Identification of biomarkers predictive of secondary spondylo-arthritis in patients with inflammatory bowel disease (IBD)


Background

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are systemic inflammatory diseases affecting 200.000 people in France and overall 3 millions people across Europe[1]. Spondyloarthritis is the most frequent extraintestinal manifestations (EIM) reported in IBD patients, occurring in up to one third of IBD patients. These EIM can be very disabling and are associated with a more severe disease course[2]. The treatment of EIM in IBD patients remains challenging in clinical practice and often requires the use of biologics raising both safety and cost issues. Understanding the mechanisms underlying the development of such complications in IBD is a prerequisite to improving their management and remains an unmet need for these patients.

Dysbiosis, which refers to an imbalance of the normal intestinal microflora, has been shown to play a role in the initiation and perpetuation of intestinal or joint inflammation, both in animal models of colitis or arthritis and in IBD or arthritis patients[3],[4]. However, it remains to be established whether bacterial dysbiosis may account or not for secondary arthritis in IBD patients.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor superfamily of transcription factors whose PhD co-heads have demonstrated the key pathophysiological role during experimental colitis[5] and arthritis[6]. Thus, PPARγ has been identified as a key regulator of antimicrobial defence in IBD patients and may contribute to imbalance in gut microbiome. In addition, PPARγ has been shown to be a master regulator of IL-17/Th17/Treg pathways through inhibition of the transcription factor RORγT[7]. When considering the pivotal role of T helper 17 (Th17) lymphocytes in extracellular pathogen defences in the gastro-intestinal tract (especially the lamina propria) and the major influence of bacteria species on the local balance between Th17 and Treg differentiation[8], we hypothesize that a dysregulation of PPARg or microbiota or both may contribute to the occurrence of joint inflammation secondary to uncontrolled gut inflammation through a modified immune response.

 

Aims and methods

The main objective of this translational and interdisciplinary project is to investigate the interplay between PPARγ, gut microbiota and IL-17 expressing cells, including Th17, in mediating pathological inflammation within the gut-joint axis. The project is based on a translational approach between human diseases, i.e. groups of patients suffering either from IBD alone, IBD + spondylo-arthritis or spondylo-arthritis alone, and mice models, i.e. PPARg-deficient animals, which develop arthritis spontaneously, and dextran sodium sulfate (DSS)-induced-colitis.

To address this objective, we propose to develop the following dual approach:

1: To search for biomarkers in cohort of clinically well-phenotyped patients having developed IBD with or without secondary spondyloarthritis, using patients with spondyloarthritis alone as controls.
Three lines of biomarkers will be searched: i) microbiota signatures in feces (identification of specific pathogenic strains and/or imbalance between commensals) using 16S rRNA gene sequencing with the Illumina MiSeq technology; ii) genetic predisposing factors in peripheral blood mononuclear cells (PBMC), i.e. single nucleotide polymorphisms (SNP) of the PPARg gene (some being reported to be associated with an increased incidence of IBD[1] or psoriatic arthritis[2]) and of genes known to be associated with an increased incidence of IBD and/or spondyloarthritis. The latter will be performed using TaqMan SNP Genotyping Assays (Applied Biosystems) and mutations will be confirmed by Sanger sequencing; iii) circulating cytokines profiles as biomarkers of the immunological and/or inflammatory state using the multiplex technology.

2: To validate in mice the ability of PPARγ impairment and/or bacterial dysbiosis to mediate arthritis occurrence secondary to intestinal inflammation through a dysregulated IL-17/Th17/Treg immune response.
These experiments will focus on: i) the search of a microbiota signature in feces as a biomarker of PPARg-deficient or arthritis-induced mice using the previously mentioned 16S rRNA gene sequencing methodology; ii) the characterization of the Th17/Treg balance at the systemic and local levels, i.e. in the intestine and joints, as biomarkers of a dysregulated immune response using FACS; iii) the profiling of cytokines as a biomarker of the immunological and/or inflammatory state using the previously mentioned multiplexing approach.

 

PhD supervisors: Pr Jean-Yves Jouzeau and Dr David Moulin (UMR 7365 IMoPA), Pr Laurent Peyrin-Biroulet (INSERM U954 NGERE).

Partners:
UMR 7365 CNRS-UL “Ingénierie Moléculaire et Physiopathologie Articulaire”,
UMR_S954 INSERM-UL “Nutrition, Génomique, Exposition aux Risques Environnementaux”,

 

Doctoral school for PhD recruitment/follow-up: BioSE (Biology, Health, Environment – ED 266)

 

Contacts: Pr Jean-Yves Jouzeau (jean-yves.jouzeau@univ-lorraine.fr) or Dr David Moulin (david.moulin@univ-lorraine.fr) and Pr Laurent Peyrin-Biroulet (lpeyrin-biroulet@gmail.com)

 

How to apply

In order to prepare a PhD thesis within the Lorraine Université d’Excellence Program, the interested candidate should consult the PhD topics offered in each social and economic challenges.
These PhD thesis topics are proposed by faculty members or researchers accredited to supervise research.

Candidate application period: according to graduate school schedule (visit each topic)
Each candidate may submit an application on up to three separate research topics.

Application analysis period by each graduate school
The graduate school reviews the applicants for a doctoral contract in the relevant disciplines. They check the level of supervision for each supervisor and the situation of trained doctors. Each candidate will meet the laboratory director, supervisor and a representative from the graduate school. This interview is to identify the candidate’s motivations and suitability as a candidate for the PhD project proposed by the supervisor. A recommendation will be made to the graduate school. This will summarize the strengths and/or weaknesses of the application.

PhD grants will include monthly income for the PhD student (roughly 1700 € for research only, complement can be provided for teaching missions) and environment for research in the research unit.

Please be aware that in order to offer a variety of subjects, more positions are posted here than available funding. The LUE executive committee will make the final choice on the granted funding (up to 12 positions), based on the recommendations by the doctoral schools.

[1] S. Bank et al., PLoS ONE. 9, e98815 (2014).
[2] C. Butt et al., J. Rheumatol. 33, 1631–1633 (2006).
[1] L. A. Bourikas & K. A. Papadakis, Inflamm Bowel Dis. 15,1915–1924 (2009).
[2] S. R. Vavricka et al., Am. J. Gastroenterol. 106, 110–119 (2010).
[3] D. Gevers et al., Cell Host Microbe. 15, 382–392 (2014).
[4] J. U. Scheret al., Arthritis & Rheumatology. 68, 35–45 (2015).
[5] L. Peyrin-Biroulet et al., Proc. Natl. Acad. Sci. U.S.A. 107, 8772–8777 (2010).
[6] M. Koufany et al., Arthritis Rheum. 65, 3084–3095 (2013).
[7] J. Barbiet al., Immunol. Rev. 252, 52–77 (2013).
[8] Y. Belkaid & T. W. Hand, Cell. 157, 121–141 (2014).