Pharmacological hypothesis: A recombinant probiotic for taming bacterial β-glucuronidase in drug-induced enteropathy

Advances in pharmacomicrobiomics have shed light on the pathophysiology of drug-induced enteropathy associated with the therapeutic use of certain non-steroidal anti-inflammatory drugs, anticancer chemotherapies and immunosuppressants. The toxicity pathway results from the post-glucuronidation release and digestive accumulation of an aglycone generated in the context of intestinal dysbiosis characterized by the expansion of β-glucuronidase-expressing bacteria. The active aglycone could trigger direct or indirect inflammatory signaling on the gut epithelium. Therefore, taming bacterial β-glucuronidase (GUS) activity is a druggable target for preventing drug-induced enteropathy. In face of the limitations of antibiotic strategies that can worsen intestinal dysbiosis and impair immune functions, we hereby propose the use of a recombinant probiotic capable of mimicking repressive conditions of GUS through an inducible plasmid vector

Is Intestinal Dysbiosis-Associated With Immunosuppressive Therapy a Key Factor in the Pathophysiology of Post-Transplant Diabetes Mellitus?

Post-transplant diabetes mellitus (PTDM) is one of the most common and deleterious comorbidities after solid organ transplantation (SOT). Its incidence varies depending on the organs transplanted and can affect up to 40% of patients. Current research indicates that PTDM shares several common features with type 2 diabetes mellitus (T2DM) in non-transplant populations. However, the pathophysiology of PTDM is still poorly characterized. Therefore, ways should be sought to improve its diagnosis and therapeutic management. A clear correlation has been made between PTDM and the use of immunosuppressants. Moreover, immunosuppressants are known to induce gut microbiota alterations, also called intestinal dysbiosis. Whereas the role of intestinal dysbiosis in the development of T2DM has been well documented, little is known about its impacts on PTDM. Functional alterations associated with intestinal dysbiosis, especially defects in pathways generating physiologically active bacterial metabolites (e.g., short-chain fatty acids, trimethylamine N-oxide, indole and kynurenine) are known to favour several metabolic disorders. This publication aims at discussing the potential role of intestinal dysbiosis and dysregulation of bacterial metabolites associated with immunosuppressive therapy in the occurrence of PTDM

Rôle du co-métabolome intestinal en transplantation : contribution des acides gras à chaine courte à l’homéostasie digestive et à l’immunomodulation

