Publications by authors named "Harry Sokol"

196 Publications

Patient knowledge of gut microbiota and acceptability of fecal microbiota transplantation in various diseases.

Neurogastroenterol Motil 2022 Jan 17:e14320. Epub 2022 Jan 17.

Gastroenterology Department, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Sorbonne Université, Saint Antoine Hospital, Paris, France.

Background: Fecal microbiota transplantation (FMT) is now evaluated in various diseases. However, large-scale population treatment may encounter feasibility issues in terms of acceptance. We aim to evaluate patient knowledge of gut microbiota and the acceptability of FMT in various diseases.

Methods: Patients of Carenity's French online community were invited by email to participate in a questionnaire. The following parameters were assessed: patient's principal illness and duration, demographic data, therapeutics, dietary habits, knowledge of gut microbiota, probiotics and FMT, and its acceptability.

Key Results: In total, 877 patients participated in the online questionnaire: 156 with inflammatory bowel disease (17.8%), 127 with rheumatoid arthritis (14.5%), 222 with ankylosing spondylitis (25.3%), 52 with lupus (5.9%), 64 with psoriasis (7.3%), 61 with obesity (7%), and 195 with type 2 diabetes (22.2%). Characteristics of participating patients were similar to those of the entire cohort (n = 23084). Overall, 47.1% (n = 413/877) of patients knew what the microbiota is with no difference among diseases. Knowledge was reported to be developed by patients themselves (203/413; 49.2%) without involving a healthcare professional. If proposed by a healthcare professional, 37.2% (326/877) reported being interested or very interested in undergoing FMT. Factors associated with good acceptability of FMT were the male sex (OR: 1.63, CI95% [1.14 to 2.32]), previous knowledge of FMT (OR: 4.16, CI95% [2.92 to 5.96]), and previous knowledge of gut microbiota (OR: 1.54, CI95% [1.05 to 2.24]).

Conclusion And Inferences: Knowledge of gut microbiota is still limited in patients' communities and mainly developed by patients themselves, impacting FMT acceptability.
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http://dx.doi.org/10.1111/nmo.14320DOI Listing
January 2022

Alteration of the gut microbiota following SARS-CoV-2 infection correlates with disease severity in hamsters.

Gut Microbes 2022 Jan-Dec;14(1):2018900

Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France.

Mounting evidence suggests that the gut-to-lung axis is critical during respiratory viral infections. We herein hypothesized that disruption of gut homeostasis during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may associate with early disease outcomes. To address this question, we took advantage of the Syrian hamster model. Our data confirmed that this model recapitulates some hallmark features of the human disease in the lungs. We further showed that SARS-CoV-2 infection associated with mild intestinal inflammation, relative alteration in intestinal barrier property and liver inflammation and altered lipid metabolism. These changes occurred concomitantly with an alteration of the gut microbiota composition over the course of infection, notably characterized by a higher relative abundance of deleterious bacterial taxa such as Enterobacteriaceae and Desulfovibrionaceae. Conversely, several members of the Ruminococcaceae and Lachnospiraceae families, including bacteria known to produce the fermentative products short-chain fatty acids (SCFAs), had a reduced relative proportion compared to non-infected controls. Accordingly, infection led to a transient decrease in systemic SCFA amounts. SCFA supplementation during infection had no effect on clinical and inflammatory parameters. Lastly, a strong correlation between some gut microbiota taxa and clinical and inflammation indices of SARS-CoV-2 infection severity was evidenced. Collectively, alteration of the gut microbiota correlates with disease severity in hamsters making this experimental model valuable for the design of interventional, gut microbiota-targeted, approaches for the control of COVID-19. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019; SCFAs, short-chain fatty acids; dpi, day post-infection; RT-PCR, reverse transcription polymerase chain reaction; IL, interleukin. ACE2, angiotensin converting enzyme 2; TMPRSS2, transmembrane serine protease 2.
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http://dx.doi.org/10.1080/19490976.2021.2018900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726722PMC
January 2022

Circulating bile acids concentration is predictive of coronary artery disease in human.

Sci Rep 2021 11 22;11(1):22661. Epub 2021 Nov 22.

Centre de Recherche Sur I'inflammation, Inserm, UMR 1149, Université de Paris, 75018, Paris, France.

