Harry Sokol Professor of Gastroenterology, MD, PhD
Course and current status
Gastroenterology Department, Saint-Antoine Hospital, APHP, Paris
Co-director Microbiota, gut & inflammation Lab, CRSA UMRS 938, INSERM/Sorbonne Université
Group leader, Team ProbiHote, MICALIS, INRA
Coordinator of the “Paris Center for Microbiome Medicine” FHU
Coordinator of the APHP Fecal Microbiota Transplantation Center
Appointments at Hospitals:
Resident (Hepatology-Gastroenterology), APHP Paris Hospital, France (2001-2006)
Assistant Professor (Saint-Antoine Hospital, APHP, Paris, France, 2007-2009)
Associate Professor (Saint-Antoine Hospital, APHP, Paris, France, 2011-2016)
Full Professor (Saint-Antoine Hospital, APHP, Paris, France, 2016- present)
Research activity
- Master Degree (Microbiology), Paris XI University 2003-2004)
- PhD (Microbiology), Paris XI University (2005-2008)
- Postdoctoral research Fellow (Ramnik J. Xavier, Massachusetts General Hospital, Harvard medical school, Boston, USA, 2009-2011).
- Current research activity: Co-director of the team « Microbiota, gut & inflammation », CRSA UMRS938, (INSERM/Sorbonne Université) and Group Leader MICALIS, INRA.
Scientific summary
Although the important role of the gut microbiota was known before, its deep exploration and the analysis of its effects on the host really started in early 2000 with the advent of molecular biology. As a medical resident in Gastroenterology at this time, I was particularly interested in inflammatory bowel disease (IBD) pathogenesis, and I started to get interested in the gut microbiota.
Initial description of the gut microbiota alterations in IBD and identification of Faecalibacterium prausnitzii
During a master degree in microbiology, I contributed to the initial description of the IBD-associated alterations in microbiota composition that led to several major publications (Sokol et al., 2006, 2007). Following an MD degree in Gastroenterology, I did a PhD (under the supervision of Joel Doré, INRA, France) and described the role of the pivotal commensal bacteria Faecalibacterium prausnitzii in gut homeostasis and in IBD in 2 landmark publications ( (Sokol et al., 2008, 2009), 2,241 and 724 citations respectively). The human microbiota data we generated showed that F. prausnitzii was a dominant member of the normal microbiota that was decreased in patients with IBD and also predictive of disease recurrence. We thus hypothesized and demonstrated that this bacterium is a keystone bacterial species with anti-inflammatory effects. This “in humans” discovery strategy leading to the identification of a microbiota-derived bacterium with therapeutic potential was unique at this time, and this contribution to the field has been recognized worldwide (Velasquez-Manoff 2015). In the following years, we identified several mechanisms of action underlying the anti-inflammatory effects F. prausnitzii (Quevrain et al., 2015; Sarrabayrouse et al., 2014). This bacterium is currently developed as a live biotherapeutic product by Exeliom Biosciences (https://www.exeliombio.com/), and it will be tested in humans for the first time in 2022.
Exploration of the role of CARD9 in intestinal homeostasis and IBD pathogenesis, Tryptophan metabolism
Following a two years assistant Professor position in the Gastroenterology department of the Saint-Antoine hospital (APHP, Paris, France), I moved to the laboratory of Pr. Ramnik Xavier as a postdoctoral research Fellow (Massachusetts General Hospital and Harvard Medical School, Boston, USA) in order to improve my skills on the host side of the IBD pathogenesis, mainly regarding immunology, genetics and bioinformatics. I worked on several IBD susceptibility genes and particularly on the role of Caspase Recruitment Domain 9 (CARD9) in colitis setting (Sokol et al., 2013) as well as on TAGAP (Kumar et al., 2014) and NCF4 (Conway et al., 2012). I was also involved in a gut microbiota study in IBD patients (Morgan et al., 2012). Back in France in September 2011, I obtained an associate Professor position in the Gastroenterology department of the Saint Antoine Hospital (APHP & Sorbonne Université, Paris, France), which has an internationally recognized expertise in IBD. I started to build my own group in 2012 in the Commensals and Probiotics-Host Interactions Laboratory (MICALIS Institute, INRA, France) and got junior funding from INSERM in 2013 (Atip-Avenir program). In parallel, I also built a biobank of blood, DNA and fecal samples from the patients with IBD followed in St Antoine hospital (Suivitheque Biobank) in order to be able to generate human-relevant hypotheses, but also to challenge the relevance of the results obtained in mice. For all my projects, my research strategy is based on a bedside-to-bench and bench-to-bedside approach to ensure the human relevance of the results.
