Impact of the gut microbiota on transplant outcomes


Contact - Information

Pr. Nicolas Picard

Dr. Roland Lawson

  

UMR-1248 INSERM

CBRS – Université de Limoges

2, rue du Pr Bernard Descottes

87000 Limoges

Deadline:  CLOSED

Documents:

  • Resume
  • Cover Letter
  • Contact for recommandation letter(s)

Funding Source:

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  • Arns, W. Noninfectious Gastrointestinal (GI) Complications of Mycophenolic Acid Therapy: A Consequence of Local GI Toxicity? Transplant. Proc. 39, 88–93 (2007).
  • Zhang, Z., Tang, H., Chen, P., Xie, H. & Tao, Y. Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome. Signal Transduct. Target. Ther. 4, 41 (2019).
  • Wang, W., Xu, S., Ren, Z., Jiang, J. & Zheng, S. Gut microbiota and allogeneic transplantation. J. Transl. Med. 13, 275 (2015).
  • Xiao, J. et al. Organ transplantation and gut microbiota: current reviews and future challenges. Am. J. Transl. Res. 10, 3330–3344 (2018).
  • Nellore, A. & Fishman, J. A. The Microbiome, Systemic Immune Function, and Allotransplantation. Clin. Microbiol. Rev. 29, 191–199 (2016).
  • Bik, E. M. et al. Microbial biotransformations in the human distal gut. Br. J. Pharmacol. 175, 4404–4414 (2018).
  • Parada Venegas, D. et al. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. Front. Immunol. 10, (2019).
  • Alvarez-Curto, E. & Milligan, G. Metabolism meets immunity: The role of free fatty acid receptors in the immune system. Biochem. Pharmacol. 114, 3–13 (2016).
  • Huang, W., Zhou, L., Guo, H., Xu, Y. & Xu, Y. The role of short-chain fatty acids in kidney injury induced by gut-derived inflammatory response. Metabolism. 68, 20–30 (2017).
  • Li, M. et al. Pro- and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells. Eur. J. Pharmacol. 831, 52–59 (2018).

PhD Project

Impact of the gut microbiota on transplant outcomes: short-chain fatty acids (SCFAs) as predictive biomarkers or potential targets for precision care in transplantation.

Advances in immunosuppression have propelled transplantation from a scientific curiosity to an optimal treatment for patients by reducing the rate of acute rejection and prolonging graft survival. However, the clinical use of immunosuppressive drugs is often hampered by severe side effects that can lead to treatment discontinuation, hence graft rejection1. Immunosuppressive drugs are known to induce modifications in the gut microbial community. Gut microbiome plays a central role in shaping the host immune system2 and its changes, also named dysbiosis, have been linked to the transplant outcomes3– 5. Dysbiosis can affect the ability of specific bacterial populations to produce short-chain fatty acids (SCFAs), which are crucial for host homeostasis6,7. Immune cells also express specific receptors for SCFAs with downstream signalling pathways involved in cell differentiation8.

Epigenetics have shed light on the possible involvement of SCFAs (acetate, propionate and butyrate) in histone modification. Amongst SCFAs, butyrate is the most efficient in inducing histone acetylation by inhibiting histone deacetylases (HDACs). In general, histone acetylation is associated with transcriptional activation by rendering the corresponding DNA strand more accessible to transcription factors. It is also known that histone modifications are associated with malignant or autoimmune diseases9,10. HDAC inhibitors (HDACi) have already demonstrated their therapeutic potential in oncology and for the treatment of autoimmune diseases. However, to date, very few studies have investigated the correlation between dysbiosis, SCFAs profile and graft rejection.

This PhD project aims to explore the causal link between graft rejection and the level of SCFAs and also the therapeutic potential of either food supplementation with SCFAs or HDACi for preventing graft rejection. The candidate will use a rodent model of skin transplantation to study the relationships between graft rejection, SCFAs profiles, histones acetylation and the therapeutic effect of SCFAs supplementation or HDACi for preventing graft rejection. She or he will also use immune cellular models (T and B cells) to decipher the pharmacological mechanisms of SCFAs. 

GOALS and CONTEXT

This work will combine cellular and animal investigations to study the relationships between graft rejection, SCFAs profiles and histones acetylation. A proof-of-concept experiment of SCFAs supplementation (butyrate) or HDACi (valproic acid) will be performed using a mouse model of allogenic skin graft rejection. These investigations will allow the exploration of different immune tissues (mesenteric lymph nodes, Peyer’s patch, bone marrow, peripheral blood and spleen). Appropriate analytical methods for SCFAs determination are already available in the laboratory and developed in collaboration with the mass spectrometry platform. In addition, T and B cells models will be used to understand the molecular targets involved.

This work will allow a better description of the role of SCFAs and will pave the way toward precision medicine in transplantation. We aim to validate the usefulness of routine butyrate monitoring in the clinics as a new and strong predictive biomarker of graft rejection. This project will also open perspectives for future clinical developments of HDACi or supplementation with SCFAs as an add-on therapy for transplant patients.