Association of Gut Bacterial Beta Glucuronidase Activity with Mycophenolate Mofetil Induced Cytopenia

Abstract

<h3>Purpose</h3> Mycophenolate mofetil (MMF) is the anti-metabolite of choice in heart transplantation (HT). MMF tolerability is limited by its toxicity, including bone marrow suppression. MMF metabolism is dependent on gastrointestinal flora, particularly pathogens carrying β-D-glucuronidases (GUS). We investigated association between cytopenia and gut microbial composition focusing on GUS bacteria in HT pts. <h3>Methods</h3> 45 HT pts (53±12.9yo, 78.6% M) with 1-month post HT stool samples were included. Stool samples were analyzed using 16S rRNA sequencing. Gut alpha-diversity was defined using Shannon Index (SI). GUS bacteria abundance was computed as sum of individual known GUS-producing bacteria, matched by genus and species. The DESeq2 package and linear regression models were used to identify differentially abundant taxa and analyze difference in SI and GUS abundance by cytopenia occurrence. <h3>Results</h3> Leukopenia and neutropenia occurred in 30(66.7%) and 26(57.8%) pts. Mean SI±SD was similar in pts with leukopenia vs not (5.78±0.59 vs 5.58±0.58, p=0.29) and neutropenia vs not (5.73±0.57 vs 5.68±0.62, p=0.76). In DESeq2 analyses, 8 bacteria species were found to be significantly more abundant among those who had leukopenia, including two known GUS producing taxa <i>Bacteroides dorei</i> and <i>Bacteroides cellulosilyticus</i> (<b>Fig 1A</b><i>).</i>Seven bacteria species were significantly more abundant among those who had neutropenia, including <i>Bacteroides dorei</i> (<b>Fig 1B</b>)<i>.</i> Patients with leukopeniat had higher abundance of GUS bacteria 0.21±0.16 vs 0.12±0.18 (p=0.09) (<b>Fig 1C</b>). This difference became significant following adjustment for valcyte (p=0.04). Patients who experienced neutropenia vs not had a similar abundance of GUS bacteria 0.17±0.14 and 0.18±0.20 (p=0.88) (<b>Fig 1D</b>). <h3>Conclusion</h3> GUS bacteria were expanded among HT recipients with cytopenia, potentially highlighting mechanisms of MMF toxicity. Robust clinical trials delineating the effects of gut microbiome on MMF metabolism are warranted.