Synthetized by the liver and metabolized by the gut microbiota, BA are involved in metabolic liver diseases that are associated with cardiovascular disorders. Animal models of atheroma documented a powerful anti-atherosclerotic effect of bile acids (BA). This prospective study examined whether variations in circulating BA are predictive of coronary artery disease (CAD) in human. Consecutive patients undergoing coronary angiography were enrolled. Circulating and fecal BA were measured by high pressure liquid chromatography and tandem mass spectrometry. Of 406 screened patients, 80 were prospectively included and divided in two groups with (n = 45) and without (n = 35) CAD. The mean serum concentration of total BA was twice lower in patients with, versus without CAD (P = 0.005). Adjusted for gender and age, this decrease was an independent predictor of CAD. In a subgroup of 17 patients, statin therapy doubled the serum BA concentration. Decreased serum concentrations of BA were predictors of CAD in humans. A subgroup analysis showed a possible correction by statins. With respect to the anti-atherosclerotic effect of BA in animal models, and their role in human lipid metabolism, this study describe a new metabolic disturbance associated to CAD in human.
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http://dx.doi.org/10.1038/s41598-021-02144-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608912PMC
November 2021

Reporting guidelines for human microbiome research: the STORMS checklist.

Nat Med 2021 11 17;27(11):1885-1892. Epub 2021 Nov 17.

F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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.
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http://dx.doi.org/10.1038/s41591-021-01552-xDOI Listing
November 2021

The use of Faecal Microbiota Transplantation (FMT) in Europe: A Europe-wide survey.

Lancet Reg Health Eur 2021 Oct 19;9:100181. Epub 2021 Jul 19.

Nutrition-Gut-Brain Interactions Research Centre, Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.

Background: Faecal microbiota transplantation (FMT) is an emerging treatment modality, but its current clinical use and organisation are unknown. We aimed to describe the clinical use, conduct, and potential for FMT in Europe.

Methods: We invited all hospital-based FMT centres within the European Council member states to answer a web-based questionnaire covering their clinical activities, organisation, and regulation of FMT in 2019. Responders were identified from trials registered at clinicaltrials.gov and from the United European Gastroenterology (UEG) working group for stool banking and FMT.

Findings: In 2019, 31 FMT centres from 17 countries reported a total of 1,874 (median 25, quartile 10-64) FMT procedures; 1,077 (57%) with infection (CDI) as indication, 791 (42%) with experimental indications, and 6 (0•3%) unaccounted for. Adjusted to population size, 0•257 per 100,000 population received FMT for CDI and 0•189 per 100,000 population for experimental indications. With estimated 12,400 (6,100-28,500) annual cases of multiple, recurrent CDI and indication for FMT in Europe, the current European FMT activity covers approximately 10% of the patients with indication. The participating centres demonstrated high safety standards and adherence to international consensus guidelines. Formal or informal regulation from health authorities was present at 21 (68%) centres.

Interpretation: FMT is a widespread routine treatment for multiple, recurrent CDI and an experimental treatment. Embedded within hospital settings, FMT centres operate with high standards across Europe to provide safe FMT. A significant gap in FMT coverage suggests the need to raise clinical awareness and increase the FMT activity in Europe by at least 10-fold to meet the true, indicated need.

Funding: NordForsk under the Nordic Council and Innovation Fund Denmark (j.no. 8056-00006B).
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http://dx.doi.org/10.1016/j.lanepe.2021.100181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513118PMC
October 2021

Vasoactive intestinal peptide promotes host defense against enteric pathogens by modulating the recruitment of group 3 innate lymphoid cells.

Proc Natl Acad Sci U S A 2021 10;118(41)

Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada;

Group 3 innate lymphoid cells (ILC3s) control the formation of intestinal lymphoid tissues and play key roles in intestinal defense. They express neuropeptide vasoactive intestinal peptide (VIP) receptor 2 (VPAC2), through which VIP modulates their function, but whether VIP exerts other effects on ILC3 remains unclear. We show that VIP promotes ILC3 recruitment to the intestine through VPAC1 independent of the microbiota or adaptive immunity. VIP is also required for postnatal formation of lymphoid tissues as well as the maintenance of local populations of retinoic acid (RA)-producing dendritic cells, with RA up-regulating gut-homing receptor CCR9 expression by ILC3s. Correspondingly, mice deficient in VIP or VPAC1 suffer a paucity of intestinal ILC3s along with impaired production of the cytokine IL-22, rendering them highly susceptible to the enteric pathogen This heightened susceptibility to infection was ameliorated by RA supplementation, adoptive transfer of ILC3s, or by recombinant IL-22. Thus, VIP regulates the recruitment of intestinal ILC3s and formation of postnatal intestinal lymphoid tissues, offering protection against enteric pathogens.
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http://dx.doi.org/10.1073/pnas.2106634118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521691PMC
October 2021

Blockage of bacterial FimH prevents mucosal inflammation associated with Crohn's disease.

