Abstract
BackgroundMycophenolic acid (MPA) is the most widely used immunosuppressive drug in transplantation and for autoimmune diseases. Unfortunately, more than 30% of patients experience a typical gastrointestinal adverse effect also referred to as mycophenolate-induced enteropathy. Due to its antibacterial, antifungal, and antiviral properties, MPA exposure is associated with intestinal dysbiosis characterized by a decrease in density and diversity of the microbiome regarding the main bacterial phyla (Firmicutes and Bacteroidetes). These bacterial phyla are known for their metabolic role in maintaining the homeostasis of the digestive tract, particularly through the production of short-chain fatty acids (SCFA) that could contribute to the pathophysiology of mycophenolate-induced enteropathy. Our study aimed at deciphering short-chain fatty acids (SCFA) profile alterations associated with gastrointestinal toxicity of MPA at the digestive and systemic levels in a mouse model.MethodsTen-week old C57BL/6 (SOPF) mice were randomly assigned in 2 groups of 9 subjects: control, and mycophenolate mofetil (MMF, 900 mg/kg/day). All mice were daily treated by oral gavage for 7 days. Individual faecal pellets were collected at days 0, 4 and 8 as well as plasma at day 8 for SCFA profiling. Additionally, after the sacrifice on day 8, the caecum was weighted, and colon length was measured. The proximal colon was cut for histological analysis.ResultsMMF treatment induced around 10% weight loss at the end of the protocol associated with a significant decrease in caecum weight and a slight reduction in colon length. Histological analysis showed significant architectural changes in colon epithelium. Moreover, we observed an overall decrease in SCFA concentrations in faecal samples, especially regarding acetate (at day 8, control 1040.6 ± 278.161 μM versus MMF 384.7 ± 80.5 μM, p < 0.01) and propionate (at day 8, control 185.94 ± 51.96 μM versus MMF 44.07 ± 14.66 μM, p < 0.001), and in plasma samples for butyrate (at day 8, control 0.91 ± 0.1 μM versus MMF 0.46 ± 0.1 μM, p < 0.01).ConclusionsThese results are consistent with functional impairment of the gut microbiome linked with digestive or systemic defects during MMF treatment.
Highlights
Mycophenolic acid (MPA) is the most widely used immunosuppressive drug in transplantation and for autoimmune diseases
MPA-induced enteropathy mouse model Mycophenolic mofetil (MMF) treatment is associated with a significant weight loss starting at day 5 to reach approximately 10% at day 7 (Fig. 1A)
This body weight loss is accompanied by a significant reduction in caecum weight (Fig. 1B) and a slight, non-significant decrease in colon length (Fig. 1C)
Summary
Mycophenolic acid (MPA) is the most widely used immunosuppressive drug in transplantation and for autoimmune diseases. Antifungal, and antiviral properties, MPA exposure is associated with intestinal dysbiosis characterized by a decrease in density and diversity of the microbiome regarding the main bacterial phyla (Firmicutes and Bacteroidetes). These bacterial phyla are known for their metabolic role in maintaining the homeostasis of the digestive tract, through the production of short-chain fatty acids (SCFA) that could contribute to the pathophysiology of mycophenolateinduced enteropathy. MPA can reach lymphoid tissues (e.g., bone marrow, thymus, lymph nodes and spleen) for modulating in situ lymphocyte differentiation and activation [5, 6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
