Abstract
Clostridium difficile infections are associated with the use of broad-spectrum antibiotics and result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. To better understand the dynamics of mucosal immunity during C. difficile infection from initiation through expansion to resolution, we built a computational model of the mucosal immune response to the bacterium. The model was calibrated using data from a mouse model of C. difficile infection. The model demonstrates a crucial role of T helper 17 (Th17) effector responses in the colonic lamina propria and luminal commensal bacteria populations in the clearance of C. difficile and colonic pathology, whereas regulatory T (Treg) cells responses are associated with the recovery phase. In addition, the production of anti-microbial peptides by inflamed epithelial cells and activated neutrophils in response to C. difficile infection inhibit the re-growth of beneficial commensal bacterial species. Computational simulations suggest that the removal of neutrophil and epithelial cell derived anti-microbial inhibitions, separately and together, on commensal bacterial regrowth promote recovery and minimize colonic inflammatory pathology. Simulation results predict a decrease in colonic inflammatory markers, such as neutrophilic influx and Th17 cells in the colonic lamina propria, and length of infection with accelerated commensal bacteria re-growth through altered anti-microbial inhibition. Computational modeling provides novel insights on the therapeutic value of repopulating the colonic microbiome and inducing regulatory mucosal immune responses during C. difficile infection. Thus, modeling mucosal immunity-gut microbiota interactions has the potential to guide the development of targeted fecal transplantation therapies in the context of precision medicine interventions.
Highlights
Clostridium difficile, a Gram-positive spore-forming, anaerobic bacterium, often colonizes the human gastrointestinal tract after disruption of the normal intestinal flora
Cdiff may interact with a dendritic cell, iDCEp, to produce an activated dendritic cell, with the effector and tolerogenic balance regulated by the comparative population of CommB to the dead commensal species, CommD
The Cdiff species acts as a modifier of five reactions: the inflammation of colonic epithelial cells, the activation and migration of neutrophils, the activation of macrophages, the death of Treg cells, and the plasticity between Treg and T helper 17 (Th17) CD4+ T cell subsets
Summary
Clostridium difficile, a Gram-positive spore-forming, anaerobic bacterium, often colonizes the human gastrointestinal tract after disruption of the normal intestinal flora. The rate of C. difficile-associated infections and deaths may be rising due to the emergence of the hyper virulent strains that exhibit resistance to traditional fluoroquinolone antibiotics [4]. Standard treatment of C. difficile associated disease (CDAD), an illness linked to antimicrobial usage, includes administration of more antibiotics such as metronidazole or vancomycin. This therapeutic approach may contribute to the considerable rates of recurrence, estimated to be between 5 to 30% [5]. Alternative strategies have been devised to decrease rates of recurrence through use of toxin neutralizing antibodies or gut microbiome reconstitution through fecal transplantation [6, 7]. The baiCD gene, which encodes a bile acid processing enzyme, allows commensal microbes to utilize host-produced bile salts to synthesize metabolites, such as deoxycholate and lithocholate that provide resistance against C. difficile [9]
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