Organ transplantation is offered to patients for the treatment of some terminal pathologies. Immunosuppressive treatments are currently one of the mainstays of transplant management. However, this lifelong management of transplant patients can give rise to drug-related iatrogenesis. Recent advances in the study of the intestinal microbiota highlight the fundamental role of this microbiota in the homeostasis of the digestive tract, often the target of certain immunosuppressants, and in the regulation of the immune system. In this thesis, we investigated the impact of alterations in the intestinal microbiota in the post-transplant period on the response to immunosuppressants. We started by studying the integrity of the intestinal barrier during immunosuppressive treatment. These results lead to the development of a severity score for this permeability that combines the lipopolysaccharide assay with the plasma assay for short-chain fatty acids (SCFA), which are metabolites mainly produced by the microbiota. This work is the first to report the existence of intestinal permeability in transplant patients. Secondly, we characterised the functional alterations in the intestinal microbiota that could explain this loss of integrity of the intestinal barrier and evaluated a therapeutic strategy. Using a model of mycophenolic acid-related enteropathy at different stages of severity (moderate and severe), we were able to show a functional alteration in the microbiota characterised by a reduction in the production of SCFA and an alteration in the tight junctions between epithelial cells in the colon. Supplementation with SCFA in this model of moderate enteropathy corrects the loss of junction protein expression. In the same work, we also developed, validated, and standardised a preclinical model of allogeneic skin grafting in mice. This model will be used to explore the impact of short-chain fatty acid supplementation on graft outcome.La transplantation d’organe est proposée aux patients pour la prise en charge de certaines pathologies terminales. Les traitements immunosuppresseurs sont actuellement l’un des piliers de la prise en charge des transplantés. Cependant, cette prise en charge tout au long de la vie d’un patient transplanté peut être à l’origine d’une iatrogénie médicamenteuse. De récentes avancées dans l’étude du microbiote digestif soulignent le rôle fondamental de ce microbiote dans l’homéostasie du tube digestif, souvent altérée par certains immunosuppresseurs ainsi que dans la régulation du système immunitaire. Au cours de cette thèse, nous nous sommes intéressés à l’impact des altérations du microbiote digestif en période post-transplantation sur la réponse aux immunosuppresseurs. Dans un premier temps, nous nous sommes consacrés à l’étude de l’intégrité de la barrière intestinale lors d’un traitement immunosuppresseur. Ces résultats nous ont permis de proposer un score de gravité de cette perméabilité qui combine le dosage des lipopolysaccharides avec le dosage plasmatique des acides gras à chaîne courte (SCFA) qui sont des métabolites majoritairement issus du microbiote. Ces travaux rapportent pour la première fois l’existence d’une perméabilité intestinale chez les patients transplantés. Dans un deuxième temps, nous avons caractérisé les altérations fonctionnelles du microbiote digestif pouvant expliquer cette perte d’intégrité de la barrière intestinale et évalué une stratégie thérapeutique. Nous avons montré, à l’aide d’un modèle d’entéropathie liée à l’acide mycophénolique à différents stades de gravité (modéré et sévère), une altération fonctionnelle du microbiote caractérisée par la diminution de la production des SCFA et une altération des jonctions serrées entre les cellules épithéliales au niveau du côlon. La supplémentation en SCFA dans ce modèle d’entéropathie modéré corrige la perte d’expression des protéines de jonction. Au cours de ces travaux, nous avons également développé, validé et standardisé un modèle préclinique de greffe allogénique de peau chez la souris. Ce modèle servira à explorer l’impact d’une supplémentation en acide gras à chaine courte sur le devenir du greffon

Pharmacological hypothesis: A recombinant probiotic for taming bacterial β-glucuronidase in drug-induced enteropathy

Advances in pharmacomicrobiomics have shed light on the pathophysiology of drug-induced enteropathy associated with the therapeutic use of certain non-steroidal anti-inflammatory drugs, anticancer chemotherapies and immunosuppressants. The toxicity pathway results from the post-glucuronidation release and digestive accumulation of an aglycone generated in the context of intestinal dysbiosis characterized by the expansion of β-glucuronidase-expressing bacteria. The active aglycone could trigger direct or indirect inflammatory signaling on the gut epithelium. Therefore, taming bacterial β-glucuronidase (GUS) activity is a druggable target for preventing drug-induced enteropathy. In face of the limitations of antibiotic strategies that can worsen intestinal dysbiosis and impair immune functions, we hereby propose the use of a recombinant probiotic capable of mimicking repressive conditions of GUS through an inducible plasmid vector

Is Intestinal Dysbiosis-Associated With Immunosuppressive Therapy a Key Factor in the Pathophysiology of Post-Transplant Diabetes Mellitus?

Post-transplant diabetes mellitus (PTDM) is one of the most common and deleterious comorbidities after solid organ transplantation (SOT). Its incidence varies depending on the organs transplanted and can affect up to 40% of patients. Current research indicates that PTDM shares several common features with type 2 diabetes mellitus (T2DM) in non-transplant populations. However, the pathophysiology of PTDM is still poorly characterized. Therefore, ways should be sought to improve its diagnosis and therapeutic management. A clear correlation has been made between PTDM and the use of immunosuppressants. Moreover, immunosuppressants are known to induce gut microbiota alterations, also called intestinal dysbiosis. Whereas the role of intestinal dysbiosis in the development of T2DM has been well documented, little is known about its impacts on PTDM. Functional alterations associated with intestinal dysbiosis, especially defects in pathways generating physiologically active bacterial metabolites (e.g., short-chain fatty acids, trimethylamine N-oxide, indole and kynurenine) are known to favour several metabolic disorders. This publication aims at discussing the potential role of intestinal dysbiosis and dysregulation of bacterial metabolites associated with immunosuppressive therapy in the occurrence of PTDM