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1. BOC.01.2: THE IMPACT OF UNNECESSARY GLUTEN-FREE DIET ON GUT MICROBIOTA

Author: Manza, F., primary, Lungaro, L., additional, Costanzini, A., additional, Segata, N., additional, Pinto, F., additional, Puncochár, M., additional, Asnicar, F., additional, Armanini, F., additional, Carroccio, A., additional, Mansueto, P., additional, Calabrò, A., additional, Cavalieri, D., additional, Barbara, G., additional, Stanghellini, V., additional, Volta, U., additional, De Giorgio, R., additional, and Caio, G., additional
Published: 2024
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2. Considerations for the design and conduct of human gut microbiota intervention studies relating to foods

Author: Swann, J. R., Rajilic-Stojanovic, M., Salonen, A., Sakwinska, O., Gill, C., Meynier, A., Fança-Berthon, P., Schelkle, B., Segata, N., Shortt, C., Tuohy, K., and Hasselwander, O.
Published: 2020
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3. A Fecal Metabolite Signature of Impaired Fasting Glucose: Results From Two Independent Population-Based Cohorts

Author: Nogal, A, Tettamanzi, F, Dong, Q, Louca, P, Visconti, A, Christiansen, C, Breuninger, T, Linseisen, J, Grallert, H, Wawro, N, Asnicar, F, Wong, K, Baleanu, A, Michelotti, G, Segata, N, Falchi, M, Peters, A, Franks, P, Bagnardi, V, Spector, T, Bell, J, Gieger, C, Valdes, A, Menni, C, Nogal A., Tettamanzi F., Dong Q., Louca P., Visconti A., Christiansen C., Breuninger T., Linseisen J., Grallert H., Wawro N., Asnicar F., Wong K., Baleanu A. -F., Michelotti G. A., Segata N., Falchi M., Peters A., Franks P. W., Bagnardi V., Spector T. D., Bell J. T., Gieger C., Valdes A. M., Menni C., Nogal, A, Tettamanzi, F, Dong, Q, Louca, P, Visconti, A, Christiansen, C, Breuninger, T, Linseisen, J, Grallert, H, Wawro, N, Asnicar, F, Wong, K, Baleanu, A, Michelotti, G, Segata, N, Falchi, M, Peters, A, Franks, P, Bagnardi, V, Spector, T, Bell, J, Gieger, C, Valdes, A, Menni, C, Nogal A., Tettamanzi F., Dong Q., Louca P., Visconti A., Christiansen C., Breuninger T., Linseisen J., Grallert H., Wawro N., Asnicar F., Wong K., Baleanu A. -F., Michelotti G. A., Segata N., Falchi M., Peters A., Franks P. W., Bagnardi V., Spector T. D., Bell J. T., Gieger C., Valdes A. M., and Menni C.
Abstract: Prediabetes is a metabolic condition associated with gut mi-crobiome composition, although mechanisms remain elu-sive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicoti-nate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02–5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16–1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97–8], P = 0.0002). Although these are host-produced me-tabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset.
Published: 2023

4. The inflammatory potential of diet is associated with future development of pre-clinical carotid atherosclerosis

Author: Mattavelli, E., primary, Piperni, E., additional, Nabinejad, A., additional, Redaelli, L., additional, Grigore, L., additional, Pellegatta, F., additional, Magni, P., additional, Tamburini, S., additional, Asnicar, F., additional, Segata, N., additional, De Gaetano, L. Nicolini, additional, Catapano, A., additional, and Baragetti, A., additional
Published: 2023
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5. Colorectal cancer, Vitamin D and microbiota: A double-blind Phase II randomized trial (ColoViD) in colorectal cancer patients

Author: Bellerba, F, Serrano, D, Harriet, J, Pozzi, C, Segata, N, Nabinejad, A, Piperni, E, Gnagnarella, P, Macis, D, Aristarco, V, Accornero, C, Manghi, P, Gonzaga, A, Biffi, R, Bottiglieri, L, Trovato, C, Zampino, M, Corso, F, Bellocco, R, Raimondi, S, Rescigno, M, Gandini, S, Bellerba F., Serrano D., Harriet J., Pozzi C., Segata N., NabiNejad A., Piperni E., Gnagnarella P., Macis D., Aristarco V., Accornero C. A., Manghi P., Gonzaga A. G., Biffi R., Bottiglieri L., Trovato C., Zampino M. G., Corso F., Bellocco R., Raimondi S., Rescigno M., Gandini S., Bellerba, F, Serrano, D, Harriet, J, Pozzi, C, Segata, N, Nabinejad, A, Piperni, E, Gnagnarella, P, Macis, D, Aristarco, V, Accornero, C, Manghi, P, Gonzaga, A, Biffi, R, Bottiglieri, L, Trovato, C, Zampino, M, Corso, F, Bellocco, R, Raimondi, S, Rescigno, M, Gandini, S, Bellerba F., Serrano D., Harriet J., Pozzi C., Segata N., NabiNejad A., Piperni E., Gnagnarella P., Macis D., Aristarco V., Accornero C. A., Manghi P., Gonzaga A. G., Biffi R., Bottiglieri L., Trovato C., Zampino M. G., Corso F., Bellocco R., Raimondi S., Rescigno M., and Gandini S.
Abstract: Background: Several studies suggest a role of gut microbiota in colorectal cancer (CRC) initiation and progression. Vitamin D (vitD) blood levels are also inversely correlated with CRC risk and prognosis. However, these factors’ interplay remains unknown. Methods: 74 CRC patients after standard treatment were randomized to 1-year 2000 IU/day vitD or placebo. Baseline and post-treatment fecal microbiota for shotgun metagenomics sequencing was collected. Coda-lasso and Principal Component Analysis were used to select and summarize treatment-associated taxa and pathways. Associations between vitD and taxa/pathways were investigated with logistic regression. Mediation analysis was performed to study if treatment-associated taxa mediated the effect of supplementation on 25(OH)D levels. Cox proportional-hazards model was used for disease-free survival (DFS). Results: 60 patients were analyzed. Change in alpha diversity (Shannon: p = 0.77; Simpson: p = 0.63) and post-treatment beta diversity (p = 0.70) were comparable between arms. Post-treatment abundances of 63 taxa and 32 pathways differed between arms. The 63 taxa also mediated the effect of supplementation on 25(OH)D (p = 0.02). There were sex differences in vitD levels, microbiota and pathways. Pathways of essential amino acids’ biosynthesis were more abundant in supplemented women. Fusobacterium nucleatum presence at baseline was associated with worse DFS (p = 0.02). Those achieving vitD sufficiency (25(OH)D≥30 ng/ml) had lower post-treatment abundances (p = 0.05). Women were more likely to have F. nucleatum post-treatment (p = 0.02). Conclusions: VitD supplementation may contribute shaping the gut microbiota and the microbiota may partially mediate the effect of supplementation on 25(OH)D. The observed sex-specific differences highlight the necessity of including sex/gender as a variable in microbiome studies.
Published: 2022

6. LBA77 Fecal microbiota transplantation (FMT) versus placebo in patients receiving pembrolizumab plus axitinib for metastatic renal cell carcinoma: Preliminary results of the randomized phase II TACITO trial

Author: Ciccarese, C., Porcari, S., Buti, S., Fornarini, G., Primi, F., Giudice, G.C., Damassi, A., Giron Berrios, J.R., Stumbo, L., Arduini, D., Severino, A., Rondinella, D., Masucci, L., Sanguinetti, M., Gasbarrini, A., Cammarota, G., Segata, N., Tortora, G., Ianiro, G., and Iacovelli, R.
Published: 2024
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7. Recent genetic exchanges and admixture shape the genome and population structure of the zoonotic pathogen Cryptosporidium parvum

Author: Corsi, G, Tichkule, S, Sannella, AR, Vatta, P, Asnicar, F, Segata, N, Jex, AR, van Oosterhout, C, Caccio, SM, Corsi, G, Tichkule, S, Sannella, AR, Vatta, P, Asnicar, F, Segata, N, Jex, AR, van Oosterhout, C, and Caccio, SM
Abstract: Cryptosporidium parvum is a globally distributed zoonotic pathogen and a major cause of diarrhoeal disease in humans and ruminants. The parasite's life cycle comprises an obligatory sexual phase, during which genetic exchanges can occur between previously isolated lineages. Here, we compare 32 whole genome sequences from human- and ruminant-derived parasite isolates collected across Europe, Egypt and China. We identify three strongly supported clusters that comprise a mix of isolates from different host species, geographic origins, and subtypes. We show that: (1) recombination occurs between ruminant isolates into human isolates; (2) these recombinant regions can be passed on to other human subtypes through gene flow and population admixture; (3) there have been multiple genetic exchanges, and most are probably recent; (4) putative virulence genes are significantly enriched within these genetic exchanges, and (5) this results in an increase in their nucleotide diversity. We carefully dissect the phylogenetic sequence of two genetic exchanges, illustrating the long-term evolutionary consequences of these events. Our results suggest that increased globalization and close human-animal contacts increase the opportunity for genetic exchanges between previously isolated parasite lineages, resulting in spillover and spillback events. We discuss how this can provide a novel substrate for natural selection at genes involved in host-parasite interactions, thereby potentially altering the dynamic coevolutionary equilibrium in the Red Queens arms race.
Published: 2022

