images should detect areas where flood-induced surface changes occured, possibly corresponding to the maximal flood extent within the repeat-pass acquisition window

Short Chain Fatty Acids – mechanisms and functional importance in the gut

International audienceIn recent years, the importance of the gut microbiota in human health has been revealed and many publications have highlighted its role as a key component of human physiology. Owing to the use of modern sequencing approaches, the characterisation of the microbiome in healthy individuals and in disease has demonstrated a disturbance of the microbiota, or dysbiosis, associated with pathological conditions. The microbiota establishes a symbiotic crosstalk with their host: commensal microbes benefit from the nutrient-rich environment provided by the gut and the microbiota produces hundreds of proteins and metabolites that modulate key functions of the host, including nutrient processing, maintenance of energy homoeostasis and immune system development. Many bacteria-derived metabolites originate from dietary sources. Among them, an important role has been attributed to the metabolites derived from the bacterial fermentation of dietary fibres, namely SCFA linking host nutrition to intestinal homoeostasis maintenance. SCFA are important fuels for intestinal epithelial cells (IEC) and regulate IEC functions through different mechanisms to modulate their proliferation, differentiation as well as functions of subpopulations such as enteroendocrine cells, to impact gut motility and to strengthen the gut barrier functions as well as host metabolism. Recent findings show that SCFA, and in particular butyrate, also have important intestinal and immuno-modulatory functions. In this review, we discuss the mechanisms and the impact of SCFA on gut functions and host immunity and consequently on human health

Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells

Abstract The ligand activated transcription factor, aryl hydrocarbon receptor (AhR) emerged as a critical regulator of immune and metabolic processes in the gastrointestinal tract. In the gut, a main source of AhR ligands derives from commensal bacteria. However, many of the reported microbiota-derived ligands have been restricted to indolyl metabolites. Here, by screening commensal bacteria supernatants on an AhR reporter system expressed in human intestinal epithelial cell line (IEC), we found that the short chain fatty acid (SCFA) butyrate induced AhR activity and the transcription of AhR-dependent genes in IECs. We showed that AhR ligand antagonists reduced the effects of butyrate on IEC suggesting that butyrate could act as a ligand of AhR, which was supported by the nuclear translocation of AhR induced by butyrate and in silico structural modelling. In conclusion, our findings suggest that (i) butyrate activates AhR pathway and AhR-dependent genes in human intestinal epithelial cell-lines (ii) butyrate is a potential ligand for AhR which is an original mechanism of gene regulation by SCFA