Microbiome 2021 08 23;9(1):176. Epub 2021 Aug 23.

Enterome, 94-96 Avenue Ledru-Rollin, 75011, Paris, France.

Background: An Escherichia coli (E. coli) pathotype with invasive properties, first reported by Darfeuille-Michaud and termed adherent-invasive E. coli (AIEC), was shown to be prevalent in up to half the individuals with Crohn's Disease (CD), suggesting that these bacteria could be involved in the pathophysiology of CD. Among the genes related to AIEC pathogenicity, fim has the potential to generate an inflammatory reaction from the intestinal epithelial cells and macrophages, as it interacts with TLR4, inducing the production of inflammatory cytokines independently of LPS. Therefore, targeting the bacterial adhesion of FimH-expressing bacteria seems a promising therapeutic approach, consisting of disarming bacteria without killing them, representing a selective strategy to suppress a potentially critical trigger of intestinal inflammation, without disturbing the intestinal microbiota.

Results: We analyzed the metagenomic composition of the gut microbiome of 358 patients with CD from two different cohorts and characterized the presence of FimH-expressing bacteria. To assess the pathogenic role of FimH, we used human intestinal explants and tested a specific FimH blocker to prevent bacterial adhesion and associated inflammation. We observed a significant and disease activity-dependent enrichment of Enterobacteriaceae in the gut microbiome of patients with CD. Bacterial FimH expression was functionally confirmed in ileal biopsies from 65% of the patients with CD. Using human intestinal explants, we further show that FimH is essential for adhesion and to trigger inflammation. Finally, a specific FimH-blocker, TAK-018, inhibits bacterial adhesion to the intestinal epithelium and prevents inflammation, thus preserving mucosal integrity.

Conclusions: We propose that TAK-018, which is safe and well tolerated in humans, is a promising candidate for the treatment of CD and in particular in preventing its recurrence. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01135-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383459PMC
August 2021

Butyrate, a new microbiota-dependent player in CD8+ T cells immunity and cancer therapy?

Cell Rep Med 2021 Jul 7;2(7):100328. Epub 2021 Jul 7.

INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France.

The intestinal microbiota is a new promising avenue in cancer immunotherapy, but mechanisms remain elusive. He et al. demonstrate that butyrate, a bacterial metabolite, enhances the CD8+ T cell response and improve chemotherapy efficacy through ID2-dependent IL-12 signaling.
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http://dx.doi.org/10.1016/j.xcrm.2021.100328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324458PMC
July 2021

Impact of gut fungal and bacterial communities on the outcome of allogeneic hematopoietic cell transplantation.

Mucosal Immunol 2021 09 19;14(5):1127-1132. Epub 2021 Jul 19.

APHP, Hôpital Saint Antoine, Service d'Hématologie Clinique et de Thérapie cellulaire, 75012, Paris, France.

Patients receiving allogeneic hematopoietic cell transplantation (alloHCT) were previously shown to display a bacterial gut dysbiosis; however, limited data are available regarding the role of fungal microbiota in these patients. We evaluated the bacterial and fungal composition of the fecal microbiota at day 0 of alloHCT. Higher bacterial diversity was associated with an improved overall survival (OS) and disease-free survival (DFS). While fungal diversity had no impact on patient outcomes, we observed that high versus low relative abundance of Candida albicans in alloHCT patients at day 0 was associated with a significantly lower OS, DFS and graft-versus-host-free, relapse-free survival (GRFS) (p = 0.0008, p = 0.0064 and p = 0.026, respectively). While these results are limited by low patient numbers and low fungal read counts in some samples, they suggest a potentially important role for C albicans in alloHCT.
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http://dx.doi.org/10.1038/s41385-021-00429-zDOI Listing
September 2021

Immune-mediated inflammatory diseases and nutrition: results from an online survey on patients' practices and perceptions.

BMC Nutr 2021 Jul 16;7(1):38. Epub 2021 Jul 16.

Carenity, Communauté de patients en ligne, Paris, France.