8. Critical Assessment of Metagenome Interpretation: the second round of challenges

Author: Meyer, F, Fritz, A, Deng, Z-L, Koslicki, D, Lesker, TR, Gurevich, A, Robertson, G, Alser, M, Antipov, D, Beghini, F, Bertrand, D, Brito, JJ, Brown, CT, Buchmann, J, Buluc, A, Chen, B, Chikhi, R, Clausen, PTLC, Cristian, A, Dabrowski, PW, Darling, AE, Egan, R, Eskin, E, Georganas, E, Goltsman, E, Gray, MA, Hansen, LH, Hofmeyr, S, Huang, P, Irber, L, Jia, H, Jorgensen, TS, Kieser, SD, Klemetsen, T, Kola, A, Kolmogorov, M, Korobeynikov, A, Kwan, J, LaPierre, N, Lemaitre, C, Li, C, Limasset, A, Malcher-Miranda, F, Mangul, S, Marcelino, VR, Marchet, C, Marijon, P, Meleshko, D, Mende, DR, Milanese, A, Nagarajan, N, Nissen, J, Nurk, S, Oliker, L, Paoli, L, Peterlongo, P, Piro, VC, Porter, JS, Rasmussen, S, Rees, ER, Reinert, K, Renard, B, Robertsen, EM, Rosen, GL, Ruscheweyh, H-J, Sarwal, V, Segata, N, Seiler, E, Shi, L, Sun, F, Sunagawa, S, Sorensen, SJ, Thomas, A, Tong, C, Trajkovski, M, Tremblay, J, Uritskiy, G, Vicedomini, R, Wang, Z, Warren, A, Willassen, NP, Yelick, K, You, R, Zeller, G, Zhao, Z, Zhu, S, Zhu, J, Garrido-Oter, R, Gastmeier, P, Hacquard, S, Haeussler, S, Khaledi, A, Maechler, F, Mesny, F, Radutoiu, S, Schulze-Lefert, P, Smit, N, Strowig, T, Bremges, A, Sczyrba, A, McHardy, AC, Meyer, F, Fritz, A, Deng, Z-L, Koslicki, D, Lesker, TR, Gurevich, A, Robertson, G, Alser, M, Antipov, D, Beghini, F, Bertrand, D, Brito, JJ, Brown, CT, Buchmann, J, Buluc, A, Chen, B, Chikhi, R, Clausen, PTLC, Cristian, A, Dabrowski, PW, Darling, AE, Egan, R, Eskin, E, Georganas, E, Goltsman, E, Gray, MA, Hansen, LH, Hofmeyr, S, Huang, P, Irber, L, Jia, H, Jorgensen, TS, Kieser, SD, Klemetsen, T, Kola, A, Kolmogorov, M, Korobeynikov, A, Kwan, J, LaPierre, N, Lemaitre, C, Li, C, Limasset, A, Malcher-Miranda, F, Mangul, S, Marcelino, VR, Marchet, C, Marijon, P, Meleshko, D, Mende, DR, Milanese, A, Nagarajan, N, Nissen, J, Nurk, S, Oliker, L, Paoli, L, Peterlongo, P, Piro, VC, Porter, JS, Rasmussen, S, Rees, ER, Reinert, K, Renard, B, Robertsen, EM, Rosen, GL, Ruscheweyh, H-J, Sarwal, V, Segata, N, Seiler, E, Shi, L, Sun, F, Sunagawa, S, Sorensen, SJ, Thomas, A, Tong, C, Trajkovski, M, Tremblay, J, Uritskiy, G, Vicedomini, R, Wang, Z, Warren, A, Willassen, NP, Yelick, K, You, R, Zeller, G, Zhao, Z, Zhu, S, Zhu, J, Garrido-Oter, R, Gastmeier, P, Hacquard, S, Haeussler, S, Khaledi, A, Maechler, F, Mesny, F, Radutoiu, S, Schulze-Lefert, P, Smit, N, Strowig, T, Bremges, A, Sczyrba, A, and McHardy, AC
Abstract: Evaluating metagenomic software is key for optimizing metagenome interpretation and focus of the Initiative for the Critical Assessment of Metagenome Interpretation (CAMI). The CAMI II challenge engaged the community to assess methods on realistic and complex datasets with long- and short-read sequences, created computationally from around 1,700 new and known genomes, as well as 600 new plasmids and viruses. Here we analyze 5,002 results by 76 program versions. Substantial improvements were seen in assembly, some due to long-read data. Related strains still were challenging for assembly and genome recovery through binning, as was assembly quality for the latter. Profilers markedly matured, with taxon profilers and binners excelling at higher bacterial ranks, but underperforming for viruses and Archaea. Clinical pathogen detection results revealed a need to improve reproducibility. Runtime and memory usage analyses identified efficient programs, including top performers with other metrics. The results identify challenges and guide researchers in selecting methods for analyses.
Published: 2022

9. T.07.2 LONGITUDINAL EVALUATION OF GUT MICROBIOME AFTER FECAL MICROBIOTA TRANSPLANTATION FOR ERADICATING CLOSTRIDIOIDES DIFFICILE INFECTION

Author: Porcari, S., primary, Karcher, N., additional, Puncochár, M., additional, Valles Colomer, M., additional, Quaranta, G., additional, Bibbo, S., additional, De Giorgi, S., additional, Masucci, L., additional, Sanguinetti, M., additional, Gasbarrini, A., additional, Cammarota, G., additional, Segata, N., additional, and Ianiro, G., additional
Published: 2022
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10. Endogenous murine microbiota member Faecalibaculum rodentium and its human homologue protect from intestinal tumour growth

Author: Zagato, E, Pozzi, C, Bertocchi, A, Schioppa, T, Saccheri, F, Guglietta, S, Fosso, B, Melocchi, L, Nizzoli, G, Troisi, J, Marzano, M, Oresta, B, Spadoni, I, Atarashi, K, Carloni, S, Arioli, S, Fornasa, G, Asnicar, F, Segata, N, Guglielmetti, S, Honda, K, Pesole, G, Vermi, W, Penna, G, Rescigno, M, Zagato E., Pozzi C., Bertocchi A., Schioppa T., Saccheri F., Guglietta S., Fosso B., Melocchi L., Nizzoli G., Troisi J., Marzano M., Oresta B., Spadoni I., Atarashi K., Carloni S., Arioli S., Fornasa G., Asnicar F., Segata N., Guglielmetti S., Honda K., Pesole G., Vermi W., Penna G., Rescigno M., Zagato, E, Pozzi, C, Bertocchi, A, Schioppa, T, Saccheri, F, Guglietta, S, Fosso, B, Melocchi, L, Nizzoli, G, Troisi, J, Marzano, M, Oresta, B, Spadoni, I, Atarashi, K, Carloni, S, Arioli, S, Fornasa, G, Asnicar, F, Segata, N, Guglielmetti, S, Honda, K, Pesole, G, Vermi, W, Penna, G, Rescigno, M, Zagato E., Pozzi C., Bertocchi A., Schioppa T., Saccheri F., Guglietta S., Fosso B., Melocchi L., Nizzoli G., Troisi J., Marzano M., Oresta B., Spadoni I., Atarashi K., Carloni S., Arioli S., Fornasa G., Asnicar F., Segata N., Guglielmetti S., Honda K., Pesole G., Vermi W., Penna G., and Rescigno M.
Abstract: The microbiota has been shown to promote intestinal tumourigenesis, but a possible anti-tumourigenic effect has also been postulated. Here, we demonstrate that changes in the microbiota and mucus composition are concomitant with tumourigenesis. We identified two anti-tumourigenic strains of the microbiota—Faecalibaculum rodentium and its human homologue, Holdemanella biformis—that are strongly under-represented during tumourigenesis. Reconstitution of ApcMin/+ or azoxymethane- and dextran sulfate sodium-treated mice with an isolate of F. rodentium (F. PB1) or its metabolic products reduced tumour growth. Both F. PB1 and H. biformis produced short-chain fatty acids that contributed to control protein acetylation and tumour cell proliferation by inhibiting calcineurin and NFATc3 activation in mouse and human settings. We have thus identified endogenous anti-tumourigenic bacterial strains with strong diagnostic, therapeutic and translational potential.
Published: 2020

11. Reporting guidelines for human microbiome research: the STORMS checklist

Author: MacIntyre, D, Mirzayi, C, Renson, A, Zohra, F, Elsafoury, S, Geistlinger, L, Kasselman, L, Eckenrode, K, Van de Wijgert, J, Loughman, A, Marques, FZ, STORMS Consortium, Genomic Standards Consortium, Massive Analysis and Quality Control 8 Society, Segata, N, Huttenhower, C, Dowd, JB, Jones, HE, and Waldron, L
Subjects: Genomic Standards Consortium, Biochemistry & Molecular Biology, Science & Technology, Massive Analysis and Quality Control Society, STATEMENT, NULL, Immunology, Cell Biology, Research & Experimental Medicine, GENETIC ASSOCIATION, TRIALS, Medicine, Research & Experimental, CAUSAL INFERENCE, QUALITY, EPIDEMIOLOGY, Life Sciences & Biomedicine, EXTENSION, 11 Medical and Health Sciences
Abstract: The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called ‘Strengthening The Organization and Reporting of Microbiome Studies’ (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.
Published: 2021

12. Analysis of 1321 Eubacterium rectale genomes from metagenomes uncovers complex phylogeographic population structure and subspecies functional adaptations

Author: Karcher N., Pasolli E., Asnicar F., Huang K. D., Tett A., Manara S., Armanini F., Bain D., Duncan S. H., Louis P., Zolfo M., Manghi P., Valles-Colomer M., Raffaeta R., Rota-Stabelli O., Collado M. C., Zeller G., Falush D., Maixner F., Walker A. W., Huttenhower C., Segata N., Karcher, N., Pasolli, E., Asnicar, F., Huang, K. D., Tett, A., Manara, S., Armanini, F., Bain, D., Duncan, S. H., Louis, P., Zolfo, M., Manghi, P., Valles-Colomer, M., Raffaeta, R., Rota-Stabelli, O., Collado, M. C., Zeller, G., Falush, D., Maixner, F., Walker, A. W., Huttenhower, C., and Segata, N.
Subjects: Adult, Adolescent, lcsh:QH426-470, Population genetics, Biology, Subspecies, Settore BIO/19 - Microbiologia Generale, Genome, Population genomics, Young Adult, 03 medical and health sciences, Genomic island, Humans, Settore M-DEA/01 - Discipline Demoetnoantropologiche, Child, lcsh:QH301-705.5, Aged, 030304 developmental biology, Isolation by distance, 0303 health sciences, Settore BIO/11 - BIOLOGIA MOLECOLARE, Eubacterium, 030306 microbiology, Research, Glycosyltransferases, Infant, Middle Aged, Gastrointestinal Microbiome, Phylogeography, lcsh:Genetics, lcsh:Biology (General), Evolutionary biology, Metagenomics, Child, Preschool, Carbohydrate Metabolism, Metagenome, Genome, Bacterial
Abstract: Background Eubacterium rectale is one of the most prevalent human gut bacteria, but its diversity and population genetics are not well understood because large-scale whole-genome investigations of this microbe have not been carried out. Results Here, we leverage metagenomic assembly followed by a reference-based binning strategy to screen over 6500 gut metagenomes spanning geography and lifestyle and reconstruct over 1300 E. rectale high-quality genomes from metagenomes. We extend previous results of biogeographic stratification, identifying a new subspecies predominantly found in African individuals and showing that closely related non-human primates do not harbor E. rectale. Comparison of pairwise genetic and geographic distances between subspecies suggests that isolation by distance and co-dispersal with human populations might have contributed to shaping the contemporary population structure of E. rectale. We confirm that a relatively recently diverged E. rectale subspecies specific to Europe consistently lacks motility operons and that it is immotile in vitro, probably due to ancestral genetic loss. The same subspecies exhibits expansion of its carbohydrate metabolism gene repertoire including the acquisition of a genomic island strongly enriched in glycosyltransferase genes involved in exopolysaccharide synthesis. Conclusions Our study provides new insights into the population structure and ecology of E. rectale and shows that shotgun metagenomes can enable population genomics studies of microbiota members at a resolution and scale previously attainable only by extensive isolate sequencing.
Published: 2020

13. Critical Assessment of Metagenome Interpretation - the second round of challenges

Author: Meyer, F., primary, Fritz, A., additional, Deng, Z.-L., additional, Koslicki, D., additional, Gurevich, A., additional, Robertson, G., additional, Alser, M., additional, Antipov, D., additional, Beghini, F., additional, Bertrand, D., additional, Brito, J. J., additional, Brown, C.T., additional, Buchmann, J., additional, Buluç, A., additional, Chen, B., additional, Chikhi, R., additional, Clausen, P. T., additional, Cristian, A., additional, Dabrowski, P. W., additional, Darling, A. E., additional, Egan, R., additional, Eskin, E., additional, Georganas, E., additional, Goltsman, E., additional, Gray, M. A., additional, Hansen, L. H., additional, Hofmeyr, S., additional, Huang, P., additional, Irber, L., additional, Jia, H., additional, Jørgensen, T. S., additional, Kieser, S. D., additional, Klemetsen, T., additional, Kola, A., additional, Kolmogorov, M., additional, Korobeynikov, A., additional, Kwan, J., additional, LaPierre, N., additional, Lemaitre, C., additional, Li, C., additional, Limasset, A., additional, Malcher-Miranda, F., additional, Mangul, S., additional, Marcelino, V. R., additional, Marchet, C., additional, Marijon, P., additional, Meleshko, D., additional, Mende, D. R., additional, Milanese, A., additional, Nagarajan, N., additional, Nissen, J., additional, Nurk, S., additional, Oliker, L., additional, Paoli, L., additional, Peterlongo, P., additional, Piro, V. C., additional, Porter, J. S., additional, Rasmussen, S., additional, Rees, E. R., additional, Reinert, K., additional, Renard, B., additional, Robertsen, E. M., additional, Rosen, G. L., additional, Ruscheweyh, H.-J., additional, Sarwal, V., additional, Segata, N., additional, Seiler, E., additional, Shi, L., additional, Sun, F., additional, Sunagawa, S., additional, Sørensen, S. J., additional, Thomas, A., additional, Tong, C., additional, Trajkovski, M., additional, Tremblay, J., additional, Uritskiy, G., additional, Vicedomini, R., additional, Wang, Zi., additional, Wang, Zhe., additional, Wang, Zho., additional, Warren, A., additional, Willassen, N. P., additional, Yelick, K., additional, You, R., additional, Zeller, G., additional, Zhao, Z., additional, Zhu, S., additional, Zhu, J., additional, Garrido-Oter, R., additional, Gastmeier, P., additional, Hacquard, S., additional, Häußler, S., additional, Khaledi, A., additional, Maechler, F., additional, Mesny, F., additional, Radutoiu, S., additional, Schulze-Lefert, P., additional, Smit, N., additional, Strowig, T., additional, Bremges, A., additional, Sczyrba, A., additional, and McHardy, A. C., additional
Published: 2021
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14. 863P Microbiota and cytokines profile in patients (pts) affected by recurrent metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs) +/- chemotherapy (CT) and prebiotic inulin in the PRINCESS study

