Assessment of a rationally-designed experimental microbial consortium to reduce systemic inflammation in a murine model of chemotherapy-induced mucositis.

Abstract

e15062 Background: Gastrointestinal (GI) mucositis is a frequent complication of chemotherapy for cancer treatment and conditioning regimens for hematopoietic stem cell transplant (HSCT). Clinical and preclinical data suggest that disruption of the gut microbiome may be implicated in GI mucositis pathophysiology by affecting GI barrier integrity, immune homeostasis, and colonization resistance to pathogens. Here, we evaluated the ability of a rationally-designed microbial consortium, DE486, to reduce systemic inflammation and toxicity in a chemotherapy-induced murine mucositis model. Methods: Germ-free mice were used to evaluate the impact of the microbiome in a 5-fluorouracil-induced (5-FU) mucositis model. Mice were colonized with either DE486 or an inflammatory composition (INFL2). DE486 was rationally designed as a consortium of strains for experimental investigation to restore colonization resistance, improve GI barrier integrity, and reduce inflammatory responses. After 4-5 weeks of colonization, mice were intraperitoneally injected with 5-FU or vehicle control on three consecutive days (days 0-2) to initiate mucositis. The degree of 5-FU-induced toxicity was assessed by daily body weight measurements from the start of 5-FU treatment (day 0) until study end (day 8) and expressed as the mean body weight loss ± SD. Serum levels of pro-inflammatory cytokines were assessed on days 5 and 8 by mouse cytokine/chemokine immunoassays (Luminex xMAP). Data reported are the group mean pg/mL and the statistical significance of group mean differences was analyzed using one-way ANOVA. Results: In the 5-FU-induced mucositis model, mice colonized with DE486 or INFL2 exhibited a mean body weight loss of 10% ± 2% by day 4. However, on day 5, mice colonized with DE486 began to recover body weight and by day 8 returned to their body weight before 5-FU treatment. In contrast, mice colonized with INFL2 continued to lose body weight and by day 8 had a mean body weight loss of 18% ± 4%. Serum analyses showed that on day 5 cytokine levels in mice colonized with DE486 or INFL2 remained low and did not differ significantly between the two groups. However, on day 8, mice colonized with INFL2 developed significantly higher proinflammatory cytokine levels than mice colonized with DE486 (TNFα: 21.68 vs. 2.26, P = 0.018, IL-6: 1860.55 vs. 2.15, P = 0.007, IFN-γ: 177.37 vs. 0.37, P < 0.001). Conclusions: Preclinical assessments in a murine model of chemotherapy-induced mucositis showed that colonization with DE486 promoted body weight recovery and protected against increased levels of key pro-inflammatory cytokines, as compared to colonization with an inflammatory microbiome. These data support the ability of a rationally-designed microbial consortium to ameliorate systemic inflammation following chemotherapy as a strategy to prevent or manage GI mucositis.