Background: The central role of microbiota and the contribution of diet in immune-mediated inflammatory diseases (IMID) are increasingly examined. However, patients' perspectives on nutrition and its impact on their disease has not received a lot of attention. We aimed to directly collect information from patients with IMID about their dietary behaviors and their perceptions of the influence of nutrition on their disease.

Methods: Adult patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis or psoriasis registered in an online patient community were invited to participate in the study and complete an online self-administered questionnaire. We assessed patients' dietary knowledge and choices by collecting information on the diet regimens they were following or recommended and their perceptions of the diet and its consequences on their disease.

Results: Fifty patients per target disease were included with a mean age of 48.1 years (95%CI 46.7-49.6). Other sociodemographic and clinical characteristics varied across the diseases. Since diagnosis, 44% of the patients changed their eating habits, mainly patients with inflammatory bowel disease with 69% of these making the change on their own initiative. Patients who did not change their diet habits reported not having received nutritional advice from their healthcare professionals (HCP) in 69% of the cases. The perceived impact of nutrition on their symptoms was mixed (overall 74% of the patients reported positive consequences and 60% negative ones) and varied across the diseases. Patients with psoriasis only experienced positive consequences from changing their diet, such as reduction of stress and improved mental health, while patients with Crohn's disease reported more negative effects such as increased fatigue and disturbed sleep. Patients with rheumatic diseases and ulcerative colitis reported weight loss and better physical fitness, but also increased fatigue.

Conclusions: Even if differences exist across diseases, the importance of nutrition and its potential positive role in symptom management is acknowledged by the majority of the patients. However, there is a need and a demand from patients to receive more dietary advice. Developing therapeutic education tools on nutrition for people with IMID and involving patients' organizations would provide useful information and encourage communication between HCP and patients.
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http://dx.doi.org/10.1186/s40795-021-00446-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283994PMC
July 2021

Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal γδ T cells.

Cell Rep 2021 07;36(1):109332

Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350 Jouy-en-Josas, France; Paris Center for Microbiome Medicine (PaCeMM) FHU, Paris, France. Electronic address:

Gut interleukin-17A (IL-17)-producing γδ T cells are tissue-resident cells that are involved in both host defense and regulation of intestinal inflammation. However, factors that regulate their functions are poorly understood. In this study, we find that the gut microbiota represses IL-17 production by cecal γδ T cells. Treatment with vancomycin, a Gram-positive bacterium-targeting antibiotic, leads to decreased production of short-chain fatty acids (SCFAs) by the gut microbiota. Our data reveal that these microbiota-derived metabolites, particularly propionate, reduce IL-17 and IL-22 production by intestinal γδ T cells. Propionate acts directly on γδ T cells to inhibit their production of IL-17 in a histone deacetylase-dependent manner. Moreover, the production of IL-17 by human IL-17-producing γδ T cells from patients with inflammatory bowel disease (IBD) is regulated by propionate. These data contribute to a better understanding of the mechanisms regulating gut γδ T cell functions and offer therapeutic perspectives of these cells.
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http://dx.doi.org/10.1016/j.celrep.2021.109332DOI Listing
July 2021

Pembrolizumab with Capox Bevacizumab in patients with microsatellite stable metastatic colorectal cancer and a high immune infiltrate: The FFCD 1703-POCHI trial.

Dig Liver Dis 2021 Oct 30;53(10):1254-1259. Epub 2021 Jun 30.

Service d'Hépato-gastroentérologie, CHU de Poitiers et Université de Poitiers, Poitiers, France. Electronic address:

Pembrolizumab, a PD1 immune checkpoint inhibitor (ICI), was recently reported to be very effective in patients with microsatellite instable/deficient mismatch repair metastatic colorectal cancer (MSI/dMMR mCRC), unlike patients with microsatellite stable/proficient MMR (MSS/pMMR) mCRC, in whom ICIs are generally ineffective. However, about 15% of MSS/pMMR CRCs are highly infiltrated by tumour infiltrating lymphocytes. In addition, both oxaliplatin and bevacizumab have been shown to have immunomodulatory properties that may increase the efficacy of an ICI. We formulated the hypothesis that patients with MSS/pMMR mCRC with a high immune infiltrate can be sensitive to ICI plus oxalipatin and bevacizumab-based chemotherapy. POCHI is a multicenter, open-label, single-arm phase II trial to evaluate efficacy of Pembrolizumab with Capox Bevacizumab as first-line treatment of MSS/pMMR mCRC with a high immune infiltrate for which we plan to enrol 55 patients. Primary endpoint is progression-free survival (PFS) at 10 months, which is expected greater than 50%, but a 70% rate is hoped for. Main secondary objectives are overall survival, secondary resection rate and depth of response. Patients must have been resected of their primary tumour so as to evaluate two different immune scores (Immunoscore® and TuLIS) and are eligible if one score is "high". The first patient was included on April 20, 2021.
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http://dx.doi.org/10.1016/j.dld.2021.06.009DOI Listing
October 2021

Osteoarthritis and gut microbiome.