Author: Galizia, D., Minei, S., Abbona, A., Paccagnella, M., Piccinno, G., Polidori, A., De Zarlo, L., Albini, M., Rizzo, A., Campanella, D., Cappello, G., Enrico, F., Bondi, S., Segata, N., Gregorc, V., and Merlano, M.C.
Published: 2023
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15. Closely related Lak megaphages replicate in the microbiomes of diverse animals

Author: Crisci, MA, Chen, L-X, Devoto, AE, Borges, AL, Bordin, N, Sachdeva, R, Tett, A, Sharrar, AM, Segata, N, Debenedetti, F, Bailey, M, Burt, R, Wood, RM, Rowden, LJ, Corsini, PM, van Winden, S, Holmes, MA, Lei, S, Banfield, JF, Santini, JM, Crisci, MA, Chen, L-X, Devoto, AE, Borges, AL, Bordin, N, Sachdeva, R, Tett, A, Sharrar, AM, Segata, N, Debenedetti, F, Bailey, M, Burt, R, Wood, RM, Rowden, LJ, Corsini, PM, van Winden, S, Holmes, MA, Lei, S, Banfield, JF, and Santini, JM
Abstract: Lak phages with alternatively coded ∼540 kbp genomes were recently reported to replicate in Prevotella in microbiomes of humans that consume a non-Western diet, baboons, and pigs. Here, we explore Lak phage diversity and broader distribution using diagnostic polymerase chain reaction and genome-resolved metagenomics. Lak phages were detected in 13 animal types, including reptiles, and are particularly prevalent in pigs. Tracking Lak through the pig gastrointestinal tract revealed significant enrichment in the hindgut compared to the foregut. We reconstructed 34 new Lak genomes, including six curated complete genomes, all of which are alternatively coded. An anomalously large (∼660 kbp) complete genome reconstructed for the most deeply branched Lak from a horse microbiome is also alternatively coded. From the Lak genomes, we identified proteins associated with specific animal species; notably, most have no functional predictions. The presence of closely related Lak phages in diverse animals indicates facile distribution coupled to host-specific adaptation.
Published: 2021

16. P142 Lung and gut microbiota signatures in cystic fibrosis mice challenged with Pseudomonas aeruginosa

Author: Bevivino, A., primary, Bacci, G., additional, Rossi, A., additional, Armanini, F., additional, Cangioli, L., additional, Segata, N., additional, Mengoni, A., additional, and Bragonzi, A., additional
Published: 2021
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17. Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy

Author: Daillere, R., Derosa, L., Bonvalet, M., Segata, N., Routy, B., Gariboldi, M., Budinska, E., Vries, I.J.M. de, Naccarati, A.G., Zitvogel, V., Caldas, C., Engstrand, L., Loilbl, S., Fieschi, J., Heinzerling, L., Kroemer, G., Zitvogel, L., Daillere, R., Derosa, L., Bonvalet, M., Segata, N., Routy, B., Gariboldi, M., Budinska, E., Vries, I.J.M. de, Naccarati, A.G., Zitvogel, V., Caldas, C., Engstrand, L., Loilbl, S., Fieschi, J., Heinzerling, L., Kroemer, G., and Zitvogel, L.
Abstract: Contains fulltext : 220857.pdf (Publisher’s version ) (Open Access), Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.
Published: 2020

18. Shed light in the dark lineages of the fungal tree of life—stres

Author: Selbmann, L, Benkő, Z, Coleine, C, de Hoog, S, Donati, C, Druzhinina, I, Emri, T, Ettinger, CL, Gladfelter, AS, Gorbushina, AA, Grigoriev, IV, Grube, M, Gunde-Cimerman, N, Karányi, ZÁ, Kocsis, B, Kubressoian, T, Miklós, I, Miskei, M, Muggia, L, Northen, T, Novak-Babič, M, Pennacchio, C, Pfliegler, WP, Pòcsi, I, Prigione, V, Riquelme, M, Segata, N, Schumacher, J, Shelest, E, Sterflinger, K, Tesei, D, U’ren, JM, Varese, GC, Vázquez-Campos, X, Vicente, VA, Souza, EM, Zalar, P, Walker, AK, Stajich, JE, Vazquez Campos, Xabier ; https://orcid.org/0000-0003-1134-5058, Selbmann, L, Benkő, Z, Coleine, C, de Hoog, S, Donati, C, Druzhinina, I, Emri, T, Ettinger, CL, Gladfelter, AS, Gorbushina, AA, Grigoriev, IV, Grube, M, Gunde-Cimerman, N, Karányi, ZÁ, Kocsis, B, Kubressoian, T, Miklós, I, Miskei, M, Muggia, L, Northen, T, Novak-Babič, M, Pennacchio, C, Pfliegler, WP, Pòcsi, I, Prigione, V, Riquelme, M, Segata, N, Schumacher, J, Shelest, E, Sterflinger, K, Tesei, D, U’ren, JM, Varese, GC, Vázquez-Campos, X, Vicente, VA, Souza, EM, Zalar, P, Walker, AK, Stajich, JE, and Vazquez Campos, Xabier ; https://orcid.org/0000-0003-1134-5058
Abstract: The polyphyletic group of black fungi within the Ascomycota (Arthoniomycetes, Dothideomycetes, and Eurotiomycetes) is ubiquitous in natural and anthropogenic habitats. Partly because of their dark, melanin-based pigmentation, black fungi are resistant to stresses including UV-and ionizing-radiation, heat and desiccation, toxic metals, and organic pollutants. Consequently, they are amongst the most stunning extremophiles and poly-extreme-tolerant organisms on Earth. Even though ca. 60 black fungal genomes have been sequenced to date, [mostly in the family Herpotrichiellaceae (Eurotiomycetes)], the class Dothideomycetes that hosts the largest majority of extremophiles has only been sparsely sampled. By sequencing up to 92 species that will become reference genomes, the “Shed light in The daRk lineagES of the fungal tree of life” (STRES) project will cover a broad collection of black fungal diversity spread throughout the Fungal Tree of Life. Interestingly, the STRES project will focus on mostly unsampled genera that display different ecologies and life-styles (e.g., ant-and lichen-associated fungi, rock-inhabiting fungi, etc.). With a resequencing strategy of 10-to 15-fold depth coverage of up to ~550 strains, numerous new reference genomes will be established. To identify metabolites and functional processes, these new genomic resources will be enriched with metabolomics analyses coupled with transcriptomics experiments on selected species under various stress conditions (salinity, dryness, UV radiation, oligotrophy). The data acquired will serve as a reference and foundation for establishing an encyclopedic database for fungal metagenomics as well as the biology, evolution, and ecology of the fungi in extreme environments.
Published: 2020

19. Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma

Author: Ianiro, Gianluca, Rossi, E., Thomas, A. M., Schinzari, Giovanni, Masucci, Luca, Quaranta, G., Settanni, Carlo Romano, Lopetuso, Loris Riccardo, Armanini, F., Blanco-Miguez, A., Asnicar, F., Consolandi, C., Iacovelli, Roberto, Sanguinetti, Maurizio, Tortora, Giampaolo, Gasbarrini, Antonio, Segata, N., Cammarota, Giovanni, Ianiro G. (ORCID:0000-0002-8318-0515), Schinzari G. (ORCID:0000-0001-6105-7252), Masucci L. (ORCID:0000-0002-8358-6726), Settanni C. R., Lopetuso L. R., Iacovelli R. (ORCID:0000-0002-1750-2117), Sanguinetti M. (ORCID:0000-0002-9780-7059), Tortora G. (ORCID:0000-0002-1378-4962), Gasbarrini A. (ORCID:0000-0002-7278-4823), Cammarota G. (ORCID:0000-0002-3626-6148), Ianiro, Gianluca, Rossi, E., Thomas, A. M., Schinzari, Giovanni, Masucci, Luca, Quaranta, G., Settanni, Carlo Romano, Lopetuso, Loris Riccardo, Armanini, F., Blanco-Miguez, A., Asnicar, F., Consolandi, C., Iacovelli, Roberto, Sanguinetti, Maurizio, Tortora, Giampaolo, Gasbarrini, Antonio, Segata, N., Cammarota, Giovanni, Ianiro G. (ORCID:0000-0002-8318-0515), Schinzari G. (ORCID:0000-0001-6105-7252), Masucci L. (ORCID:0000-0002-8358-6726), Settanni C. R., Lopetuso L. R., Iacovelli R. (ORCID:0000-0002-1750-2117), Sanguinetti M. (ORCID:0000-0002-9780-7059), Tortora G. (ORCID:0000-0002-1378-4962), Gasbarrini A. (ORCID:0000-0002-7278-4823), and Cammarota G. (ORCID:0000-0002-3626-6148)
Abstract: Diarrhoea is one of the most burdensome and common adverse events of chemotherapeutics, and has no standardised therapy to date. Increasing evidence suggests that the gut microbiome can influence the development of chemotherapy-induced diarrhoea. Here we report findings from a randomised clinical trial of faecal microbiota transplantation (FMT) to treat diarrhoea induced by tyrosine kinase inhibitors (TKI) in patients with metastatic renal cell carcinoma (ClinicalTrials.gov number: NCT04040712). The primary outcome is the resolution of diarrhoea four weeks after the end of treatments. Twenty patients are randomised to receive FMT from healthy donors or placebo FMT (vehicle only). Donor FMT is more effective than placebo FMT in treating TKI-induced diarrhoea, and a successful engraftment is observed in subjects receiving donor faeces. No serious adverse events are observed in both treatment arms. The trial meets pre-specified endpoints. Our findings suggest that the therapeutic manipulation of gut microbiota may become a promising treatment option to manage TKI-dependent diarrhoea.
Published: 2020

20. 1452MO Longitudinal analysis reveals gut microbiota shift during standard therapies in metastatic renal cell carcinoma (mRCC)

Author: Alves Costa Silva, C., Piccinno, G., Cerbone, L., Iebba, V., Colomba, E., Flippot, R., C. Sow, Darik, I., Maltez Thomas, A., Naoun, N., Bernard-Tessier, A., Reni, A., Segata, N., Escudier, B., Zitvogel, L., Albiges, L., and Derosa, L.
Published: 2022
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21. Habitual diet selects distinct genetic and functional subtypes of intestinal Prevotella copri

Author: De Filippis F., PASOLLI, EDOARDO, Tett A., De Angelis M., Neviani E., Turroni S., Cocolin L., Gobbetti M., Segata N., Ercolini D., 7th International Human Microbiome Consortium Meeting 2018 Organising Committee, De Filippis, F., Pasolli, Edoardo, Tett, A., De Angelis, M., Neviani, E., Turroni, S., Cocolin, L., Gobbetti, M., Segata, N., and Ercolini, D.
Published: 2018

