Some of the best talks at our congress in Prague last year were about the influence of gut microbiota on drug exposure. It feels recent work has brought us a lot closer to understand this, and how it may vary between drugs and individuals. Mycophenolate is a drug particularly affected and we are fortunate in this month’s blog to hear from Roland Lawson about his team’s work that has helped decipher the complexity behind the phenomenon, and also propose potential solutions to the problems it can cause for patients. This piece was originally published in December Compass, on behalf of the Immunosuppressive Drugs Committee.
The human microbiome comprises trillions of bacteria, archaea, viruses, protozoans and fungi that form the symbiotic microbial cells hosted by each individual in various sites (e.g., oral cavity, skin, gastrointestinal and urogenital tract). The gut microbiome, which is the most important in terms of density and diversity, plays a key role in protecting against pathogens, maintaining the integrity of the digestive epithelial barrier and contributing to digestion and metabolism.1,2 Several factors can modulate the composition of the gut microbiome (e.g., aging, diet or medication).2 Imbalance of the gut microbiome, also known as dysbiosis, has been associated with epithelial barrier dysfunction and local or systemic disorders, including activation of the immune system.3
In transplant patients, the surgical procedure of organ transplantation performed under anesthesia and the chronic use of immunosuppressants and anti-infective agents are frequently associated with gut dysbiosis, which may explain the increase in cardiovascular or metabolic disorders in the post-transplant period.4,5 In addition, gut dysbiosis may alter adaptive immune responses through depletion of regulatory T cells, and increase in effector T cells, causing an activation of the immune system that contributes to graft rejection.6 A recently published study of a cohort of kidney (n=594) and liver (n=328) transplant recipients confirms the existence of dysbiosis of the gut microbiome in transplant patients. This study also identified the immunosuppression protocol as the main trigger for these microbiome changes. In addition, the use of mycophenolic acid (MPA) was largely linked to these changes.7
A full description of the bidirectional interaction between the gut microbiome and drugs, in general, should document both the ability of the drug to induce dysbiosis and the changes in the metabolic profile of the drug induced by the gut microbiome.
A perfect example to illustrate this interaction between the immunosuppressive drug and the gut microbiome is the case of MPA. MPA, originally isolated as a fermentation product of Penicillium species, is a broad-spectrum drug with antibacterial, antifungal and antiviral properties, in addition to its immunosuppressive properties. This pharmacological profile may explain its ability to modify the microbial composition and/or metabolism. Another key element is the contribution of the gut microbiome to MPA metabolism. Regarding the metabolic profile, MPA inactivation occurs primarily in the liver through glucuronidation, where MPA is conjugated to glucuronic acid. This leads to the production of the major metabolite, mycophenolic acid glucuronide (MPAG). While the majority of MPAG is excreted in urine (approximately 90%), the remainder is excreted in the bile. Once excreted, MPAG interacts with commensal gut bacteria in the lower gastrointestinal tract where bacterial β-glucuronidase (β-G) hydrolyzes MPAG back to its active form, MPA.8 MPA in turn interacts with the intestinal epithelium and undergoes enterohepatic recirculation, which contributes to 30 to 40% of the plasma MPA concentration. Local accumulation of MPA close to digestive epithelial cells is thought to initiate severe gastrointestinal adverse symptoms such as nausea, vomiting, abdominal pain and diarrhea associated with MPA therapy, a typical drug-induced enteropathy characterized by architectural disorganization of the gastrointestinal epithelium with edema, erosion and hemorrhagic ulceration.9–13 In this context, a functional alteration of the gut microbiome with a decrease in the production of short-chain fatty acids (SCFA) in a preclinical model of MPA-induced enteropathy has been described.14 SCFA are fermentation products of dietary fibers produced by the gut microbiome with anti-inflammatory properties. The main SCFA are acetate, propionate and butyrate. SCFA play a crucial role in maintaining the epithelial barrier, regulating the composition of the microbiome and shaping the immune system.15 Very recently, using strategies of microbiome depletion with large spectrum antibiotics or using germ-free mice, it has been shown that the gut microbiome is required for MPA-induced enteropathy to occur.16 In this mouse model, MPA treatment promotes selective growth of β-G expressing bacteria, augmenting their cleavage activity in the distal part of the gastrointestinal tract. In addition, vancomycin treatment prevents MPA-induced enteropathy by eliminating bacterial β-G activity.17
All of this demonstrates the interplay relationship between mycophenolic acid and the gut microbiome and suggests that the gut microbiome has a strong contribution to the pathophysiology of MPA- induced enteropathy.
MPA treatment is associated with typical dysbiosis18 that promotes the digestive reactivation and accumulation of MPA and its direct deleterious impact on digestive epithelial cells, in addition to local and systemic inflammation. Future strategies to tame bacterial β-G activity may be effective in preventing and/or treating MPA-induced enteropathy. Studies should be directed towards finding a potential small inhibitory molecule of bacterial β-G that could be used routinely as an adjunct therapy. Amoxapine, which is a well-known antidepressant, has shown promising results in vitro and in vivo in inhibiting bacterial β-G19.
Immunosuppressive drugs could alter the composition of the gut microbiome, which could influence the metabolism of immunosuppressive drugs and the immune system of transplant patients. The gut microbiome offers a new opportunity for precision medicine in transplantation.
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[9] Jia, Y., et al. (2018). BMC Pharmacology and Toxicology 19, 39.
[10] Calmet, F.H., et al. (2015). Ann Gastroenterol 28, 366–373.
[11] Al-Absi, A.I., et al. (2010). Transplantation Proceedings 42, 3591–3593.
[12] Selbst, M.K., et al. (2009). Modern Pathology 22, 737–743.
[13] Behrend, M. (2001). Drug-Safety 24, 645–663.
[14] Jardou, M., et al. (2021). BMC Pharmacol Toxicol 22, 66.
[15] Zhang, Z., et al. (2019). Signal Transduct Target Ther 4, 41.
[16] Flannigan, K.L., et al. (2018). J. Heart Lung Transplant. 37, 1047–1059.
[17] Taylor, M.R., et al. (2019). Sci Adv 5, eaax2358.
[18] Gabarre, P., et al. (2022). Am J Transplant 22, 1014–1030.
[19] Ahmad, S., et al. (2012). J Biomol Screen 17, 957–965.
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