Joint Bone Spine 2021 10 4;88(5):105203. Epub 2021 May 4.

Sorbonne Université, Department of Rheumatology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Inserm UMRS_938, FHU PaCeMM, 184, Rue du Faubourg Saint-Antoine, 75012 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jbspin.2021.105203DOI Listing
October 2021

Recipient factors in faecal microbiota transplantation: one stool does not fit all.

Nat Rev Gastroenterol Hepatol 2021 07 27;18(7):503-513. Epub 2021 Apr 27.

INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France.

Faecal microbiota transplantation (FMT) is a promising therapy for chronic diseases associated with gut microbiota alterations. FMT cures 90% of recurrent Clostridioides difficile infections. However, in complex diseases, such as inflammatory bowel disease, irritable bowel syndrome and metabolic syndrome, its efficacy remains variable. It is accepted that donor selection and sample administration are key determinants of FMT success, yet little is known about the recipient factors that affect it. In this Perspective, we discuss the effects of recipient parameters, such as genetics, immunity, microbiota and lifestyle, on donor microbiota engraftment and clinical efficacy. Emerging evidence supports the possibility that controlling inflammation in the recipient intestine might facilitate engraftment by reducing host immune system pressure on the newly transferred microbiota. Deciphering FMT engraftment rules and developing novel therapeutic strategies are priorities to alleviate the burden of chronic diseases associated with an altered gut microbiota such as inflammatory bowel disease.
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http://dx.doi.org/10.1038/s41575-021-00441-5DOI Listing
July 2021

SARS-CoV-2 infection in nonhuman primates alters the composition and functional activity of the gut microbiota.

Gut Microbes 2021 Jan-Dec;13(1):1-19

Univ. Lille, US 41 - UMS 2014 - PLBS, U1019 - UMR 9017 - CIIL - Centre d'Infection Et d'Immunité De Lille, Lille, France.

The current pandemic of coronavirus disease (COVID) 2019 constitutes a global public health issue. Regarding the emerging importance of the gut-lung axis in viral respiratory infections, analysis of the gut microbiota's composition and functional activity during a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection might be instrumental in understanding and controling COVID 19. We used a nonhuman primate model (the macaque), that recapitulates mild COVID-19 symptoms, to analyze the effects of a SARS-CoV-2 infection on dynamic changes of the gut microbiota. 16S rRNA gene profiling and analysis of β diversity indicated significant changes in the composition of the gut microbiota with a peak at 10-13 days post-infection (dpi). Analysis of bacterial abundance correlation networks confirmed disruption of the bacterial community at 10-13 dpi. Some alterations in microbiota persisted after the resolution of the infection until day 26. Some changes in the relative bacterial taxon abundance associated with infectious parameters. Interestingly, the relative abundance of (Proteobacteria) and some genera of the Ruminococcaceae family (Firmicutes) was positively correlated with the presence of SARS-CoV-2 in the upper respiratory tract. Targeted quantitative metabolomics indicated a drop in short-chain fatty acids (SCFAs) and changes in several bile acids and tryptophan metabolites in infected animals. The relative abundance of several taxa known to be SCFA producers (mostly from the Ruminococcaceae family) was negatively correlated with systemic inflammatory markers while the opposite correlation was seen with several members of the genus . Collectively, SARS-CoV-2 infection in a nonhuman primate is associated with changes in the gut microbiota's composition and functional activity.
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http://dx.doi.org/10.1080/19490976.2021.1893113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951961PMC
March 2021

Tryptophan metabolites get the gut moving.