22. Large scale reconstruction of over a thousand Wolbachia genomes sheds light on its co-evolution

Author: Scholz, M., Albanese, D., Tuohy, K., Donati, C., Segata, N., and Rota-Stabelli, O.
Subjects: Settore BIO/19 - MICROBIOLOGIA GENERALE
Published: 2019

23. Intestinal microbiota and energy metabolism: measuring the impact of diet: microbe interactions on host health

Author: Gaudioso, G., Fava, F., Mattivi, F., Vrhovsek, U., Bellosta, P., Segata, N., Collino, M., and Tuohy, K.M.
Subjects: Settore BIO/11 - BIOLOGIA MOLECOLARE, Health, Gut microbiota, Diet, Nutrition
Published: 2019

24. WS19-4 The personalised temporal dynamics of microbiome in the airways of cystic fibrosis patients

Author: Bevivino, A., primary, Bacci, G., additional, Taccetti, G., additional, Lucidi, V., additional, Dolce, D., additional, Fiscarelli, E., additional, Di Cesare, F., additional, Armanini, F., additional, Negroni, A., additional, Morelli, P., additional, Casciaro, R., additional, Segata, N., additional, and Mengoni, A., additional
Published: 2019
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25. P072 Taxonomic and functional microbial signatures of cystic fibrosis lung disease

Author: Bacci, G., primary, Armanini, F., additional, Taccetti, G., additional, Lucidi, V., additional, Dolce, D., additional, Fiscarelli, E., additional, Negroni, A., additional, Morelli, P., additional, Casciaro, R., additional, Segata, N., additional, Mengoni, A., additional, and Bevivino, A., additional
Published: 2018
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26. Machine Learning Leveraging Genomes from Metagenomes Identifies Influential Antibiotic Resistance Genes in the Infant Gut Microbiome.

Author: Segata, N, Rahman, SF, Olm, MR, Morowitz, MJ, Banfield, JF, Segata, N, Rahman, SF, Olm, MR, Morowitz, MJ, and Banfield, JF
Abstract: Antibiotic resistance in pathogens is extensively studied, and yet little is known about how antibiotic resistance genes of typical gut bacteria influence microbiome dynamics. Here, we leveraged genomes from metagenomes to investigate how genes of the premature infant gut resistome correspond to the ability of bacteria to survive under certain environmental and clinical conditions. We found that formula feeding impacts the resistome. Random forest models corroborated by statistical tests revealed that the gut resistome of formula-fed infants is enriched in class D beta-lactamase genes. Interestingly, Clostridium difficile strains harboring this gene are at higher abundance in formula-fed infants than C. difficile strains lacking this gene. Organisms with genes for major facilitator superfamily drug efflux pumps have higher replication rates under all conditions, even in the absence of antibiotic therapy. Using a machine learning approach, we identified genes that are predictive of an organism's direction of change in relative abundance after administration of vancomycin and cephalosporin antibiotics. The most accurate results were obtained by reducing annotated genomic data to five principal components classified by boosted decision trees. Among the genes involved in predicting whether an organism increased in relative abundance after treatment are those that encode subclass B2 beta-lactamases and transcriptional regulators of vancomycin resistance. This demonstrates that machine learning applied to genome-resolved metagenomics data can identify key genes for survival after antibiotics treatment and predict how organisms in the gut microbiome will respond to antibiotic administration. IMPORTANCE The process of reconstructing genomes from environmental sequence data (genome-resolved metagenomics) allows unique insight into microbial systems. We apply this technique to investigate how the antibiotic resistance genes of bacteria affect their ability to flourish in the
Published: 2018

27. Dating the impossible: the origin and divergence of the largest infection on Earth

Author: Drago, F., Scholz, M., Segata, N., and Rota Stabelli, O.
Subjects: Settore BIO/18 - GENETICA
Published: 2017

28. Pangenome-based computational metagenomic profiling enables strain-level culture-free epidemiology and population genomics studies

Author: Scholz, M.U., Ward, D.V., Pasolli, E., Tolio, T., Zolfo, M., Asnicar, F., Truong, D.T., Tett, A., Morrow, L.A., and Segata, N.
Subjects: Pangenome, Epidemiology, Settore BIO/18 - GENETICA, Metagenomics, Strain-level metagenomics, Population genomics, Metatranscriptomics
Published: 2016

29. The metagenomics and metadesign of the subways and Urban biomes (MetaSUB) international consortium inaugural meeting report

Author: Afshinnekoo, E, Ahsanuddin, S, Ghedin, E, Read, T, Fraser, C, Dudley, J, Bowler, C, Mason, CE, Chernomoretz, A, Stolovitzky, G, Łabaj, PP, Graf, AB, Darling, A, Burke, C, Noushmehr, H, Dias-Neto, E, Guo, Y, Xie, Z, Lee, PKH, Shi, L, Ruiz-Perez, CA, Zambrano, MM, Siam, R, Ouf, A, Richard, H, Lafontaine, I, Wieler, LH, Semmler, T, Prithiviraj, B, Nedunuri, N, Mehr, S, Banihashemi, K, Lista, F, Anselmo, A, Suzuki, H, Kuroda, M, Yamashita, R, Sato, Y, Kaminuma, E, Aranda, CMA, Martinez, J, Dada, C, Dybwad, M, Oliveira, M, Schuster, S, Siwo, GH, Jang, S, Seo, SC, Hwang, SH, Ossowski, S, Bezdan, D, Chaker, S, Chatziefthimiou, AD, Udekwu, K, Liungdahl, P, Sezerman, U, Meydan, C, Elhaik, E, Gonnet, G, Schriml, LM, Mongodin, E, Huttenhower, C, Gilbert, J, Eisen, J, Hirschberg, D, Hernandez, M, McGrath, K, McGrath, L, Gray, A, Osuolale, O, Segata, N, Fillo, S, Iraola, G, Zhou, Y, Chang, Y, Li, Y, Zhend, Y, Hou, W, Ramirez, A, Cepeda, M, Desnues, C, Rascovan, N, Baron, C, Nagarajan, N, Ercolini, D, Menary, W, Tighe, S, Donia, M, Levy, S, Benito, J, Jones, A, Kasarskis, A, Maritz, J, Jorgensen, E, Neches, R, Livelli, T, Barnetche, JM, Pasolli, E, Greenfield, N, and Hasan, N
Subjects: Research Design, Databases, Genetic, Humans, Public Health, Metagenomics, City Planning, Ecosystem
Abstract: © 2016 The MetaSUB International Consortium. The Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) International Consortium is a novel, interdisciplinary initiative comprised of experts across many fields, including genomics, data analysis, engineering, public health, and architecture. The ultimate goal of the MetaSUB Consortium is to improve city utilization and planning through the detection, measurement, and design of metagenomics within urban environments. Although continual measures occur for temperature, air pressure, weather, and human activity, including longitudinal, cross-kingdom ecosystem dynamics can alter and improve the design of cities. The MetaSUB Consortium is aiding these efforts by developing and testing metagenomic methods and standards, including optimized methods for sample collection, DNA/RNA isolation, taxa characterization, and data visualization. The data produced by the consortium can aid city planners, public health officials, and architectural designers. In addition, the study will continue to lead to the discovery of new species, global maps of antimicrobial resistance (AMR) markers, and novel biosynthetic gene clusters (BGCs). Finally, we note that engineered metagenomic ecosystems can help enable more responsive, safer, and quantified cities.
Published: 2016

30. WS03.2 Longitudinal metagenomic analysis of the airways of patients with cystic fibrosis to uncover microbial signatures of lung disease progression

Author: Bacci, G., primary, Armanini, F., additional, Taccetti, G., additional, Lucidi, V., additional, Dolce, D., additional, Morelli, P., additional, Fiscarelli, E.V., additional, Segata, N., additional, Mengoni, A., additional, and Bevivino, A., additional
Published: 2017
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31. 101 Longitudinal study of methicillin-resistant Staphylococcus aureus genetic background isolated from cystic fibrosis patients

Author: Dolce, D., primary, Ravenni, N., additional, Campana, S., additional, Camera, E., additional, Neri, S., additional, Braggion, C., additional, Manara, S., additional, Pasolli, E., additional, Armanini, F., additional, Segata, N., additional, and Taccetti, G., additional
Published: 2017
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32. Building essential biodiversity variables (EBVs) of species distribution and abundance at a global scale

Author: Kissling, W.D., Ahumada, J.A., Bowser, A., Fernandez, M., Fernández, N., García, E.A., Guralnick, R.P., Isaac, N.J.B., Kelling, S., Los, W., McRae, L., Mihoub, Jean-Baptiste, Obst, M., Santamaria, M., Skidmore, A.K., Williams, K.J., Agosti, D., Amariles, D., Arvanitidis, C., Bastin, L., De Leo, F., Egloff, W., Elith, J., Hobern, D., Martin, D., Pereira, H.M., Pesole, G., Peterseil, J., Saarenmaa, H., Schigel, D., Schmeller, Dirk Sven, Segata, N., Turak, E., Uhlir, P.F., Wee, B., Hardisty, A.R., Kissling, W.D., Ahumada, J.A., Bowser, A., Fernandez, M., Fernández, N., García, E.A., Guralnick, R.P., Isaac, N.J.B., Kelling, S., Los, W., McRae, L., Mihoub, Jean-Baptiste, Obst, M., Santamaria, M., Skidmore, A.K., Williams, K.J., Agosti, D., Amariles, D., Arvanitidis, C., Bastin, L., De Leo, F., Egloff, W., Elith, J., Hobern, D., Martin, D., Pereira, H.M., Pesole, G., Peterseil, J., Saarenmaa, H., Schigel, D., Schmeller, Dirk Sven, Segata, N., Turak, E., Uhlir, P.F., Wee, B., and Hardisty, A.R.
Abstract: Much biodiversity data is collected worldwide, but it remains challenging to assemble the scattered knowledge for assessing biodiversity status and trends. The concept of Essential Biodiversity Variables (EBVs) was introduced to structure biodiversity monitoring globally, and to harmonize and standardize biodiversity data from disparate sources to capture a minimum set of critical variables required to study, report and manage biodiversity change. Here, we assess the challenges of a ‘Big Data’ approach to building global EBV data products across taxa and spatiotemporal scales, focusing on species distribution and abundance. The majority of currently available data on species distributions derives from incidentally reported observations or from surveys where presence-only or presence–absence data are sampled repeatedly with standardized protocols. Most abundance data come from opportunistic population counts or from population time series using standardized protocols (e.g. repeated surveys of the same population from single or multiple sites). Enormous complexity exists in integrating these heterogeneous, multi-source data sets across space, time, taxa and different sampling methods. Integration of such data into global EBV data products requires correcting biases introduced by imperfect detection and varying sampling effort, dealing with different spatial resolution and extents, harmonizing measurement units from different data sources or sampling methods, applying statistical tools and models for spatial inter- or extrapolation, and quantifying sources of uncertainty and errors in data and models. To support the development of EBVs by the Group on Earth Observations Biodiversity Observation Network (GEO BON), we identify 11 key workflow steps that will operationalize the process of building EBV data products within and across research infrastructures worldwide. These workflow steps take multiple sequential activities into account, including identification and aggre
Published: 2017

33. 99 Investigating the airway microbiome in cystic fibrosis patients with normal and severe pulmonary function decline: an opportunity for a personalized microbiome-based therapy

