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Le microbiote intestinal humain, tel que nous le connaissons aujourd’hui, apparaît d’une très grande complexité. Afin d'avancer vers une prise en compte holistique incluant sa composante non cultivable encore majoritaire à ce jour, nous avons contribué à l'élaboration d’une approche nouvelle et puissante, la métagénomique qui a permis des progrès rapides dans la caractérisation de la diversité génomique et génétique du microbiote intestinal. Ainsi, le génome microbien (microbiome) contient ~150 fois plus de gènes que le génome humain et le microbiote est considéré comme un organe de l’hôte à part entière.
The general objective of the team is the identification of the mechanisms of food-microbiota-host interactions, in healthy humans and in the context of diverse pathologies including inflammatory and metabolic diseases, to better understand the intestinal ecosystem and to define strategies for its modulation in order to prevent or cure diseases.
Our activity profile goes from the genes and molecules to the bed of the patients (cohorts). We combine fundamental cell and molecular biology, immunology, enzymology, microbiology and preclinical animal models. The use of well-characterized human cohorts of patients through our participation in major research consortia such as MetaCardis, MetaHIT or MicroObes or their ancillary research programs such as ObOmics or ProteoCardis, allow us to study the human gut microbiota in its complexity.
FInE is a mixed team linked to two INRA divisions AlimH and Mica.
The team is organized in 4 research themes, each coordinated by one staff scientist. It is noteworthy that our work is conducted in close collaboration with the PAPPSO and Anaxem platforms within Micalis, and with the 4 platforms of MetaGenoPolis.
Theme 1 coordinated by Christel Béra-Maillet (CRCN) is geared towards an understanding of the enzymatic mechanisms of food degradation, especially complex carbohydrates, and their consequences for the host. Using a validated functional metagenomic approach, we seek enzymes involved in cell wall polysaccharides degradation. Then, by searching the metagenome sequence databases, we try to document the preponderance of genes of interest in diverse population of healthy donors and patients;
Theme 2 is coordinated by Nicolas Lapaque (CRCN) and is geared towards the identification of bacterial effectors of the microbiota-host cross-talk, and the documentation of the health consequences of these interactions. Using a collection of commensal bacteria on the one side, and metagenomic libraries from human donors on the other side, we study the impact of bacterial metabolites (or compounds) on various signaling pathways and genes in human intestinal epithelial cells. Using an innovative functional metagenomic approach, we identify bacterial genes and molecules/metabolites modulating the homeostasis of the intestinal barrier in its epithelial, immune (especially Treg) and metabolic components..
Theme 3 is coordinated by Catherine Juste (CRCN) and seeks to identify bacterial peptides from fecal samples and other biological matrices including plasma, that are early predictive signatures of pathologies, notably inflammatory and metabolic disorders. We have developed and fully validated an innovative metaproteomic pipeline to probe several hundreds of fecal samples from large cohorts of healthy and diseased populations.
Thème 4 has for main objective to tackle a "reasoned ecological engineering” of the human intestinal ecosystem and is driven by Joël Doré (DRex) and Maarten van de Guchte (DR2). We believe that the intestinal ecosystem is subject to hysteresis and postulate that disease-associated dysbiosis represents an alternative stable state resulting from a critical transition. Our challenge is to develop rational approaches for ecological engineering of the human intestinal microbiota. We aim to prove the existence of alternative stable states in the intestinal ecosystem, and to show and predict critical transition through the identification of forerunner warning signals in order to propose and validate preventive or curative strategies.
KEY RESULTS/ HIGHLIGHTS FROM THE FInE TEAM
Among the key results, our team has a strong leadership in human intestinal metagenomics, being associated with the majority of INRA publication on quantitative and functional metagenomics from 2008 to 2018. As member of major European consortia including MetaHIT, IHMS and MetaCardis, our team has participated in i) the revelation of the importance of microbiota richness in human health (Le Chatelier, Nature, 2013, Cotillard, Nature, 2013), ii) the construction of human, mouse and pig microbiome catalogues (Li, Nat Biotechnol 2014; Xiao, Nat Biotechnol 2015; Xiao, Nat Microbiol 2016), iii) the definition of metagenomic species (Nielsen, Nat Biotechnol 2014), iv) the identification of microbiota signatures in several diseases (Juste et al, Gut 2014; Viaud, Science, 2013; Forslund, Nature 2015; Tap, Gastroenterology, 2017; Pedersen, Nature, 2016; Mondot, Gut, 2016; Fadlallah, Sci Trans Med, 2017; Aron-Wisnewsky, Gut 2018), and v) the standardization of the quantitative metagenomic pipeline (Costea et al, Nature Biotechnol, 2017).
Considering theme 1, we would like to highlight the work performed by Orlane Patrascu as a PhD student under the supervision of C. Béra-Maillet (Patrascu, Sci Rep, 2017). Using a functional metagenomics approach, she explored the fibrolytic potential of gut microbes focusing on a poorly explored ecosystem, the mucosa-associated microbiota of the ileum. After screening of a metagenomic library obtained from a human ileal segment (20 000 clones), 21 bioactive clones were isolated and characterized. This work first revealed the important role of the ileal microbiota in fiber degradation. Moreover, three new enzymes were identified leading to a declaration of invention and to a financial support for a pre-maturation project by Idex Paris-Saclay, Carzymtech, (in collaboration with B. Henrissat in Marseille), as well as a market survey delivered by the SATT Paris-Saclay. These enzymes were purified and two companies are interested in potential future industrial applications.