Cell Host Microbe 2021 02;29(2):145-147

Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Paris, France; French Group of Faecal Microbiota Transplantation (GFTF), Paris, France; Paris Center for Microbiome Medicine, Fédération Hospitalo-Universitaire, Paris, France; INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France. Electronic address:

How gut microbes can regulate the enteric nervous system and gut-brain communications is a field of intense research. In this issue of Cell Host & Microbe, Ye et al. demonstrate that bacteria can control intestinal motility and vagal neuronal activation via tryptophan catabolites through the receptor TrpA1 of enteroendocrine cells.
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http://dx.doi.org/10.1016/j.chom.2021.01.009DOI Listing
February 2021

PRODIGE 59-DURIGAST trial: A randomised phase II study evaluating FOLFIRI + Durvalumab ± Tremelimumab in second-line of patients with advanced gastric cancer.

Dig Liver Dis 2021 04 6;53(4):420-426. Epub 2021 Jan 6.

Service d'Oncologie Médicale, CHU de Poitiers, Poitiers, France; Service d'Hépato-gastroentérologie, CHU de Poitiers et Université de Poitiers, 2 rue de la Milétrie, Poitiers 86021, France. Electronic address:

Gastric or gastro-oesophageal junction (GEJ) adenocarcinomas present poor overall survival (OS). First-line chemotherapy regimen for patients with HER2-negative tumours is based on a doublet or triplet of fluoropyrimidine plus platinum salt ± taxane. Second-line chemotherapy (Docetaxel or Irinotecan) improves OS which nonetheless remains poor (around 5 months). The first results of immune checkpoint inhibitors (anti-PD-1) combined with chemotherapy in metastatic gastric and GEJ cancers were discordant in recent phase III trials. Data on dual-blockade (anti-PD-L1 or anti-PD-1 plus anti-CTLA-4) plus chemotherapy are lacking. DURIGAST is a randomised, multicenter, non-comparative, phase II study, evaluating safety and efficacy of FOLFIRI plus Durvalumab (anti-PD-L1) versus FOLFIRI plus Durvalumab and Tremelimumab (anti-CTLA-4) as second-line treatment of advanced gastric and GEJ adenocarcinoma. The primary objective is the rate of patients alive and without progression at 4 months. The main inclusion criteria are: patients with advanced gastric or GEJ adenocarcinoma, pre-treated with fluoropyrimidine + platinum salt ± taxane. Due to a lack of data on FOLFIRI, Durvalumab and Tremelimumab combination, a 2-step safety run-in phase has been performed before the randomised phase II. The safety run-in phase did not show any safety issue and the randomised phase II starts in September 2020.
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http://dx.doi.org/10.1016/j.dld.2020.11.036DOI Listing
April 2021

Gut microbiota-derived metabolites as central regulators in metabolic disorders.

Gut 2021 06 3;70(6):1174-1182. Epub 2020 Dec 3.

Paris Center for Microbiome Medicine (PaCeMM) FHU, AP-HP, Paris, Île-de-France, France

Metabolic disorders represent a growing worldwide health challenge due to their dramatically increasing prevalence. The gut microbiota is a crucial actor that can interact with the host by the production of a diverse reservoir of metabolites, from exogenous dietary substrates or endogenous host compounds. Metabolic disorders are associated with alterations in the composition and function of the gut microbiota. Specific classes of microbiota-derived metabolites, notably bile acids, short-chain fatty acids, branched-chain amino acids, trimethylamine N-oxide, tryptophan and indole derivatives, have been implicated in the pathogenesis of metabolic disorders. This review aims to define the key classes of microbiota-derived metabolites that are altered in metabolic diseases and their role in pathogenesis. They represent potential biomarkers for early diagnosis and prognosis as well as promising targets for the development of novel therapeutic tools for metabolic disorders.
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http://dx.doi.org/10.1136/gutjnl-2020-323071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108286PMC
June 2021

Tryptophan Metabolism as a Pharmacological Target.

Trends Pharmacol Sci 2021 01 27;42(1):60-73. Epub 2020 Nov 27.

Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, F-75012 Paris, France; Paris Centre for Microbiome Medicine FHU, Paris, France; INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France. Electronic address:

L-Tryptophan is an essential amino acid required for protein synthesis. It undergoes an extensive and complex metabolism along several pathways, resulting in many bioactive molecules acting in various organs through different action mechanisms. Enzymes involved in its metabolism, metabolites themselves, or their receptors, represent potential therapeutic targets, which are the subject of dynamic research. Disruptions in L-tryptophan metabolism are reported in several neurological, metabolic, psychiatric, and intestinal disorders, paving the way to develop drugs to target it. This review will briefly describe L-tryptophan metabolism and present and discuss the most recent pharmacological developments targeting it.
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http://dx.doi.org/10.1016/j.tips.2020.11.006DOI Listing
January 2021

Expert centres for faecal microbiota transplantation: The guarantee for safe and effective use of faecal transplants.