Author: Bacci, G., primary, Paganin, P., additional, Segata, N., additional, Armanini, F., additional, Taccetti, G., additional, Dolce, D., additional, Alessandri, A. De, additional, Morelli, P., additional, Tuccio, V., additional, Fiscarelli, E.V., additional, Lucidi, V., additional, Mengoni, A., additional, and Bevivino, A., additional
Published: 2016
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34. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis

Author: Scher, JU, Sczesnak, A, Longman, RS, Segata, N, Ubeda, C, Bielski, C, Rostron, T, Cerundolo, V, Pamer, EG, Abramson, SB, Huttenhower, C, and Littman, DR
Abstract: Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease, caused by a combination of genetic and environmental factors. Animal models suggest a role for intestinal bacteria in supporting the systemic immune response required for joint inflammation. Here we performed 16S sequencing on 114 stool samples from rheumatoid arthritis patients and controls, and shotgun sequencing on a subset of 44 such samples. We identified the presence of Prevotella copri as strongly correlated with disease in new-onset untreated rheumatoid arthritis (NORA) patients. Increases in Prevotella abundance correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in NORA subjects. We also identified unique Prevotella genes that correlated with disease. Further, colonization of mice revealed the ability of P. copri to dominate the intestinal microbiota and resulted in an increased sensitivity to chemically induced colitis. This work identifies a potential role for P. copri in the pathogenesis of RA. © Scher et al.
Published: 2013

35. Towards the integration of computational systems biology and high-throughput data: supporting differential analysis of microarray gene expression data

Author: Segata Nicola, Blanzieri Enrico, and Priami Corrado
Subjects: Biotechnology, TP248.13-248.65
Abstract: The paradigmatic shift occurred in biology that led first to high-throughput experimental techniques and later to computational systems biology must be applied also to the analysis paradigm of the relation between local models and data to obtain an effective prediction tool. In this work we introduce a unifying notational framework for systems biology models and high-throughput data in order to allow new integrations on the systemic scale like the use of in silico predictions to support the mining of gene expression datasets. Using the framework, we propose two applications concerning the use of system level models to support the differential analysis of microarray expression data. We tested the potentialities of the approach with a specific microarray experiment on the phosphate system in Saccharomyces cerevisiae and a computational model of the PHO pathway that supports the systems biology concepts.
Published: 2008
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36. Fast and scalable Local Kernel machines

Author: Segata, N. and Enrico Blanzieri

37. Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment

Author: Andrew Maltez Thomas, Aude Sirven, Filippo Pietrantonio, Romy Aarnoutse, Carlos Caldas, Sibille Everhard, Marine Fidelle, Valerio Iebba, Fanny Aprahamian, Stergios Christodoulidis, Sylvère Durand, Lisa Derosa, Sibylle Loibl, Janine Ziemons, François Ghiringhelli, Carsten Denkert, Suzette Delaloge, Nicola Segata, Edoardo Pasolli, Anne-Laure Martin, Nitharsshini Nirmalathasan, Safae Terrisse, Laurence Zitvogel, Fabrice Andre, Marjolein L. Smidt, Guido Kroemer, Ines Vaz-Luis, Bertrand Routy, Claudia Iglesias, Terrisse, Safae, Derosa, Lisa, Iebba, Valerio, Ghiringhelli, Françoi, Vaz-Luis, Ine, Kroemer, Guido, Fidelle, Marine, Christodoulidis, Stergio, Segata, Nicola, Thomas, Andrew Maltez, Martin, Anne-Laure, Sirven, Aude, Everhard, Sibille, Aprahamian, Fanny, Nirmalathasan, Nitharsshini, Aarnoutse, Romy, Smidt, Marjolein, Ziemons, Janine, Caldas, Carlo, Loibl, Sibylle, Denkert, Carsten, Durand, Sylvere, Iglesias, Claudia, Pietrantonio, Filippo, Routy, Bertrand, André, Fabrice, Pasolli, Edoardo, Delaloge, Suzette, Zitvogel, Laurence, Institut Gustave Roussy (IGR), Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique Biothérapie [Paris] (CICBT), Institut Curie [Paris], Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), University of Trento [Trento], Università degli studi di Trieste = University of Trieste, Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), Maastricht University [Maastricht], University of Cambridge [UK] (CAM), Goethe-University Frankfurt am Main, Philipps Universität Marburg = Philipps University of Marburg, IRCCS Istituto Nazionale dei Tumori [Milano], Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), University of Naples Federico II = Università degli studi di Napoli Federico II, ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Surgery, MUMC+: MA Heelkunde (9), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), University of Trieste, University of Naples Federico II, Ghiringhelli, François [0000-0002-5465-8305], Kroemer, Guido [0000-0002-9334-4405], Christodoulidis, Stergios [0000-0002-8773-1070], Segata, Nicola [0000-0002-1583-5794], Thomas, Andrew Maltez [0000-0001-5789-3354], Aarnoutse, Romy [0000-0002-8713-9747], Ziemons, Janine [0000-0002-4559-5488], Caldas, Carlos [0000-0003-3547-1489], Zitvogel, Laurence [0000-0003-1596-0998], Apollo - University of Cambridge Repository, Terrisse, S., Derosa, L., Iebba, V., Ghiringhelli, F., Vaz-Luis, I., Kroemer, G., Fidelle, M., Christodoulidis, S., Segata, N., Thomas, A. M., Martin, A. -L., Sirven, A., Everhard, S., Aprahamian, F., Nirmalathasan, N., Aarnoutse, R., Smidt, M., Ziemons, J., Caldas, C., Loibl, S., Denkert, C., Durand, S., Iglesias, C., Pietrantonio, F., Routy, B., Andre, F., Pasolli, E., Delaloge, S., and Zitvogel, L.
Subjects: Oncology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], GUT MICROBIOME, THERAPY, Breast cancer, Breast Neoplasms, Female, Gastrointestinal Microbiome, Humans, Prognosis, Prospective Studies, Treatment Outcome, TUMOR-INFILTRATING LYMPHOCYTES, Prospective cohort study, Cancer, Early breast cancer, Microbiota, ADENOSINE, SOLID TUMORS, Intestinal Microbiome, Immunotherapy, PATHOLOGISTS, Adjuvant, Shotgun metagenomics, medicine.medical_specialty, CARCINOMA, CANTO study, Article, Immune system, STANDARDIZED METHOD, Internal medicine, medicine, Chemotherapy, Clinical significance, metagenomic, IMMUNOTHERAPY, Molecular Biology, metagenomics, business.industry, neoadjuvant, Cell Biology, Translational research, EFFICACY, networks, network, business
Abstract: The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.
Published: 2021
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38. Neonatal antibiotic exposure impairs child growth during the first six years of life by perturbing intestinal microbial colonization

Author: Regina Ensenauer, Oren Ziv, Himanshu Kumar, Nicola Segata, Christina Kunz, Aia Oz, Hila Ben-Amram, Olli Turta, Helena Ollila, Anna Belogolovski, Hanna Lagström, Seppo Salminen, Itai Sharon, Hadar Neuman, Sarah Perschbacher, Yoram Louzoun, Anne Kaljonen, Samuli Rautava, Edoardo Pasolli, Omry Koren, Atara Uzan-Yulzari, Erika Isolauri, Uzan-Yulzari, A., Turta, O., Belogolovski, A., Ziv, O., Kunz, C., Perschbacher, S., Neuman, H., Pasolli, E., Oz, A., Ben-Amram, H., Kumar, H., Ollila, H., Kaljonen, A., Isolauri, E., Salminen, S., Lagstrom, H., Segata, N., Sharon, I., Louzoun, Y., Ensenauer, R., Rautava, S., Koren, O., Children's Hospital, University of Helsinki, HUS Children and Adolescents, and Helsinki University Hospital Area
Subjects: 0301 basic medicine, Male, Antibiotics, General Physics and Astronomy, Physiology, Body Mass Index, Feces, Mice, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Growth Disorder, Pregnancy, Risk Factors, Early childhood, Intestinal Mucosa, Child, Growth Disorders, 2. Zero hunger, Multidisciplinary, Confounding, Bacterial Infections, Fecal Microbiota Transplantation, 3. Good health, Anti-Bacterial Agents, Child, Preschool, Female, Human, medicine.drug_class, Science, Bacterial Infection, Article, General Biochemistry, Genetics and Molecular Biology, Follow-Up Studie, 03 medical and health sciences, Sex Factors, 030225 pediatrics, Anti-Bacterial Agent, medicine, Animals, Germ-Free Life, Humans, Microbiome, Preschool, Full Term, business.industry, Animal, Risk Factor, Body Weight, Infant, Newborn, Antibiotic exposure, Infant, General Chemistry, Newborn, Body Height, Gastrointestinal Microbiome, Disease Models, Animal, 030104 developmental biology, Follow-Up Studies, Disease Models, Fece, Metagenomics, business, Body mass index
Abstract: Exposure to antibiotics in the first days of life is thought to affect various physiological aspects of neonatal development. Here, we investigate the long-term impact of antibiotic treatment in the neonatal period and early childhood on child growth in an unselected birth cohort of 12,422 children born at full term. We find significant attenuation of weight and height gain during the first 6 years of life after neonatal antibiotic exposure in boys, but not in girls, after adjusting for potential confounders. In contrast, antibiotic use after the neonatal period but during the first 6 years of life is associated with significantly higher body mass index throughout the study period in both boys and girls. Neonatal antibiotic exposure is associated with significant differences in the gut microbiome, particularly in decreased abundance and diversity of fecal Bifidobacteria until 2 years of age. Finally, we demonstrate that fecal microbiota transplant from antibiotic-exposed children to germ-free male, but not female, mice results in significant growth impairment. Thus, we conclude that neonatal antibiotic exposure is associated with a long-term gut microbiome perturbation and may result in reduced growth in boys during the first six years of life while antibiotic use later in childhood is associated with increased body mass index., In this study, Omry Koren, Samuli Rautava and colleagues report a sex-specific association between neonatal antibiotic exposure and weight and height gain during the first six years of life and showing that boys but not girls exposed to neonatal antibiotics exhibit impaired weight and height development.
Published: 2021

39. Lung and Gut Microbiota Changes Associated with Pseudomonas aeruginosa Infection in Mouse Models of Cystic Fibrosis

Author: Federica Armanini, Nicola Segata, Alessandra Bragonzi, Alessio Mengoni, Giovanni Bacci, Annamaria Bevivino, Alice Rossi, Lisa Cangioli, Ida De Fino, Bacci, G., Rossi, A., Armanini, F., Cangioli, L., De Fino, I., Segata, N., Mengoni, A., Bragonzi, A., and Bevivino, A.
Subjects: Cystic Fibrosis Transmembrane Conductance Regulator, microbiome, Gut flora, medicine.disease_cause, Cystic fibrosis, cystic fibrosis, Feces, Mice, RNA, Ribosomal, 16S, Genotype, Biology (General), Spectroscopy, Principal Component Analysis, Microbiota, digestive, oral, and skin physiology, General Medicine, respiratory system, animal models, Computer Science Applications, Chemistry, medicine.anatomical_structure, Pseudomonas aeruginosa, gut, Persistent Infection, Animal models, CFTR mice, Gut, Gut‐lung axis, Lung, Microbiome, Animals, Body Weight, Cystic Fibrosis, Disease Models, Animal, Dysbiosis, Gastrointestinal Tract, Pseudomonas Infections, QH301-705.5, Biology, digestive system, Article, Catalysis, Microbiology, lung, Inorganic Chemistry, gut-lung axis, medicine, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, Organic Chemistry, medicine.disease, biology.organism_classification, respiratory tract diseases, Chronic infection
Abstract: Cystic fibrosis (CF) disease leads to altered lung and gut microbiomes compared to healthy subjects. The magnitude of this dysbiosis is influenced by organ-specific microenvironmental conditions at different stages of the disease. However, how this gut-lung dysbiosis is influenced by Pseudomonas aeruginosa chronic infection is unclear. To test the relationship between CFTR dysfunction and gut-lung microbiome under chronic infection, we established a model of P. aeruginosa infection in wild-type (WT) and gut-corrected CF mice. Using 16S ribosomal RNA gene, we compared lung, stool, and gut microbiota of C57Bl/6 Cftr tm1UNCTgN(FABPCFTR) or WT mice at the naïve state or infected with P. aeruginosa.&nbsp, P. aeruginosa infection influences murine health significantly changing body weight both in CF and WT mice. Both stool and gut microbiota revealed significantly higher values of alpha diversity in WT mice than in CF mice, while lung microbiota showed similar values. Infection with P. aeruginosa did not changed the diversity of the stool and gut microbiota, while a drop of diversity of the lung microbiota was observed compared to non-infected mice.However, the taxonomic composition of gut microbiota was shown to be influenced by P. aeruginosa infection in CF mice but not in WT mice. This finding indicates that P. aeruginosa chronic infection has a major impact on microbiota diversity and composition in the lung. In the gut, CFTR genotype and P. aeruginosa infection affected the overall diversity and taxonomic microbiota composition, respectively. Overall, our results suggest a cross-talk between lung and gut microbiota in relation to P. aeruginosa chronic infection and CFTR mutation.
Published: 2021
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40. Multifaceted modes of action of the anticancer probiotic Enterococcus hirae