In the context of theme 2, by using a reporter gene technology focusing on pathways involved in gut homeostasis and immune regulation, we screened dozens of commensal strains for their impact on human intestinal epithelial cells. This led to the identification of short chain fatty acids, especially butyrate, as major bacterial metabolites impacting on host cells (Korecka, Am J Physiol, 2013; Larraufie, Cell microbiol, 2017; Nepelska, Sci Rep, 2017; Martin-Gallausiaux, Sci rep, 2018; Larraufie Sci rep, 2018). Moreover, using the functional metagenomic approach that was developed to study gut microbiota/host cross-talk, we were able to identify several metagenomic clones regulating pathways of interest in human cells. The strategy was fully validated for high throughput screening (de Wouters, PloS one, 2014) and transferred to MetaGenoPolis for further studies with industrial and academic partners. Among the clones of interest, we identified a lipoprotein from B. vulgatus that activates the NF-kB pathway (O’cuiv, anaerobes, 2017). Moreover, we identified 6 clones for which patents were deposited and for which Enterome biosciences and Janssens (J&J) took licences and contracted with us for further characterization. Among the clones, two allowed us to identify the TIFA pathway as a new pathway activating NF-kB in a MyD88/TLR independent manner. Interestingly, we also identified commensal strains able to activate this pathway.
The metaproteomic approach for which our team pioneered the development (Theme 3), has allowed the identification of peptides/proteins that are signature for IBD (Juste, Gut, 2014; patent). The whole procedure to extract both cytosolic and membrane proteins has been fully validated and shotgun-label free proteomics is now performed routinely. Our unique expertise to extract residue-free microbial populations was also used for other purposes besides for metaproteomics: to the production of lyophilizable residue-free microbiota with a high revivification potential than can be used for fecal transplants (Idex-Paris-Saclay prematuration project RFM-Prep), immunological studies focused on Ig coated bacteria (Fadlallah, Sci Trans Med, 2018) or specifc strains (Lecuyer Immunity, 2014). Through the coordination of the ANR project Proteocardis (ancillary to Metacardis), Catherine Juste is now studying a cohort of patients with metabolic disorders. Moreover, through the Idex Paris-Saclay pre-maturation project Mici-Pep, we are pursuing the metaproteomic discovery of early predictive peptidic biomarkers of IBD in feces and plasma.
The novel gut ecology theme (Theme 4) was initiated thanks to collaborative works with Danone Research funding cognitive works on intestinal ecology. This initially led us to demonstrate in a rat model that the dynamics of bacterial strains given in fermented milk is totally dependent on the baseline microbiota, as suspected from published work in humans (Zhang, ISME J, 2016). We currently focus on the concept of alternative stable states to describe the intestinal microbiota-host symbiosis. Our hypothesis is that 1) alternative stable states exist in the intestinal ecosystem, and 2) contribute to health, disease, or “pre-disease” (i.e., an increased susceptibility to develop disease), which 3) would have important implications for the development of cure and prevention strategies (van de Guchte et al, Microbiome, 2018). Preclinical experimental results appear to confirm point 1) (publication in preparation). Joël Doré obtained an ERC advanced grant (2019-2023) to pursue these studies in preclinical and clinical contexts.
MGP : US 1367 MetaGenoPolis. Some of the team members are strongly involved in the MetagenoPolis project.
2) Juste C, Kreil DP, Beauvallet C, Guillot A, Vaca S, Carapito C, Mondot S, Sykacek P, Sokol H, Blon F, Lepercq P, Levenez F, Valot B, Carré W, Loux V, Pons N, David O, Schaeffer B, Lepage P, Martin P, Monnet V, Seksik P, Beaugerie L, Ehrlich SD, Gibrat JF, Van Dorsselaer A, Doré J. (2014) Bacterial protein signals are associated with Crohn's disease. Gut 63 :1566-77.
3) Nielsen HB, Almeida M, Juncker AS, Rasmussen S, Li J, Sunagawa S, Plichta DR, Gautier L, Pedersen AG, Le Chatelier E, Pelletier E, Bonde I, Nielsen T, Manichanh C, Arumugam M, Batto JM, Quintanilha Dos Santos MB, Blom N, Borruel N, Burgdorf KS, Boumezbeur F, Casellas F, Doré J, Dworzynski P, Guarner F, Hansen T, Hildebrand F, Kaas RS, Kennedy S, Kristiansen K, Kultima JR, Léonard P, Levenez F, Lund O, Moumen B, Le Paslier D, Pons N, Pedersen O, Prifti E, Qin J, Raes J, Sørensen S, Tap J, Tims S, Ussery DW, Yamada T; MetaHIT Consortium, Renault P, Sicheritz-Ponten T, Bork P, Wang J, Brunak S, Ehrlich SD. (2014) Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes. Nat Biotechnol, 32:822-828.
4) Costea PI, Zeller G, Sunagawa S, Pelletier E, Alberti A, Levenez F, Tramontano M, Driessen M, Hercog R, Jung FE, Kultima JR, Hayward MR, Coelho LP, Allen-Vercoe E, Bertrand L, Blaut M, Brown JRM, Carton T, Cools-Portier S, Daigneault M, Derrien M, Druesne A, de Vos WM, Finlay BB, Flint HJ, Guarner F, Hattori M, Heilig H, van Hylckama Vlieg J, Junick J, Klymiuk I, Langella P, Le Chatelier E, Mai V, Manichanh C, Martin JC, Mery C, Morita H, O'Toole PW, Orvain C, Patil KR, Penders J, Persson S, Pons N, Popova M, Salonen A, Saulnier D, Scott KP, Singh B, Slezak K, Veiga P, Versalovic J, Zhao L, Zoetendal EG, Ehrlich SD, Dore J, Bork P. Towards standards for human fecal sample processing in metagenomic studies. Nat Biotechnol. 2017 Oct 2. doi: 10.1038/nbt.3960.