United European Gastroenterol J 2020 12 9;8(10):1145-1146. Epub 2020 Nov 9.

French Group of Faecal Microbiota Transplantation (GFTF), Paris, France.

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http://dx.doi.org/10.1177/2050640620970372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724530PMC
December 2020

A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group.

United European Gastroenterol J 2021 03 9;9(2):229-247. Epub 2021 Mar 9.

Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Background: Faecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of faeces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council.

Objective: Several European and international consensus statements concerning faecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document.

Methods: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about faecal microbiota transplantation.

Results: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening.

Conclusion: The implementation of faecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor faeces preparations for patients.
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http://dx.doi.org/10.1177/2050640620967898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259288PMC
March 2021

Infections in Patients with Chronic Granulomatous Disease Treated with Tumor Necrosis Factor Alpha Blockers for Inflammatory Complications.

J Clin Immunol 2021 01 4;41(1):185-193. Epub 2020 Nov 4.

Department of Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, AP-HP, Paris, France.

Purpose: Management of inflammatory complications of chronic granulomatous disease (CGD) is challenging. The aim of this study was to assess safety, with a focus on infections, and effectiveness of tumor necrosis factor alpha (TNF-α) blockers in CGD patients.

Methods: A retrospective, single-center cohort study of CGD patients treated by anti-TNF-α agents at Necker-Enfants Malades University Hospital (Paris, France) and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH).

Results: Between 2006 and 2019, 14 (X-linked: n = 10, 71.4%; autosomal-recessive: n = 4, 28.6%) CGD patients with gastrointestinal (n = 12, 85.7%), pulmonary (n = 10, 71.4%), cutaneous (n = 3, 21.4%), and/or genitourinary (n = 2, 14.3%) inflammatory manifestations received one or more doses of infliximab because of steroid-dependent (n = 7, 50%), refractory (n = 4, 28.6%) inflammatory disease or as first-line drug (n = 2, 14.3%; missing data, n = 1). All patients received adequate antimicrobial prophylaxis. Infliximab achieved complete (n = 2, 14.3%) or partial (n = 9, 64.3%) response in 11 (78.6%) patients. Seven (50%) patients were switched to adalimumab. During anti-TNF-α treatment, 11 infections (pneumonia, adenitis, invasive candidiasis, each n = 2; intra-abdominal abscess, bacteremic salmonellosis, Pseudomonas aeruginosa-related folliculitis, cat-scratch disease, proven pulmonary mucormycosis, each n = 1) occurred in 7 (50%) patients. All infectious complications had a favorable outcome. Anti-TNF-α treatment was definitively stopped because of infection in two patients. Nine (64.3%) patients finally underwent hematopoietic stem cell transplantation. No death occurred during follow-up.

Conclusions: Anti-TNF-α treatment could improve the outcome of severe inflammatory complications in CGD patients, but increases their risk of infections. We suggest that anti-TNF-α treatment might be of short-term benefit in selected CGD patients with severe inflammatory complications awaiting hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1007/s10875-020-00901-8DOI Listing
January 2021

Drug Mimicry: Promiscuous Receptors PXR and AhR, and Microbial Metabolite Interactions in the Intestine.

Trends Pharmacol Sci 2020 12 20;41(12):900-908. Epub 2020 Oct 20.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:

Significant attrition limits drug discovery. The available chemical entities present with drug-like features contribute to this limitation. Using specific examples of promiscuous receptor-ligand interactions, a case is made for expanding the chemical space for drug-like molecules. These ligand-receptor interactions are poor candidates for the drug discovery process. However, provided herein are specific examples of ligand-receptor or transcription-factor interactions, namely, the pregnane X receptor (PXR) and the aryl hydrocarbon receptor (AhR), and itsinteractions with microbial metabolites. Discrete examples of microbial metabolite mimicry are shown to yield more potent and non-toxic therapeutic leads for pathophysiological conditions regulated by PXR and AhR. These examples underscore the opinion that microbial metabolite mimicry of promiscuous ligand-receptor interactions is warranted, and will likely expand the existing chemical space of drugs.
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http://dx.doi.org/10.1016/j.tips.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669654PMC
December 2020

Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation.