Author: Marion Leduc, Didier Raoult, Laura Mondragón, Kristina Iribarren, Anne-Gaëlle Goubet, Diane Derrien, Satoru Yonekura, Noélie Bossut, Valerio Iebba, Nicola Segata, Guo Chen, Ivo G. Boneca, Lisa Derosa, Adrien Joseph, Fabrice Andre, Sylvère Durand, Aurélie Fluckiger, Maryam Tidjani Alou, Fanny Aprahamian, Richard J. Wheeler, Maryse Moya-Nilges, Eugenie Pizzato, Bo Qu, Guido Kroemer, Oliver Kepp, Nicolas Pons, Romain Daillère, Fabien Lemaitre, Laurence Zitvogel, Department of Radiology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France, Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Shanghai Jiao Tong University [Shanghai], Institut Gustave Roussy (IGR), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, UMR 1015 Immunologie des tumeurs et immunothérapie contre le cancer (ITIC), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris], MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Trento [Trento], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska University Hospital [Stockholm], Fondation pour la Recherche Médicale, Ligue contre le Cancer (équipes labellisées), Leducq Foundation, Seerave Foundation, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC Cancer Research and Personalized Medicine (CARPEM), Fondation ARC pour la Recherche sur le Cancer, Région Ile-de-France, Chancellerie des universités de Paris (Legs Poix), FRM, European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR), Gustave Roussy Odyssea, Fondation Carrefour, High-end Foreign Expert Program in China: GDW20171100085 and GDW20181100051, Institut National du Cancer (INCA) France, Inserm (HTE), Institut Universitaire de France, ANR-10-COHO-0004,CANTO,Etude des toxicités chroniques des traitements anticancéreux chez les patientes porteuses cancer(2010), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 680969,H2020,H2020-HCO-2015,ERA-CVD(2015), European Project: 825410, H2020-EU.3.1., H2020-EU.3.1.2.,ONCOBIOME (2019), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Ligue Nationale Contre le Cancer (LNCC), Institut Pasteur [Paris] (IP), Université Paris Cité (UPCité), Goubet, A. -G., Wheeler, R., Fluckiger, A., Qu, B., Lemaitre, F., Iribarren, K., Mondragon, L., Tidjani Alou, M., Pizzato, E., Durand, S., Derosa, L., Aprahamian, F., Bossut, N., Moya-Nilges, M., Derrien, D., Chen, G., Leduc, M., Joseph, A., Pons, N., Le Chatelier, E., Segata, N., Yonekura, S., Iebba, V., Kepp, O., Raoult, D., Andre, F., Kroemer, G., Boneca, I. G., Zitvogel, L., Daillere, R., Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), Université Paris Cité (UPC), Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay, Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), and European Project: 825410,ONCOBIOME
Subjects: 0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], microbiome, law.invention, Probiotic, Mice, 0302 clinical medicine, Cancer immunotherapy, Enterococcus hirae, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Neoplasms, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, CD137, 3. Good health, Bifidobacterium animalis, Anti-Bacterial Agents, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, immunotherapy, Immunotherapy, microbiota, cancer, tumor, probiotic, intratumoral IFNγ, Biology, Article, Microbiology, 03 medical and health sciences, Memory T Cells, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Microbiome, Molecular Biology, Probiotics, Autophagy, Cell Biology, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, Dysbiosis
Abstract: International audience; A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFN gamma-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.
Published: 2021
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41. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade

Author: Carolina Alves Costa Silva, Deborah Lefevre, Lisa Derosa, Claudia Grajeda-Iglesias, Gladys Ferrere, Maryam Tidjani Alou, Anne-Gaëlle Goubet, Fanny Aprahamian, Conrad Rauber, Didier Raoult, Aurélie Fluckiger, Monica Arnedos, Damien Drubay, Romain Daillère, Cassandra Thelemaque, Tim D. Spector, Sylvère Durand, Liwei Zhao, Guido Kroemer, Emeline Colomba, Oliver Kepp, Valerio Iebba, Laurence Zitvogel, Nicola Segata, Francesco Asnicar, Marine Fidelle, Peng Liu, Bernhard Ryffel, Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Università degli studi di Trieste = University of Trieste, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Oncologie gynécologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pathologie mammaire, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], King‘s College London, Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, Ferrere, G., Alou, M. T., Liu, P., Goubet, A. -G., Fidelle, M., Kepp, O., Durand, S., Iebba, V., Fluckiger, A., Daillere, R., Thelemaque, C., Grajeda-Iglesias, C., Silva, C. A. C., Aprahamian, F., Lefevre, D., Zhao, L., Ryffel, B., Colomba, E., Arnedos, M., Drubay, D., Rauber, C., Raoult, D., Asnicar, F., Spector, T., Segata, N., Derosa, L., Kroemer, G., Zitvogel, L., Gestionnaire, Hal Sorbonne Université, LUMIERE - - LUMIERE2016 - ANR-16-RHUS-0008 - RHUS - VALID, European Union’s Horizon 2020 research and innovation programme under grant agreement. - ONCOBIOME - 825410 - INCOMING, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), University of Trieste, Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Ketogenic, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Programmed Cell Death 1 Receptor, Cancer, Immunotherapy, Metabolism, Mouse models, Oncology, 3-Hydroxybutyric Acid, Animals, CTLA-4 Antigen, Cell Line, Tumor, Combined Modality Therapy, Female, Gastrointestinal Microbiome, Humans, Immune Checkpoint Inhibitors, Ketone Bodies, Kidney Neoplasms, Melanoma, Experimental, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, Receptors, G-Protein-Coupled, Diet, Ketogenic, Pharmacology, CXCR3, Inbred C57BL, 0302 clinical medicine, Neoplasms, Ketogenesis, Receptors, Ketone Bodie, Melanoma, Inbred BALB C, Tumor, Chemistry, Kidney Neoplasm, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], Immunosurveillance, 030220 oncology & carcinogenesis, Ketone bodies, Medicine, Human, Research Article, Immune Checkpoint Inhibitor, Mouse model, Cell Line, 03 medical and health sciences, Experimental, G-Protein-Coupled, Downregulation and upregulation, medicine, Animal, Immune checkpoint, Diet, 030104 developmental biology, Ketogenic diet
Abstract: International audience; Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.
Published: 2021
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42. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage

Author: Fathia Mami-Chouaib, Vincent Cattoir, Guido Kroemer, Mohamed Sassi, Krisztián Papp, Nathalie Labarrière, Valerio Iebba, Valentin Quiniou, Romain Boidot, Zsofia Sztupinszki, Nicola Segata, Ivo G. Boneca, Friedemann Loos, Sylvain Simon, Jacques Bou-Khalil, Richard J. Wheeler, Carlos López-Otín, Andréanne Gagné, Luisa De Sordi, Barbara S. Sixt, Philippe Joubert, Clara-Maria Scarlata, Fabien Lemaitre, Peng Liu, Laurent Debarbieux, Alexander M.M. Eggermont, Paola Nisticò, Didier Raoult, David Klatzmann, Connie P.M. Duong, Belinda Palermo, Lisa Derosa, Maha Ayyoub, Maryam Tidjani Alou, Meriem Messaoudene, B. Escudier, François Ghiringhelli, Aurélie Fluckiger, Gladys Ferrere, Saber Khelaifia, Bertrand Routy, Laurence Albiges, Edoardo Pasolli, Anne Gaëlle Goubet, Zoltan Szallasi, Romain Daillère, István Csabai, Laurence Zitvogel, Fabrice Andre, Francesco Facciolo, Corentin Richard, Catherine Rabu, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Umeå University, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre d'oncologie et de radiothérapie du parc [Dijon], Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), Institut Pasteur [Paris] (IP), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Cancer Institute Regina Elena [Rome, Italy], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Eötvös Loránd University (ELTE), University of Trento [Trento], Universidad de Oviedo [Oviedo], Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Centre National de Référence de la Résistance aux Antibiotiques [CHU Rennes] (CNR), CHU Pontchaillou [Rennes], Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), ANR-19-CE15-0029,Ileobiome,Régulation des réponses immunitaires iléales dans l'immunosurveillance du cancer du colon: rôle du microbiote et des antigènes des cellules souches.(2019), Bernardo, Elizabeth, École pratique des hautes études (EPHE), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Genetic and Immunology Medical Institute (GIMI), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut Pasteur [Paris], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Centre d’Investigation Clinique intégré en Biothérapies et immunologie [AP-HP pitié-salpêtrière, Paris] (CIC-BTi), CHU Pitié-Salpêtrière [AP-HP], Fluckiger, A., Daillere, R., Sassi, M., Sixt, B. S., Liu, P., Loos, F., Richard, C., Rabu, C., Alou, M. T., Goubet, A. -G., Lemaitre, F., Ferrere, G., Derosa, L., Duong, C. P. M., Messaoudene, M., Gagne, A., Joubert, P., De Sordi, L., Debarbieux, L., Simon, S., Scarlata, C. -M., Ayyoub, M., Palermo, B., Facciolo, F., Boidot, R., Wheeler, R., Boneca, I. G., Sztupinszki, Z., Papp, K., Csabai, I., Pasolli, E., Segata, N., Lopez-Otin, C., Szallasi, Z., Andre, F., Iebba, V., Quiniou, V., Klatzmann, D., Boukhalil, J., Khelaifia, S., Raoult, D., Albiges, L., Escudier, B., Eggermont, A., Mami-Chouaib, F., Nistico, P., Ghiringhelli, F., Routy, B., Labarriere, N., Cattoir, V., Kroemer, G., Zitvogel, L., and de Sordi, L.
Subjects: H-2 Antigen, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, Epitope, Epitopes, Feces, Mice, 0302 clinical medicine, Enterococcus hirae, Neoplasms, Monoclonal, Bacteriophages, 0303 health sciences, Multidisciplinary, biology, Antibodies, Monoclonal, Viral Tail Proteins, Alkylating, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cross Reaction, Immunotherapy, Human, T cell, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cross Reactions, Major histocompatibility complex, Antibodies, Microbiology, 03 medical and health sciences, Animals, Antigens, Neoplasm, Antineoplastic Agents, Alkylating, Cyclophosphamide, Gastrointestinal Microbiome, H-2 Antigens, Histocompatibility Antigens Class I, Humans, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, MHC class I, medicine, Antigens, Bacteriophage, Prophage, 030304 developmental biology, Animal, CD8-Positive T-Lymphocyte, biology.organism_classification, biology.protein, Neoplasm, Fece, CD8
Abstract: International audience; Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb-restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
Published: 2020
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43. Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients

Author: Conrad Rauber, Gladys Ferrere, Jean-Eudes Fahrner, Valerio Iebba, Nicolas Pons, Romain Daillère, Emmanuelle Le Chatellier, Hugo Roume, Filippo Pietrantonio, Nicola Segata, Marine Fidelle, Anne-Gaëlle Goubet, Carolina Alves Costa Silva, Bertrand Routy, Connie P.M. Duong, Karim Fizazi, Edoardo Pasolli, Safae Terrisse, Beatrice Casu, Laurence Albiges, Bernard Escudier, Mélodie Bonvalet, Maryam Tidjani Alou, Laurie Alla, Kristina Iribarren, Didier Raoult, Aude Desnoyer, Guido Kroemer, Lisa Derosa, Laura Mondragón, Nathalie Galleron, Anna Reni, Fabien Lemaitre, Laurence Zitvogel, Derosa, L., Routy, B., Fidelle, M., Iebba, V., Alla, L., Pasolli, E., Segata, N., Desnoyer, A., Pietrantonio, F., Ferrere, G., Fahrner, J. -E., Le Chatellier, E., Pons, N., Galleron, N., Roume, H., Duong, C. P. M., Mondragon, L., Iribarren, K., Bonvalet, M., Terrisse, S., Rauber, C., Goubet, A. -G., Daillere, R., Lemaitre, F., Reni, A., Casu, B., Alou, M. T., Alves Costa Silva, C., Raoult, D., Fizazi, K., Escudier, B., Kroemer, G., Albiges, L., Zitvogel, L., Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Université Paris-Saclay, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Naples Federico II = Università degli studi di Napoli Federico II, Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), IRCCS Istituto Nazionale dei Tumori [Milano], Université Paris-Sud - Paris 11 (UP11), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Suzhou Institute of Systems Medicine [Jiangsu, P.R. China], Karolinska University Hospital [Stockholm], Philanthropia Foundation ESMO translational research fellowship Fonds de la Recherche en Sante du Quebec Kidney Cancer Research Network of Canada Ligue nationale contre le cancerFrench National Research Agency (ANR)French National Research Agency (ANR)ERA-Net for Research on Rare Diseases Fondation ARC pour la Recherche sur le CancerRegion Ile-de-France Fondation de FranceFondation pour la Recherche MedicaleEuropean Commission Joint Research CentreEuropean Research Council (ERC)Fondation Carrefour, High-end Foreign Expert Program in China GDW20171100085 GDW20181100051Institut National du Cancer (INCA) FranceInserm (HTE) Institut Universitaire de France Leducq FoundationSearave and Carrefour Foundation SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE 2.0) BMS Foundation SIRIC Cancer Research and Personalized Medicine (CARPEM) Paris Alliance of Cancer Research Institutes (PACRI) Mediterranee Infection 10-IAHU-03Region Provence-Alpes-Cote d'AzurNational Research, Development and Innovation Fund of Hungary FIEK_16-1-20160005Research and Technology Innovation Fund NAP2-2017-1.2.1-NKP-0002Breast Cancer Research Foundation BCRF-17-156Novo Nordisk Foundation Interdisciplinary Synergy Program Grant NNF15OC0016584, ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, University of Naples Federico II, Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Gustave Roussy Cancer Campus (GRCC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Saclay, Université Paris-Sud [Le Kremlin-Bicêtre] (Faculté de Médecine), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Centre d’Investigation Clinique en Biothérapies [CHU Pitié-Salpêtrière] (CIC-BT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université Paris-Saclay, Faculté de Pharmacie, 92290 Châtenay-Malabry, France, MetaGenoPolis, European Institute of Oncology [Milan] (ESMO), Gustave Roussy Cancer Campus, Partenaires INRAE, Chinese Academy of Medical Sciences, Philanthropia Foundation ESMO translational research fellowship.Fonds de la Recherche en Sante du Quebec Kidney Cancer Research Network of CanadaLigue nationale contre le cancerFrench National Research Agency (ANR) ERA-Net for Research on Rare DiseasesFondation ARC pour la Recherche sur le CancerRegion Ile-de-FranceFondation de FranceFondation pour la Recherche MedicaleEuropean Commission Joint ResearchCentre European Research Council (ERC)Fondation Carrefour, and High-end Foreign Expert Program in China GDW20171100085 GDW20181100051Institut National du Cancer (INCA) France Inserm (HTE) Institut Universitaire de FranceLeducq FoundationSearave and Carrefour Foundation SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE 2.0) BMS Foundation SIRIC Cancer Research and Personalized Medicine (CARPEM) Paris Alliance of Cancer Research Institutes (PACRI)Mediterranee Infection 10-IAHU-03Region Provence-Alpes-Cote d'AzurNational Research, Development and Innovation Fund of Hungary FIEK_16-1-20160005Research and Technology Innovation Fund NAP2-2017-1.2.1-NKP-0002Breast Cancer Research Foundation BCRF-17-156Novo Nordisk Foundation Interdisciplinary Synergy Program Grant NNF15OC0016584
Subjects: Oncology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Antibiotics, 030232 urology & nephrology, Tyrosine kinase inhibitor, Immune checkpoint inhibitor, Tyrosine-kinase inhibitor, Feces, Mice, 0302 clinical medicine, Cancer immunotherapy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Renal cell carcinoma, Prospective Studies, Immune Checkpoint Inhibitors, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Microbiota, Kidney cancer, Kidney Neoplasms, 3. Good health, Nivolumab, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, medicine.medical_specialty, medicine.drug_class, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Predictive Value of Tests, Internal medicine, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Carcinoma, Renal Cell, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, business.industry, Antibiotic, Immunotherapy, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Immune checkpoint, Gastrointestinal Microbiome, Drug Resistance, Neoplasm, business
Abstract: Background: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC. Objective: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients. Design, setting, and participants: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed. Outcome measurements and statistical analysis: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients’ therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors. Results and limitations: Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae). Conclusions: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers. Patient summary: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy. Antibiotics prior to immune checkpoint inhibitors have a deleterious clinical impact, reduce the microbiome diversity, and increase Clostridium hathewayi bacteria associated with resistance. Higher baseline microbiome diversity and Akkermansia muciniphila are associated with longer progression-free survival. In murine fecal microbiome transplantation experiments, A. muciniphila can restore the anticancer activity of the combination of anti–PD-1 and CTLA-4.
Published: 2020
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44. Precise phylogenetic analysis of microbial isolates and genomes from metagenomes using PhyloPhlAn 3.0

Author: Edoardo Pasolli, Fabio Cumbo, Rob Knight, Qiyun Zhu, Serena Manara, Uyen May, Siavash Mirarab, Moreno Zolfo, Andrew Maltez Thomas, Paolo Manghi, Evguenia Kopylova, Nicola Segata, Claudia Mengoni, Francesco Asnicar, Francesco Beghini, Mattia Bolzan, Curtis Huttenhower, Jon G. Sanders, Asnicar, F., Thomas, A. M., Beghini, F., Mengoni, C., Manara, S., Manghi, P., Zhu, Q., Bolzan, M., Cumbo, F., May, U., Sanders, J. G., Zolfo, M., Kopylova, E., Pasolli, E., Knight, R., Mirarab, S., Huttenhower, C., and Segata, N.
Subjects: 0301 basic medicine, Microbial Genomes, Classification and taxonomy, Science, 030106 microbiology, General Physics and Astronomy, Computational biology, Biology, Genome, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Metagenomic, Phylogenetics, Bacterial genetics, lcsh:Science, Clade, Phylogeny, Multidisciplinary, Phylogenetic tree, Bacteria, Phylum, General Chemistry, Genome, Microbial, 030104 developmental biology, Metagenomics, Metagenome, lcsh:Q, Microbial genome, Software, Genome, Bacterial
Abstract: Microbial genomes are available at an ever-increasing pace, as cultivation and sequencing become cheaper and obtaining metagenome-assembled genomes (MAGs) becomes more effective. Phylogenetic placement methods to contextualize hundreds of thousands of genomes must thus be efficiently scalable and sensitive from closely related strains to divergent phyla. We present PhyloPhlAn 3.0, an accurate, rapid, and easy-to-use method for large-scale microbial genome characterization and phylogenetic analysis at multiple levels of resolution. PhyloPhlAn 3.0 can assign genomes from isolate sequencing or MAGs to species-level genome bins built from >230,000 publically available sequences. For individual clades of interest, it reconstructs strain-level phylogenies from among the closest species using clade-specific maximally informative markers. At the other extreme of resolution, it scales to large phylogenies comprising >17,000 microbial species. Examples including Staphylococcus aureus isolates, gut metagenomes, and meta-analyses demonstrate the ability of PhyloPhlAn 3.0 to support genomic and metagenomic analyses., The increasing amount of sequenced microbial genomes and metagenomes requires platforms for efficient integrated analysis. Here, Asnicar et al. present PhyloPhlAn 3.0, a pipeline allowing large-scale microbial genome characterization and phylogenetic contextualization at multiple levels of resolution.
Published: 2020

45. Untargeted metagenomic investigation of the airway microbiome of cystic fibrosis patients with moderate-severe lung disease

Author: P. Morelli, Federica Armanini, Giovanni Bacci, Nicola Segata, Vincenzina Lucidi, Annamaria Bevivino, Rosaria Casciaro, Daniela Dolce, Francesca Di Cesare, Alessio Mengoni, Ersilia Fiscarelli, Giovanni Taccetti, Anna Negroni, Bacci, G., Taccetti, G., Dolce, D., Armanini, F., Segata, N., Di Cesare, F., Lucidi, V., Fiscarelli, E., Morelli, P., Casciaro, R., Negroni, A., Mengoni, A., and Bevivino, A.
Subjects: 0301 basic medicine, Microbiology (medical), Lung microbiome, Metagenome composition, Biology, Microbiology, Cystic fibrosis, Article, cystic fibrosis, metagenome composition, 03 medical and health sciences, antibiotic resistance genes, 0302 clinical medicine, Antibiotic resistance genes, Virology, airway microbiome, medicine, Colonization, Microbiome, lcsh:QH301-705.5, Lung, medicine.disease, Metagenomics, microbiome, Cystic Fibrosis, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), 030228 respiratory system, Metagenomics, Cohort, Immunology, Sputum, Airway microbiome, medicine.symptom
Abstract: Although the cystic fibrosis (CF) lung microbiota has been characterized in several studies, little is still known about the temporal changes occurring at the whole microbiome level using untargeted metagenomic analysis. The aim of this study was to investigate the taxonomic and functional temporal dynamics of the lower airway microbiome in a cohort of CF patients. Multiple sputum samples were collected over 15 months from 22 patients with advanced lung disease regularly attending three Italian CF Centers, given a total of 79 samples. DNA extracted from samples was subjected to shotgun metagenomic sequencing allowing both strain-level taxonomic profiling and assessment of the functional metagenomic repertoire. High inter-patient taxonomic heterogeneity was found with short-term compositional changes across clinical status. Each patient exhibited distinct sputum microbial communities at the taxonomic level, and strain-specific colonization of both traditional and atypical CF pathogens. A large core set of genes, including antibiotic resistance genes, were shared across patients despite observed differences in clinical status, and consistently detected in the lung microbiome of all subjects independently from known antibiotic exposure. In conclusion, an overall stability in the microbiome-associated genes was found despite taxonomic fluctuations of the communities.
Published: 2020

46. Microbial genomes from non-human primate gut metagenomes expand the primate-associated bacterial tree of life with over 1000 novel species

