Gut microbiota profiles and fecal beta‐glucuronidase activity in kidney transplant recipients with and without post‐transplant diarrhea

Abstract

Post‐transplant diarrhea is a common complication after solid organ transplantation and is frequently attributed to the widely prescribed immunosuppressant mycophenolate mofetil (MMF). Given recent work identifying the relationship between MMF toxicity and gut bacterial β‐glucuronidase activity, we evaluated the relationship between gut microbiota composition, fecal β‐glucuronidase activity, and post‐transplant diarrhea. We recruited 97 kidney transplant recipients and profiled the gut microbiota in 273 fecal specimens using 16S rRNA gene sequencing. We further characterized fecal β‐glucuronidase activity in a subset of this cohort. Kidney transplant recipients with post‐transplant diarrhea had decreased gut microbial diversity and decreased relative gut abundances of 12 genera when compared to those without post‐transplant diarrhea (adjusted p value < .15, Wilcoxon rank sum test). Among the kidney transplant recipients with post‐transplant diarrhea, those with higher fecal β‐glucuronidase activity had a more prolonged course of diarrhea (≥7 days) compared to patients with lower fecal β‐glucuronidase activity (91% vs 40%, p = .02, Fisher's exact test). Our data reveal post‐transplant diarrhea as a complex phenomenon with decreased gut microbial diversity and commensal gut organisms. This study further links commensal bacterial metabolism with an important clinical outcome measure, suggesting fecal β‐glucuronidase activity could be a novel biomarker for gastrointestinal‐related MMF toxicity.

Fecal β-glucuronidase activity differs between hematopoietic cell and kidney transplantation and a possible mechanism for disparate dose requirements

“…4.4 mg free phenolphthalein/mg protein/h, P = .78). 26 A significantly greater percentage of diarrheal patients with high β-glucuronidase activity (91%) had a prolonged course (≥7 days) of diarrhea, while only 40% of low β-glucuronidase-activity patients had a prolonged course. 27 In a murine study, exposure to MMF resulted in an altered microbial community composition with increased β-glucuronidase activity that was ablated when vancomycin was given.…”

Temporal shifts in safety and efficacy profile of mycophenolate mofetil 2 g versus 3 g daily early after heart transplantation

“…Treatment for ACR included escalation of baseline immunosuppression, steroid pulse (oral or intravenous), or a combination of the above and did not differ between the two groups studied (p = 0.17). Median number of biopsies at 1 month post-HT was similar between the groups (4[4] vs. 4[4], p = 0.20), while at 6 months post-HT there were fewer biopsies in the MMF-LD compared with the MMF-HD group (9[7][8][9] vs. 10 [10], p < 0.01). Median number of biopsies stratified by year is shown in FigureS6.Cumulative 6-month freedom from ACR (≥1R/1B) was not significantly different in MMF-HD and MMF-LD groups (59.2% MMF-HD vs. 70.8% MMF-LD, p = 0.16; Figure3B).…”

“…Consequently, changes in the intestinal flora, particularly pathogens carrying β‐ d ‐glucuronidases (GUS), may influence the pharmacokinetics of MMF 8 . Recently, other authors found elevated fecal GUS activity in a subset of kidney transplant recipients to be associated with protracted post‐transplant diarrhea 9 …”

“…8 Recently, other authors found elevated fecal GUS activity in a subset of kidney transplant recipients to be associated with protracted post-transplant diarrhea. 9 Traditionally, MMF is administered as a fixed dose of 1.5 g every 12 h (q12) without considering patients' individual characteristics, timeline after transplant surgery, and therapeutic monitoring. Recently, our HT program transitioned from an initial starting MMF dose of 1.5 g q12 [high-dose, MMF-HD] to 1 g q12 [low-dose, MMF-LD] with the goal of improving MMF tolerability.…”

Synthesis, Biological Evaluation, and In Silico Studies of Novel Coumarin-Based 4H,5H-pyrano[3,2-c]chromenes as Potent β-Glucuronidase and Carbonic Anhydrase Inhibitors

“…The shortage of β-glucuronidase in body tissues consequently results in proliferation of GAGs inside the lysosomes, leading to the enlargement of their size . As a consequence of over-expression of this enzyme in various cancers like the neoplasm of bladder, liver cancer, and colon carcinoma, , the quantitative measurement of β-glucuronidase has been proved as a detection tool at the initial stage diagnosis of cancer and the assessment of therapeutic treatments. , Moreover, it is evident from the literature that an elevated level of β-glucuronidase in blood serum is related to various physiological disorders such as urinary tract infection, rejection of transplantation, epilepsy, renal diseases, rheumatoid arthritis, and larynx and breast cancer . Besides these, acquired immune deficiency syndrome (AIDs) and hepatic disorders have also been reported as a consequence of a high level of this enzyme. , …”