One of the first projects I ran as a fully independent principal investigator aimed at deepening the role of CARD9 in intestinal homeostasis and IBD pathogenesis. CARD9 encodes an adaptor protein that integrates signals downstream of pattern recognition receptors. I first showed that CARD9 is required for appropriate immune response in colitis settings in mice. I then demonstrated that CARD9 is crucial for the metabolism of tryptophan into aryl hydrocarbon receptor (AhR) ligands by the gut microbiota (Lamas et al., 2016). Importantly, thanks to the Suivitheque biobank, these results were confirmed in human patients with IBD. The activation of AhR by microbiota-derived tryptophan metabolites is crucial for intestinal homeostasis. It is now recognized as one of the major functions of the gut microbiota in health maintenance. This study was one of the first to suggests that, owing to their tight relationship, the respective roles of the host factors and the gut microbiota in IBD pathogenesis cannot be completely distinguished. Thus, altered gut microbiota should neither be considered a cause nor a consequence of IBD, but both simultaneously, leading to the concept of “circular causality”. This landmark paper (475 citations) encouraged me to explore the role of tryptophan metabolism in host-microbiota interactions more in-depth. The obtention of an ERC starting grant in 2016 allowed me to point out its role in several diseases, including metabolic syndrome and Coeliac disease (Agus et al., 2018; Lamas et al., 2020; Laurans et al., 2018; Natividad et al., 2018), and be now recognized as an international expert in this field. We are currently finalizing to decipher the mechanisms of action of several tryptophan metabolites we identified to have anti-inflammatory effects.
Fecal Microbiota Transplantation as a therapeutic proof of concept and as a discovery tool
Following the demonstration of an alteration of the gut microbiota composition and function in IBD, the clues suggesting an active role of this perturbed microbiota in IBD pathogenesis accumulated. The next logical step was thus to test a therapeutic intervention targeting the gut microbiota. I thus designed a pilot study to evaluate the role of fecal microbiota transplantation (FMT) in Crohn’s disease. As the gut microbiota is only one of the actors in IBD pathogenesis, I chose to evaluate a strategy combining host and microbiota directed approaches. For this purpose, patients with active Crohn’s disease were first treated with corticosteroids to induce clinical remission (to shut down the systemic inflammation) before being randomized to receive either a single FMT or a sham FMT. Finally, corticosteroids were progressively tapered.
This study, the first FMT clinical trial in France (all indications combined), was funded and initiated after a complex regulatory process. It is still today the only published randomized controlled trial that evaluated FMT in Crohn’s disease (Kong et al., 2020; Sokol et al., 2020). This study was not powered to demonstrate statistically significant efficacy. However, it showed promising results that were sufficient to obtain fundings for two studies evaluating similar concepts in larger populations in both Crohn’s disease and ulcerative colitis. Unfortunately, these studies were delayed because of the Covid crisis, but they are currently being resumed.
In parallel, to address the routine clinical need for FMT in recurrent Clostridioides difficile infection, I initiated the French group of fecal microbiota transplantation (GFTF, www.gftf.fr) and built the APHP Fecal Microbiota Transplantation Center (providing FMT material for the Paris area).
Although FMT is an attractive therapeutic strategy, it seems complicated to apply in routine clinical practice to frequent and chronic diseases such as IBD. However, I consider these FMT clinical trials as formidable discovery tools to identify simpler and more controlled microbiota-derived therapeutic factors, and to fuel mechanistic explorations. Following this way, we leveraged the data and samples from the above-described clinical trial to identify new microbiota-derived metabolites with therapeutic potential. We are currently deciphering their mechanisms of action.
Agus, A., Planchais, J., and Sokol, H. (2018). Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Cell Host Microbe 23, 716–724.
Conway, K.L., Goel, G., Sokol, H., Manocha, M., Mizoguchi, E., Terhorst, C., Bhan, A.K., Gardet, A., and Xavier, R.J. (2012). p40phox Expression Regulates Neutrophil Recruitment and Function during the Resolution Phase of Intestinal Inflammation. J Immunol 189, 3631–3640.
