D. A. Lyubashevsky2, G. An1 1University Of Chicago,Surgery,Chicago, IL, USA 2Washington University,School Of Engineering And Applied Science,St. Louis, MO, USA
Introduction: A contributing factor to the development of Clostridium difficile infection is the effect of enteric bile acid composition on C. difficle spore germination. Taurocholic acid (TCA) promotes spore germination, while deoxycholic acide (DCA) and chenodoxycholic acid (CDCA) inhibit germination. The commensal flora converts TCA to DCA, thereby acting as an environmental control suppressing CDI. Alternatively, CDCA acts as a competitive inhibitor of TCA by binding the C. diff receptor that triggers germination, In a healthy gut microbiome, CDCA is metabolized by the healthy microbiome into lithocholate, which also inhibits germination. However, CDCA is much more rapidly absorbed by the gut epithelium than TCA, leading to a net decrease in CDI inhibitor capacity in an antibiotic-induced commensal-depleted gut. Analogs to CDCA demonstrate less metabolic conversion by commensals and intestinal absorption, and therefore may show greater resistance to alterations in the microbiome following systemic antibiotics. We use an Agent Based Model (ABM) to simulate the dynamics of CDI, the inhibitory nature of CDCA, and the role of CDCA-analogs as a possible therapeutic for CDI.
Methods: We expanded upon a previously developed ABM of CDI (CDIABM) by adding in the effects of CDCA. These effects included the inhibitory effect of CDCA on germination of C. diff spores, and the secretory/absorptive epithelial dynamics of CDCA. Simulation experiments were performed to reproduce the generation of CDI, and its subsequent treatment with both anti-CDI antibiotics and fecal microbial transplant (FMT). Further simulation experiments were performed to examine the effect of different regimens of CDCA analogs not subject to metabolism by commensal microbes.
Results: Simulation experiments successfully recalibrated the CDIABM to the addition of CDCA by reproducing known dynamics of the development of CDI and its response to anti-CDI antibiotics and FMT. Simulations employing CDCA-analogs demonstrated a reduction in the bimodal induction of CDI, stabilizing the anti-germination potential of the bile acid composition by reducing the impact of CDCA fluctuations due to alterations in its metabolism by commensal flora and absorption by intact epithelial cells. Continued administration of CDCA-analogs led to reduced recurrence of CDI, though with a higher residual spore count.
Conclusion: The expanded CDIABM successfully incorporated an additional bile acid control mechanism involved in the pathogenesis of CDI, demonstrating the advantageous modular nature of agent-based models. The simulation of the prophylactic effect of CDCA analogs suggests a potential therapeutic role for these compounds, particularly as an adjunct to other therapeutic measures with the goal of reducing recurrent CDI. We suggest the use of dynamic computational models such as the CDIABM can serve as a useful adjunct in the investigations of host-pathogen interactions in clinically relevant scenarios.