Author: Serena Manara, Fabio Cumbo, Edoardo Pasolli, Eleonora Nigro, Francesco Beghini, Paolo Manghi, Nicolai Karcher, Marisa Isabell Metzger, Nicola Segata, Francesco Asnicar, Davide Bazzani, Moreno Zolfo, Manara, S., Asnicar, F., Beghini, F., Bazzani, D., Cumbo, F., Zolfo, M., Nigro, E., Karcher, N., Manghi, P., Metzger, M. I., Pasolli, E., and Segata, N.
Subjects: Primates, lcsh:QH426-470, Genome, 03 medical and health sciences, 0302 clinical medicine, Symbiosis, Genetic algorithm, Metagenomic assembly, Animals, Humans, Treponema, Microbiome, Microbiome sharing, lcsh:QH301-705.5, Phylogeny, 030304 developmental biology, Host-microbiome coevolution, 0303 health sciences, biology, Animal, Primate, Research, Human microbiome, biology.organism_classification, Metagenomic assembly Non-human primates microbiome Microbiome sharing Host-microbiome coevolution, Human genetics, Gastrointestinal Microbiome, Elusimicrobia, lcsh:Genetics, lcsh:Biology (General), Metagenomics, Evolutionary biology, Non-human primates microbiome, Metagenome, 030217 neurology & neurosurgery, Human
Abstract: Background Humans have coevolved with microbial communities to establish a mutually advantageous relationship that is still poorly characterized and can provide a better understanding of the human microbiome. Comparative metagenomic analysis of human and non-human primate (NHP) microbiomes offers a promising approach to study this symbiosis. Very few microbial species have been characterized in NHP microbiomes due to their poor representation in the available cataloged microbial diversity, thus limiting the potential of such comparative approaches. Results We reconstruct over 1000 previously uncharacterized microbial species from 6 available NHP metagenomic cohorts, resulting in an increase of the mappable fraction of metagenomic reads by 600%. These novel species highlight that almost 90% of the microbial diversity associated with NHPs has been overlooked. Comparative analysis of this new catalog of taxa with the collection of over 150,000 genomes from human metagenomes points at a limited species-level overlap, with only 20% of microbial candidate species in NHPs also found in the human microbiome. This overlap occurs mainly between NHPs and non-Westernized human populations and NHPs living in captivity, suggesting that host lifestyle plays a role comparable to host speciation in shaping the primate intestinal microbiome. Several NHP-specific species are phylogenetically related to human-associated microbes, such as Elusimicrobia and Treponema, and could be the consequence of host-dependent evolutionary trajectories. Conclusions The newly reconstructed species greatly expand the microbial diversity associated with NHPs, thus enabling better interrogation of the primate microbiome and empowering in-depth human and non-human comparative and co-diversification studies.
Published: 2019

47. Uncovering oral Neisseria tropism and persistence using metagenomic sequencing

Author: Valerio Iebba, Nicola Segata, Claudio Donati, Francesco Asnicar, Moreno Zolfo, Davide Albanese, Olivier Jousson, Duy Tin Truong, Curtis Huttenhower, Duccio Cavalieri, Carlotta De Filippo, Donati, C, Zolfo, M, Albanese, D, Tin Truong, D, Asnicar, F, Iebba, Valerio, Cavalieri, D, Jousson, O, De Filippo, C, Huttenhower, C, and Segata, N.
Subjects: 0301 basic medicine, 030106 microbiology, Gingiva, Computational biology, Genome, Polymorphism, Single Nucleotide, Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA, Microbiology, Population genomics, immunology, 03 medical and health sciences, Computers, Molecular, Tongue, cell biology, applied microbiology and biotechnology, Humans, microbiology (medical), genetics, Microbiome, microbiology, Tropism, Phylogeny, Mouth, biology, Microbiota, Sequence Analysis, DNA, biology.organism_classification, Viral Tropism, 030104 developmental biology, Metagenomics, Multilocus sequence typing, Metagenome, Pharynx, Neisseria, Genome, Bacterial, Human Microbiome Project, Multilocus Sequence Typing
Abstract: Microbial epidemiology and population genomics have previously been carried out near-exclusively for organisms grown in vitro. Metagenomics helps to overcome this limitation, but it is still challenging to achieve strain-level characterization of microorganisms from culture-independent data with sufficient resolution for epidemiological modelling. Here, we have developed multiple complementary approaches that can be combined to profile and track individual microbial strains. To specifically profile highly recombinant neisseriae from oral metagenomes, we integrated four metagenomic analysis techniques: single nucleotide polymorphisms in the clade's core genome, DNA uptake sequence signatures, metagenomic multilocus sequence typing and strain-specific marker genes. We applied these tools to 520 oral metagenomes from the Human Microbiome Project, finding evidence of site tropism and temporal intra-subject strain retention. Although the opportunistic pathogen Neisseria meningitidis is enriched for colonization in the throat, N. flavescens and N. subflava populate the tongue dorsum, and N. sicca, N. mucosa and N. elongata the gingival plaque. The buccal mucosa appeared as an intermediate ecological niche between the plaque and the tongue. The resulting approaches to metagenomic strain profiling are generalizable and can be extended to other organisms and microbiomes across environments.
Published: 2016
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48. Large-scale genome-wide analysis links lactic acid bacteria from food with the gut microbiome

Author: Francesca De Filippis, Aaron M. Walsh, Danilo Ercolini, John Leech, Paul D. Cotter, Edoardo Pasolli, Nicola Segata, Fabio Cumbo, Italia E. Mauriello, Pasolli, E., De Filippis, F., Mauriello, I. E., Cumbo, F., Walsh, A. M., Leech, J., Cotter, P. D., Segata, N., and Ercolini, D.
Subjects: Primates, 0301 basic medicine, Streptococcus thermophilus, Science, 030106 microbiology, General Physics and Astronomy, Microbial communities, Biology, Microbiology, Genome, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Lactobacillales, Databases, Genetic, Animals, Humans, Food microbiology, Food science, Microbiome, lcsh:Science, Life Style, Multidisciplinary, Ecology, business.industry, Probiotics, Lactococcus lactis, digestive, oral, and skin physiology, food and beverages, General Chemistry, biology.organism_classification, Gastrointestinal Microbiome, 030104 developmental biology, Metagenomics, Food Microbiology, Food processing, Metagenome, lcsh:Q, Fermented Foods, business, Bacteria
Abstract: Lactic acid bacteria (LAB) are fundamental in the production of fermented foods and several strains are regarded as probiotics. Large quantities of live LAB are consumed within fermented foods, but it is not yet known to what extent the LAB we ingest become members of the gut microbiome. By analysis of 9445 metagenomes from human samples, we demonstrate that the prevalence and abundance of LAB species in stool samples is generally low and linked to age, lifestyle, and geography, with Streptococcus thermophilus and Lactococcus lactis being most prevalent. Moreover, we identify genome-based differences between food and gut microbes by considering 666 metagenome-assembled genomes (MAGs) newly reconstructed from fermented food microbiomes along with 154,723 human MAGs and 193,078 reference genomes. Our large-scale genome-wide analysis demonstrates that closely related LAB strains occur in both food and gut environments and provides unprecedented evidence that fermented foods can be indeed regarded as a possible source of LAB for the gut microbiome., Here, Pasolli et al. perform a large-scale genome-wide comparative analysis of publicly available and newly sequenced food and human metagenomes to investigate the prevalence and diversity of lactic acid bacteria (LAB), indicating food as a major source of LAB species in the human gut.
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49. Strong oral plaque microbiome signatures for dental implant diseases identified by strain-resolution metagenomics

Author: Federico Dell’Acqua, Paolo Manghi, Federica Armanini, Nicola Segata, Romina Waldner, Francesco Tessarolo, Cristiano Tomasi, Edoardo Pasolli, Moreno Zolfo, Ester Dellasega, Alberto Bertelle, Mattia Bolzan, Paolo Ghensi, Ghensi, P., Manghi, P., Zolfo, M., Armanini, F., Pasolli, E., Bolzan, M., Bertelle, A., Dell'Acqua, F., Dellasega, E., Waldner, R., Tessarolo, F., Tomasi, C., and Segata, N.
Subjects: 0301 basic medicine, Adult, DNA, Bacterial, Male, medicine.medical_treatment, Disease, Applied Microbiology and Biotechnology, Microbiology, lcsh:Microbial ecology, Article, Bacterial genetics, Machine Learning, 03 medical and health sciences, 0302 clinical medicine, Mucositis, medicine, Humans, Microbiome, Dental implant, Phylogeny, Aged, Plaque, Aged, 80 and over, Dental Implants, Stomatitis, biology, Bacteria, business.industry, Case-control study, High-Throughput Nucleotide Sequencing, 030206 dentistry, Sequence Analysis, DNA, Middle Aged, biology.organism_classification, medicine.disease, Peri-Implantitis, 3. Good health, 030104 developmental biology, Metagenomics, Case-Control Studies, Immunology, lcsh:QR100-130, Female, Fusobacterium nucleatum, business, Biotechnology
Abstract: Dental implants are installed in an increasing number of patients. Mucositis and peri-implantitis are common microbial–biofilm-associated diseases affecting the tissues that surround the dental implant and are a major medical and socioeconomic burden. By metagenomic sequencing of the plaque microbiome in different peri-implant health and disease conditions (113 samples from 72 individuals), we found microbial signatures for peri-implantitis and mucositis and defined the peri-implantitis-related complex (PiRC) composed by the 7 most discriminative bacteria. The peri-implantitis microbiome is site specific as contralateral healthy sites resembled more the microbiome of healthy implants, while mucositis was specifically enriched for Fusobacterium nucleatum acting as a keystone colonizer. Microbiome-based machine learning showed high diagnostic and prognostic power for peri-implant diseases and strain-level profiling identified a previously uncharacterized subspecies of F. nucleatum to be particularly associated with disease. Altogether, we associated the plaque microbiome with peri-implant diseases and identified microbial signatures of disease severity.
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50. A gut-on-a-chip incorporating human faecal samples and peristalsis predicts responses to immune checkpoint inhibitors for melanoma.

Author: Ballerini M, Galiè S, Tyagi P, Catozzi C, Raji H, Nabinejad A, Macandog ADG, Cordiale A, Slivinschi BI, Kugiejko KK, Freisa M, Occhetta P, Wargo JA, Ferrucci PF, Cocorocchio E, Segata N, Vignati A, Morgun A, Deleidi M, Manzo T, Rasponi M, and Nezi L
Abstract: Patient responses to immune checkpoint inhibitors can be influenced by the gastrointestinal microbiome. Mouse models can be used to study microbiome-host crosstalk, yet their utility is constrained by substantial anatomical, functional, immunological and microbial differences between mice and humans. Here we show that a gut-on-a-chip system mimicking the architecture and functionality of the human intestine by including faecal microbiome and peristaltic-like movements recapitulates microbiome-host interactions and predicts responses to immune checkpoint inhibitors in patients with melanoma. The system is composed of a vascular channel seeded with human microvascular endothelial cells and an intestinal channel with intestinal organoids derived from human induced pluripotent stem cells, with the two channels separated by a collagen matrix. By incorporating faecal samples from patients with melanoma into the intestinal channel and by performing multiomic analyses, we uncovered epithelium-specific biomarkers and microbial factors that correlate with clinical outcomes in patients with melanoma and that the microbiome of non-responders has a reduced ability to buffer cellular stress and self-renew. The gut-on-a-chip model may help identify prognostic biomarkers and therapeutic targets., Competing Interests: Competing interests: M.R. and P.O. are founders and shareholders of BiomimX Srl. The other authors declare no competing interests., (© 2025. The Author(s).)
Published: 2025
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