Harry Sokol

The gut microbiota constitutes a complex ecosystem essential for host defense against infection and immune system maturation. Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are characterized by a severe inflammation of the intestine, arising from dysregulated control of host-microbiota crosstalk. However, neither the genetic bases of IBD nor the immune responses involved are fully understood. Pathobionts are currently under investigation for their active role in the development and severity of IBD. These bacteria are present in the gut microbiota of healthy individuals without causing disease, but have pathogenic potential when the intestinal environment is disturbed. Here, we highlight Sutterella sp. as a new commensal pathobiont for its capacity to modulate the host's immune functions. This anaerobic Gram-negative bacterium inhibits the production of IL-22 and IL-17 by lymphoid cells, ex vivo and in vivo. In the DSS-colitis model, Sutterella sp. can increase intestinal inflammation and inhibit IL-22 production. Moreover, the production of IL-22 and IL-17 by human lymphoid cells is also reduced by Sutterella sp. The bacterium acts directly on lymphoid cells through the secretion of protein-based compounds that antagonize AhR signaling. These data enhance our understanding of the mechanisms that regulate host immune functions and pave the way for new therapeutic strategies to control gut inflammation.

Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation ^1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

A marked decrease in Faecalibacterium prausnitzii is a hallmark of Crohn's disease (CD)-associated dysbiosis and predicts disease relapse. Here, we present the development and first-in-human evaluation of F. prausnitzii strain EXL01 for CD treatment. The EXL01-strain demonstrates anti-inflammatory effects in four models of colitis in rodents. A first-in-human, open-label, single-arm study of oral EXL01 was conducted in eight adult participants with mild to moderate CD, following corticosteroids-induced clinical response or remission. The primary endpoint was safety, and secondary endpoints included clinical, endoscopic, histological, molecular, and microbiome assessments. Exploratory endpoints included mucosa transcriptome and cytokine levels. EXL01 is well-tolerated with no treatment-related adverse events. Six participants completed the study; two discontinued treatment due to disease flare. While gut microbiota composition remains largely stable, transcriptomic analyses reveal distinct changes in ileal gene expression following EXL01 treatment, notably modulation of immune-related genes and upregulation of energy metabolism pathways. Compared to participants who remained in remission, those who flared show higher baseline systemic inflammation markers and innate immunity gene expression. These findings demonstrate that oral administration of EXL01 is feasible and well tolerated and establishes proof-of-concept for F. prausnitzii as a first-in-class live biotherapeutic for CD. ClinicalTrials.gov registration: NCT05542355.

Genome-wide association studies (GWAS) have been pivotal for uncovering the genetics of human phenotypes, and there is now growing interest in applying GWAS-like methods to explore the role of the microbiome in human health. Here, we developed a taxonomy free GWAS approach that uses k-mers, i.e. DNA words of length k that can capture single nucleotide polymorphisms, insertion or deletion events, and gene presence-absence, to interrogate the gut microbiome. We applied this method to 26 traits spanning demographics, physiological measurements, health, and lifestyle in 938 healthy participants from the Milieu Interieur cohort. We generated a k-mer abundance matrix encompassing 97 million distinct k-mers. GWAS of the 26 traits identified significant associations for seven of them: age, sex, depression, appetite, cooked meat consumption, soda intake, and smoking. By modeling the correlation structure among k-mers, we identified a modest number of independent signals and conducted a comprehensive in silico functional annotation of these signals, revealing potential mechanisms of host-microbiota interaction. Overall, our analyses demonstrate that k-mers can capture biologically relevant functions shared across multiple taxa and provide a refined modeling framework that complements the standard taxonomic-based screening approach.

Adherent-invasive Escherichia coli (AIEC) are enriched in the gut microbiota of patients with Crohn’s disease (CD), but bacterial genes underlying their role in intestinal inflammation remain poorly defined. By integrating in vivo whole-genome transposon sequencing (TnSeq) with and without colitis conditions, RNA sequencing and mechanistic experiments, we identified oxc, which encodes oxalyl-CoA decarboxylase, as a major and specific determinant of AIEC virulence under inflammatory conditions. Disruption of oxc in AIEC, but not in laboratory or commensal E. coli strains, eliminated survival under acid and oxidative stress, reduced motility and biofilm formation, and suppressed adhesion, invasion, and intramacrophage persistence. In vivo, oxc was (i) required for AIEC survival in all gastrointestinal segments in colitis settings and (ii) exacerbated colitis severity. Transcriptomics analysis revealed repression of flagella and acid resistance systems encoding genes, linking metabolism to motility and stress defenses. Metabolically, loss of oxc suppressed prpBCDE operon induction at low pH and altered threonine/propionate and oxalate pathways, with concordant changes in energy and respiratory activities. Diet enriched in oxalate or propionate potentiated AIEC colonization and pathology in an oxc-dependent manner. Overall, oxc is linking metabolic to virulence pathways under inflammatory conditions and may represent a treatable target for microbiome-preserving interventions

Amoebiasis is a cosmopolitan parasitic disease caused by Entamoeba histolytica . The most lethal form is extra-intestinal amoebiasis, mainly manifesting as liver abscesses. Diagnosis is based on clinical, radiological, and biological tests. However, there are currently few serology reagents still available on the European market for in vitro diagnosis, and comparative studies of existing reagents are required. We evaluated the performances of the four currently available reagents, either as standalone tests or in combination. Two enzyme-linked immunosorbent assays (ELISAs) for the detection of E. histolytica IgG were assessed: one manufactured by Bordier and the other by NovaTec. Additionally, an indirect hemagglutination technique, ELI.H.A Amoeba , and a latex particle agglutination technique, ELITex Bicolor Amoeba , both produced by ELITech Microbio, were evaluated. A total of 442 serum samples were selected from a shared centralized biobank of seven university hospitals in France. The samples included 79 from patients with amoebic abscess, 13 with amoebic colitis, and 350 from healthy donors and patients with parasitic and non-parasitic diseases, especially liver disease and immune dysfunction. The sensitivity of the four kits ranged from 87.3% to 97.5%, while their specificity ranged from 78.3% to 98.6%. Bordier ELISA demonstrated the highest sensitivity, while ELITex Bicolor Amoeba latex reagent exhibited the highest specificity. The combination of Bordier ELISA and/or ELI.H.A Amoeba for screening, combined with ELITex Bicolor Amoeba for confirmation of positive screening results, yielded the most optimal performance. This study highlights the benefits of large comparative studies of commercial assays to guide clinical microbiologists in their choices. IMPORTANCE: Amoebiasis caused by Entamoeba histolytica is common in countries with low socio-economic levels. The most lethal form is extraintestinal amoebiasis, mainly liver abscesses, which require rapid and accurate diagnosis. Diagnosis is based on clinical, radiological, and, most importantly, serological tests. Implementing a diagnostic strategy requires both knowledge of how diagnostic tests compare with each other and thorough cross-validation. To help the clinical microbiologist choose a serological reagent, we evaluated the performance of four serological reagents currently available on the European market using a large biobank of sera from seven French university hospitals. In addition to patients with amoebic abscess and healthy donors, our study included many samples from patients with other parasitic and non-parasitic pathologies (liver diseases, immune dysfunctions) in order to study particularly non-specific reactivities.