Sci Transl Med 2020 10;12(566)

Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Metabolism of tryptophan by the gut microbiota into derivatives that activate the aryl hydrocarbon receptor (AhR) contributes to intestinal homeostasis. Many chronic inflammatory conditions, including celiac disease involving a loss of tolerance to dietary gluten, are influenced by cues from the gut microbiota. We investigated whether AhR ligand production by the gut microbiota could influence gluten immunopathology in nonobese diabetic (NOD) mice expressing DQ8, a celiac disease susceptibility gene. NOD/DQ8 mice, exposed or not exposed to gluten, were subjected to three interventions directed at enhancing AhR pathway activation. These included a high-tryptophan diet, gavage with that produces AhR ligands or treatment with an AhR agonist. We investigated intestinal permeability, gut microbiota composition determined by 16 rRNA gene sequencing, AhR pathway activation in intestinal contents, and small intestinal pathology and inflammatory markers. In NOD/DQ8 mice, a high-tryptophan diet modulated gut microbiota composition and enhanced AhR ligand production. AhR pathway activation by an enriched tryptophan diet, treatment with the AhR ligand producer , or pharmacological stimulation using 6-formylindolo (3,2-b) carbazole (Ficz) decreased immunopathology in NOD/DQ8 mice exposed to gluten. We then determined AhR ligand production by the fecal microbiota and AhR activation in patients with active celiac disease compared to nonceliac control individuals. Patients with active celiac disease demonstrated reduced AhR ligand production and lower intestinal AhR pathway activation. These results highlight gut microbiota-dependent modulation of the AhR pathway in celiac disease and suggest a new therapeutic strategy for treating this disorder.
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http://dx.doi.org/10.1126/scitranslmed.aba0624DOI Listing
October 2020

Butyrate mediates anti-inflammatory effects of in intestinal epithelial cells through .

Gut Microbes 2020 11;12(1):1-16

Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute , Jouy-en-Josas, France.

The commensal bacterium plays a key role in inflammatory bowel disease (IBD) pathogenesis and serves as a general health biomarker in humans. However, the host molecular mechanisms that underlie its anti-inflammatory effects remain unknown. In this study we performed a transcriptomic approach on human intestinal epithelial cells (HT-29) stimulated with TNF-α and exposed to culture supernatant (SN) in order to determine the impact of this commensal bacterium on intestinal epithelial cells. Moreover, modulation of the most upregulated gene after SN contact was validated both and . Our results showed that SN upregulates the expression of , a gene linked to the Wnt/JNK pathway. Interestingly, when we silenced expression, the effect of SN was lost. Butyrate was identified as the effector responsible for modulation. upregulation was also validated in both healthy and inflamed mice treated with either SN or the live bacteria, respectively. Finally, we demonstrated by colon transcriptomics that gut microbiota directly influences expression. This study provides new clues about the host molecular mechanisms involved in the anti-inflammatory effects of the beneficial commensal bacterium .
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http://dx.doi.org/10.1080/19490976.2020.1826748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567499PMC
November 2020

Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury.

Gut 2021 07 1;70(7):1299-1308. Epub 2020 Oct 1.

UMR996, Université Paris-Saclay, INSERM, Clamart, Île-de-France, France

Objective: Chronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions.

Design: We used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice.

Results: Pectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the gene in alcohol-fed AhR mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists.

Conclusions: Improvement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target.
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http://dx.doi.org/10.1136/gutjnl-2020-321565DOI Listing
July 2021

Mechanisms underpinning the efficacy of faecal microbiota transplantation in treating gastrointestinal disease.

Therap Adv Gastroenterol 2020 3;13:1756284820946904. Epub 2020 Sep 3.

Gastroenterology Department, INSERM, Centre de Recherche Saint Antoine, CRSA, AP-HP, Sorbonne Université, Saint Antoine Hospital, Paris, France.

Faecal microbiota transplantation (FMT) is currently a recommended therapy for recurrent/refractory infection (CDI). The success of FMT for CDI has led to interest in its therapeutic potential in many other disorders. The mechanisms that underpin the efficacy of FMT are not fully understood. Importantly, FMT remains a crucial treatment in managing CDI and understanding the mechanisms that underpin its success will be critical to improve its clinical efficacy, safety and usability. Furthermore, a deeper understanding of this may allow us to expose FMT's full potential as a therapeutic tool for other disease states. This review will explore the current understanding of the mechanisms underlying the efficacy of FMT across a variety of diseases.
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http://dx.doi.org/10.1177/1756284820946904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475788PMC
September 2020
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