Kong, L., Lloyd-Price, J., Vatanen, T., Seksik, P., Beaugerie, L., Simon, T., Vlamakis, H., Sokol, H., and Xavier, R.J. (2020). Linking Strain Engraftment in Fecal Microbiota Transplantation With Maintenance of Remission in Crohn’s Disease. Gastroenterology 159, 2193-2202.e5.
Kumar, V., Cheng, S.-C., Johnson, M.D., Smeekens, S.P., Wojtowicz, A., Giamarellos-Bourboulis, E., Karjalainen, J., Franke, L., Withoff, S., Plantinga, T.S., et al. (2014). Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidaemia. Nat Commun 5, 4675.
Lamas, B., Richard, M.L., Leducq, V., Pham, H.-P., Michel, M.-L., Da Costa, G., Bridonneau, C., Jegou, S., Hoffmann, T.W., Natividad, J.M., et al. (2016). CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598–605.
Lamas, B., Hernandez-Galan, L., Galipeau, H.J., Constante, M., Clarizio, A., Jury, J., Breyner, N.M., Caminero, A., Rueda, G., Hayes, C.L., et al. (2020). Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation. Sci Transl Med 12.
Laurans, L., Venteclef, N., Haddad, Y., Chajadine, M., Alzaid, F., Metghalchi, S., Sovran, B., Denis, R., Dairou, J., Cardellini, M., et al. (2018). Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health. Nat Med 24, 1113–1120.
Morgan, X.C., Tickle, T.L., Sokol, H., Gevers, D., Devaney, K.L., Ward, D.V., Reyes, J.A., Shah, S.A., Leleiko, N., Snapper, S.B., et al. (2012). Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 13, R79.
Natividad, J., Agus, A., Planchais, J., Lamas, B., Jarry, A., Martin, R., Michel, M., Chong-Nguyen, C., Roussel, R., Straube, M., et al. (2018). Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome. Cell Metab 28, 737-749.e4.
Quevrain, E., Maubert, M.A., Michon, C., Chain, F., Marquant, R., Tailhades, J., Miquel, S., Carlier, L., Bermudez-Humaran, L.G., Pigneur, B., et al. (2015). Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut.
Sarrabayrouse, G., Bossard, C., Chauvin, J.-M., Jarry, A., Meurette, G., Quévrain, E., Bridonneau, C., Preisser, L., Asehnoune, K., Labarrière, N., et al. (2014). CD4CD8αα lymphocytes, a novel human regulatory T cell subset induced by colonic bacteria and deficient in patients with inflammatory bowel disease. PLoS Biol. 12, e1001833.
Sokol, H., Seksik, P., Rigottier-Gois, L., Lay, C., Lepage, P., Podglajen, I., Marteau, P., and Doré, J. (2006). Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm. Bowel Dis. 12, 106–111.
Sokol, H., Lepage, P., Seksik, P., Dore, J., and Marteau, P. (2007). Molecular comparison of dominant microbiota associated with injured versus healthy mucosa in ulcerative colitis. Gut 56, 152–154.
Sokol, H., Pigneur, B., Watterlot, L., Lakhdari, O., Bermúdez-Humarán, L.G., Gratadoux, J.-J., Blugeon, S., Bridonneau, C., Furet, J.-P., Corthier, G., et al. (2008). Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. U.S.A. 105, 16731–16736.
Sokol, H., Seksik, P., Furet, J.P., Firmesse, O., Nion-Larmurier, I., Beaugerie, L., Cosnes, J., Corthier, G., Marteau, P., and Doré, J. (2009). Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm. Bowel Dis. 15, 1183–1189.
Sokol, H., Conway, K.L., Zhang, M., Choi, M., Morin, B., Cao, Z., Villablanca, E.J., Li, C., Wijmenga, C., Yun, S.H., et al. (2013). Card9 Mediates Intestinal Epithelial Cell Restitution, T-Helper 17 Responses, and Control of Bacterial Infection in Mice. Gastroenterology 145, 591-601.e3.
Sokol, H., Landman, C., Seksik, P., Berard, L., Montil, M., Nion-Larmurier, I., Bourrier, A., Le Gall, G., Lalande, V., De Rougemont, A., et al. (2020). Fecal microbiota transplantation to maintain remission in Crohn’s disease: a pilot randomized controlled study. Microbiome 8, 12.
